MGSA/GRO Dingzhi Wang* and Ann Richmond Department of Cell Biology, Vanderbilt University School of Medicine, Department of Veterans Affairs, Nashville, TN 37232, USA * corresponding author tel: 1-615-343-7777, fax: 1-615-343-4539, e-mail:
[email protected] DOI: 10.1006/rwcy.2000.10001.
SUMMARY MGSA/GRO is a CXC chemokine which shares structural features and many biological activities with IL-8. It is widely expressed in melanocytes, melanoma, keratinocytes, monocytes and macrophages, mammary epithelial cells, and endothelial cells. Previously, MGSA/GRO was found to be important for recruitment and activation of neutrophils, lymphocytes, and monocytes in host defense. Now, it has become apparent that MGSA/GRO plays an important role in wound healing, growth regulation, angiogenesis, tumorigenesis, and apoptosis. The expression of the MGSA/GRO ligands and receptors has been detected in a number of inflammatory disorders and in viral infections.
BACKGROUND
Discovery Melanoma growth stimulatory activity (MGSA) was first described as a secreted protein produced by malignant melanoma cells that functions as an autocrine growth factor (Richmond et al., 1982, 1983, 1985). After purifying the MGSA protein from serumfree culture-conditioned medium produced by the Hs294T human melanoma cell line (Richmond and Thomas, 1986; Thomas and Richmond, 1988), a partial amino acid sequence was determined and the gene was cloned from a cDNA (Richmond et al., 1988). The identified cDNA for MGSA exhibited 100% identity to the human homolog of the growth regulated gene (GRO). GRO was first identified by subtractive hybridization using mRNAs from tumorigenic Chinese hamster embryonic fibroblasts (CHEF/16)
and nontumorigenic Chinese hamster embryonic fibroblasts (CHEF/18), and the human GRO genes were subsequently cloned (Anisowicz et al., 1987). Since the original isolation of human MGSA/GRO , two other isoforms have been identified, GRO and GRO (Baker et al., 1990; Haskill et al., 1990; Iida and Grotendorst, 1990). In addition, a fourth MGSA or GRO gene has recently been described, MGSA/ GRO (Shattuck-Brandt et al., 1997). However, we have been unable to verify the expression of this gene, which suggests that it may encode a pseudogene.
Alternative names The human MGSA/GRO gene has been described as MGSA , GRO , SCYB1, NAP-3, GRO1 oncogene and CXCL1; MGSA/GRO has been called MGSA , GRO , hMIP-2 , SCYB2, GRO2 oncogene, and CXCL2; and MGSO/GRO have been referred to as MGSA , GRO , MIP-2 , SCYB3, GRO3 oncogene and CXCL3 (Anisowicz et al., 1987; Haskill et al., 1990; Tekamp-Olson et al., 1990; Richmond and Shattuck, 1996). The murine MGSA/ GRO homologs MIP-2 and KC have been cloned (Oquendo et al., 1989; Cochran et al., 1983; TekampOlson et al., 1990). MGSA/GRO is also referred to as MGSA. In rat, the MGSA or GRO mRNA are identified as CINC1, 2a, 2b, 3 (Huang et al., 1992a; Konishi et al., 1993; Driscoll et al., 1993; Nakagawa et al., 1994).
Structure The MGSA/GRO protein is translated as an 11,391 Da precursor from which the signal peptide of 34 amino acids is cleaved to produce the mature
1024 Dingzhi Wang and Ann Richmond protein of 7894 Da (Balentien et al., 1990). Human MGSA/GRO proteins are nonglycosylated proteins which form dimers, tetramers, and larger aggregates at high protein concentrations. At physiological concentrations (0.1±100 nM), the monomer state predominates (Fairbrother et al., 1993, 1994; Kim et al., 1994). The secondary structure of the monomer is comprised of three -pleated sheet strands (residues 25±29, 39±44, and 49±52) and a C-terminal helix (residues 57±69). All MGSA/GRO , , and proteins contain four cysteines, an ELR motif at the N-terminus, and a weak binding domain for heparin near the C-terminus (Clark-Lewis et al., 1993, 1994; Baggiolini et al., 1994). These cysteines are involved in the formation of two intrachain disulfide bridges which are key for maintenance of conformational integrity for receptor binding (see Figure 2). The glutamine residue between the first two cysteines is required for CXC chemokine biological activities and receptor binding. This ELR motif is the critical structural/functional domain for high-affinity binding of IL-8, MGSA/GRO, ENA-78, GCP-2, KC, MIP-2, and other orthologs of this family to the CXC receptors (Clark-Lewis et al., 1991, 1993, 1994; HeÂbert et al., 1991; Clubb et al., 1994; Rajarathnam et al., 1994). CXC chemokines without this motif do not bind to CXCR1 or CXCR2 (ClarkLewis et al., 1993, 1994). When the ELR residues of MGSA/GRO or IL-8 are substituted with alanine, biological activity is lost and the mutated chemokines act as antagonists in the presence of physiologic concentrations of ELR motif-containing chemokines (Arenberg et al., 1997; Zagorski and Wahl, 1997). The C-terminal portion of the human MGSA/GRO is sufficient for its biological activity (Roby and Page, 1995). Mutation of the histidine residue (H19A) in MGSA/GRO is associated with a > 100-fold decrease in neutrophil chemotaxis, and pretreatment of cells with the H19A mutant inhibited the ability of MGSA/ GRO to induce elastase release and chemotaxis and to increase intracellular calcium (Baly et al., 1998). The chemokine MGSA/GRO is highly conserved among multiple isoforms (see Relevant linkages). MGSA/GRO and MGSA/GRO exhibit 93% and 82% nucleotide sequence identity to MGSA/GRO . In protein sequence, there are 11 amino acid differences between and and 15 amino acid differences between and . Four of the differences are in the 34 amino acid signal peptide, making only 7 and 11 amino acid differences in the mature 73 amino acid secreted protein between the and or forms (Haskill et al., 1990; Iida and Grotendorst, 1990; Tekamp-Olson et al., 1990) (see Figure 2). The identity between MGSA/GRO and IL-8 is about 42% at the nucleotide level and 56% at the amino
acid level (Matsushima et al., 1988). MGSA/GRO shares structural features and many biological activities with IL-8.
Main activities and pathophysiological roles MGSA/GRO plays a fundamental role in recruitment and activation of neutrophils, lymphocytes, and monocytes in host defense. Numerous investigations have shown the importance of MGSA/GRO in acute inflammation as chemotactic/activating factors for neutrophils, basophils, eosinophils, monocytes, smooth muscle cells, and lymphocytes (Balentien et al., 1990; Geiser et al., 1993; Loetscher et al., 1994; Schwartz et al., 1994; Yue et al., 1994; Erger and Casale, 1995; Jinquan et al., 1997; Van Damme et al., 1997). All three isoforms have the same pattern of activity, suggesting that the amino acid differences among these isoforms result in only minor effects on biological activity. The order of potency for the three isoforms regarding neutrophil and basophil chemotactic activity, Ca2 flux, respiratory burst, exocytosis, shape change, and receptor binding is MGSA/ GRO > > (Geiser et al., 1993). It has become apparent that MGSA/GRO plays an important role in wound healing, growth regulation, angiogenesis, tumorigenesis, and apoptosis. The expression of the MGSA/GRO ligands and receptors has been implicated in a number of inflammatory disorders and in viral infections (See Table 1).
GENE AND GENE REGULATION
Accession numbers See Table 2.
Chromosome location MGSA/GRO , , and genes are located on human chromosome 4q13-21, while the mouse orthologs are located on chromosome 5 (Anisowicz et al., 1988; Richmond et al., 1988; Seldin et al., 1990). The bovine orthologs are located on chromosome 6, which is consistent with the positions in the human (Modi et al., 1998).
Relevant linkages A subfamily of polypeptide chemoattractants known as CXC chemokines is characterized by the ability to
MGSA/GRO 1025 Table 1 Human diseases associated with increased MGSA/GRO production Inflammatory
Neoplastic
Other
Psoriasis
Schroder et al., 1992
Ulcerative colitis
Isaacs et al., 1992
Rheumatoid arthritis
Hosaka et al., 1994; Koch et al., 1995
Bacterial pneumonia
Villard et al., 1995
Adult respiratory distress syndrome
Villard et al., 1995
Helicobacter pylori infection
Shimoyama and Crabtree, 1997; Bodger and Crabtree, 1998
Intra-amniotic infection
Hsu et al., 1998
Lyme disease
Sprenger et al., 1997
Chlamydia infection
Rasmussen et al., 1997
Squamous cell carcinoma
Tettlebach et al., 1993
Melanoma
Richmond et al., 1982, Pichon and Lagarde, 1989; Rodeck et al., 1991; Luan et al., 1997
Basal cell carcinoma (sclerosing variant)
Tettlebach et al., 1993
Bladder carcinoma
Anisowicz et al., 1987
Colon carcinoma
Cuenca et al., 1992
Verruca vulgaris
Tettlebach et al., 1993
Keratoacanthoma
Tettlebach et al., 1993
Viral (HIV )
Dezube et al., 1992
Herpes simplex virus
Yan et al., 1998
Cytomegalovirus
Grundy et al., 1998
Rotavirus
Casola et al., 1998
Reprinted with modification from page 294 of ``Human Cytokines, Handbook for Basic and Clinical Research III'' (Shattuck and Richmond, 1998) with permission.
induce concentration-dependent directional migration and activation of leukocytes. The genes for CXC chemokines map to human chromosome 4q13-21, with the exception of SDF-1, which is on chromosome 10 (Miller and Krangel, 1992; Shirozu et al., 1995; Walz et al., 1996). The family displays four highly conserved cysteine residues, with the first two cysteines separated by one nonconserved amino acid residue. The percentage identity based on nucleotide sequence between family members is not strong (43% to 24%) (Figure 1).
Regulatory sites and corresponding transcription factors The genomic structure of the MGSA/GRO , , genes has been determined after gene cloning and sequence analysis (Baker et al., 1990; Haskill et al., 1990). There are four exons (179, 124, 84, and 716 bp
in size, respectively) separated by introns of 98, 113, and 531 bp for the gene (Baker et al., 1990). The sizes of exons for the gene are 102, 122, 84, and 700 bp, respectively, while the intron sizes for the gene are 95, 118, and 826 bp, respectively (Haskill et al., 1990). For the gene, there are two exons (178, 123 in size) separated by two introns (97 in size for first intron) (Shattuck-Brandt et al., 1997). The size of the second intron could not be determined because clear intron/exon boundaries were not identified in the sequence beyond exon 2 where the homology to , genes diverges. Two isoforms of CINC-2, and , are encoded by mRNAs produced by alternative splicing. Each isoform is encoded in four exons, and exon±intron boundaries are placed identically within the aligned sequences of CXC chemokines (Shibata et al., 1998). Deletion and mutational analysis of reporter constructs driven by the 50 regulatory region of the MGSA/GRO genes demonstrate the importance of
1026 Dingzhi Wang and Ann Richmond Table 2 Available MGSA/GRO cDNA sequences Species
Accession no.
Name
GenBank locus
References
Human
X12510
MGSA/GRO
HSMGSA
Richmond et al., 1988
M36820
MGSA/GRO /MIP-2
HUMGROB5/HSMIP2A
Haskill et al., 1990; Tekamp-Olson et al., 1990
M36821
MGSA/GRO /MIP-2
HUMGROG5/HSMIP2B
Haskill et al., 1990; Tekamp-Olson et al., 1990
U88432
MGSA/GRO
X53798
MIP-2
MMMIP2
J04596
KC
MUSSPKC
Oquendo et al., 1989
D11444
GRO/KC/CINC-1
RATMRSA/RA TGRO
Huang et al., 1992a; Konishi et al., 1993
D21095
CINC-2 and
RATCINC2
Nakagawa et al., 1994
X65647/U45965
MIP-2/CINC-3
RNMIP2/RNU45965
Driscoll et al., 1993
Hamster
J03560
GRO
CRUGRO
Anisowicz et al., 1987
Rabbit
L19157
GRO
RABGRO
Johnson et al., 1994
U12310
GRO homolog
OCU12310
Schwartz et al., 1994
L28933
RPF2
RABRPF2X
Johnson et al., 1994
O46677
GRO
GROB_BOVIN
Modi et al., 1998
O46676
GRO
GROA_BOVIN
Modi et al., 1998
GROG_BOVIN
Modi et al., 1998
Mouse Rat
Bovine
Shattuck-Brandt et al., 1997 Tekamp-Olson et al., 1990
O46675
GRO
Sheep
U95814
GRO
Modi et al., 1998
Pig
U95810/U95809
GRO
Modi et al., 1998
Chicken
M16199
9E3/pCEF4
CHKEF9E3
Sugano et al., 1987
Reprinted with modification from page 267 of ``Human Cytokines, Handbook for Basic and Clinical Research III'' (Shattuck and Richmond, 1998) with permission.
two regions within this reporter construct which contribute to basal promoter activity and cytokine inducibility (Shattuck-Brandt et al., 1994; Wood and Richmond, 1995). The region closest to the TATA box (ÿ30 to ÿ25) contains the NFB consensus element (at ÿ64 to ÿ74 in and ÿ66 to ÿ76 in the and genes) which is necessary for basal and cytokine-induced transcription (Anisowicz et al., 1991). Furthermore, the HMG-I(Y) motif nested within the NFB element is also important for basal and cytokine-induced transcription (Wood et al., 1995). Adjacent to the NFB element is a C/EBP-like element called immediate upstream regulatory (IUR) element. This element only contributes to the basal transcription. The SP-1 element in another region also contributes to the basal transcription of the MGSA/GRO (Wood et al., 1995). Sequence analysis of the 50 regulatory regions of each of these three genes does reveal potential differences that might account for selective isoform expression in certain
tissues and in response to certain agents (Haskill et al., 1990; Anisowicz et al., 1991; Cuenca et al., 1992; Becker et al., 1994). Also, the 50 flanking region of the CINC-2 contains a TATA box and putative binding sites for NFB and AP-1 (Shibata et al., 1998). However, no functional AP-1-binding sites have been identified in the MGSA/GRO , , and promoter region. In addition, the 30 UTRs of the MGSA/GRO genes contain a 7 bp motif (TTTTGTA) which is reported to be required for activation of transcription of the murine CC chemokine JE (Freter et al., 1992). The 7 bp motif of MGSA/GRO has been demonstrated to contribute the stabilization of its mRNA (Stoeckle, 1991, 1992; Stoeckle and Guan, 1993; Shattuck-Brandt et al., 1994; Sirenko et al., 1997). The transcriptional regulation of MGSA/GRO requires multiple transcription factors. The NFB is essential for MGSA/GRO gene transcription (Anisowicz et al., 1991). Melanoma cells (Hs294T) exhibit high basal endogenous expression of the
MGSA/GRO 1027 MGSA/GRO gene, while the nonmalignant normal retinal pigment epithelial cells (RPE) do not exhibit basal expression of MGSA/GRO , or (ShattuckBrandt et al., 1994). The constitutive MGSA/GRO gene expression in the Hs294T cells is the result of high basal transcription of the MGSA/GRO genes. The high basal transcription is due to a significant increase in the binding of NFB p50 and p65 homodimers and heterodimers to the NFB element (Wood and Richmond, 1995; Wood et al., 1995). This increase in NFB binding activity and transactivation correlates with a lower level of the inhibitor of NFB, IB , and higher activation of IKK and , compared with RPE cells (Shattuck-Brandt and Richmond, 1997; Devalaraja et al., 1999). The half-life of the IB protein in Hs294T cells is 45 minutes, compared
with 120 minutes in RPE cells. The more rapid turnover of IB in Hs294T as compared with RPE cells results in a constitutive nuclear translocation and activation of NFB, accompanied by endogenous transcription of MGSA/GRO in Hs294T cells. Cytokines such as IL-1 or TNF induce the expression of all three MGSA/GRO genes in RPE cells (Jaffe et al., 1993). The induction of MGSA/ GRO transcription by IL-1 and TNF was shown to utilize the NFB pathway in normal human RPE cells, foreskin fibroblasts, and HeLa cells. However, cytokines fail to induce MGSA/GRO gene expression in the Hs294T melanoma cells, although increased NFB p50 and p65 homodimer and heterodimer complexes in the nucleus can be demonstrated by gel mobility shift assay. This result indicated that the
Figure 1 Coding sequence of MGSA/GRO in different species.
1028 Dingzhi Wang and Ann Richmond Figure 1 (Continued )
MGSA/GRO 1029 Figure 1 (Continued )
regulation of transcription of the MGSA/GRO genes is different in the melanoma cells as compared with the nonmalignant control. The NFB element in MIP-2 is conserved in sequence and location to the MGSA/GRO , , genes. The LPS-induced transcriptional activation of the MIP-2 gene requires an NFB element (Widmer et al., 1993). MIP-2 is induced by TNF, LPS, and IL-1 through an NFB-dependent process in the hepatic stellate cell (HSC) after a fibrogenic stimulus (Widmer et al., 1993; Hellerbrand et al., 1998). In addition, MIP-2 also exhibits high basal transcription in murine melanoma cells (Widmer et al., 1993). These data suggest a common mechanism for cytokinemediated regulation of the MIP-2 gene in different
cell types. In the in vivo lung model, the activation of NFB in the nuclear extracts from lung lavage cells correlates with the increases in CINC mRNA levels (Blackwell et al., 1994). They have shown that NFB in the lung is activated by endotoxemia with consequent increased expression of CINC mRNA, secretion of biologically active CINC, and the development of neutrophilic lung inflammation.
Cells and tissues that express the gene There is endogenous expression of the MGSA/GRO genes in a number of tissues including keratinocytes,
1030 Dingzhi Wang and Ann Richmond monocytes and macrophages, mammary epithelial cells, and endothelial cells. However, in most tissues, these genes are not expressed at detectable levels in the absence of an activating agent, such as a cytokine, growth factor, endotoxin, lectin, cycloheximide, thrombin, or other stimulating agents (Haskill et al., 1990).
PROTEIN
Accession numbers See Table 2.
Sequence See Figure 2.
Description of protein The MGSA/GRO protein forms dimers, tetramers, and larger aggregates upon concentration that can be observed after crosslinking (Cheng et al., 1992) and in nonreducing polyacrylamide gels (Richmond et al., 1986). The dimers and tetramers of MGSA/GRO are capable of binding to receptor (Cheng et al., 1992). NMR confirms that MGSA/GRO chemokine is a dimer in solution (Fairbrother et al., 1993, 1994; Kim et al., 1994). The Kd for association is 73 mM at pH 5.0, but the Kd was 7.7 mM when the pH was 6.6 (Clark-Lewis et al., 1995). The forces involved in the stabilization of the dimer for MGSA/GRO appear to be weaker than those for IL-8 (Kim et al., 1994). In a more detailed analysis of the NMR structure of MGSA/GRO, the secondary structure of the MGSA/ GRO dimer was shown to be comprised of a sixstranded antiparallel sheet and a pair of C-terminal helices (Fairbrother et al., 1994). The last four Cterminal residues are probably disordered in solution. The intramolecular disulfide linkages for each subunit are between Cys9 and Cys35 as well as between Cys11 and Cys51. These linkages have right- and lefthanded order, respectively. It is noteworthy that the second histidine residue in MGSA/GRO (His34) and IL-8 (His33) exhibit very different pKa values, 5.2 and 3.7, respectively. It is also noted that the disorder of the ELR motif is greater for IL-8 than MGSA/GRO (Clore et al., 1989; Clore and Gronenborn, 1995). The differences in the loops 14±19, 30±38 and the disorder of the N-terminus probably account for the
differences in the receptor binding specificity for IL-8 and MGSA/GRO binding to the receptor. The solution structure of murine macrophage inflammatory protein 2 (MIP- 2) has been determined by two-dimensional homonuclear and heteronuclear NMR spectroscopy (Shao et al., 1998). The N- and C-terminal residues (1±8 and 70±73, respectively) are disordered. The overall structure of the MIP-2 dimer is similar to that reported previously for the NMR structures of MGSA/GRO and consists of a sixstranded antiparallel sheet (residues 25±29, 39±44, and 48±52) packed against two C-terminal antiparallel helices. At the tertiary level, the main differences between the MIP-2 solution structure and the IL-8 and MGSA structures involve the N-terminal loop between residues 9 and 23 and the loops formed by residues 30±38 and residues 53±58. At the quaternary level, the difference between MIP-2 and IL-8 and MGSA/GRO results from differing inter-helical angles and separations. The refined three-dimensional structure of CINC has been determined (Hanzawa et al., 1997, 1998). The N-terminal region containing an ELR motif is disordered in solution, as in other CXC chemokines. The overall dimer structure of CINC is similar to that of human MGSA/GRO. The major difference resides in the relative position of C-terminal helix with respect to the sheet in the dimer. The distance from helix to the sheet is wider in CINC (15 AÊ) than in MGSA/GRO (10 AÊ) and IL-8 (11.7 AÊ). CINC exists mainly as a monomer at a physiological concentration, similar to other proteins belonging to this family.
Discussion of crystal structure MIP-2 has been crystallized by the Lolis group (Lolis et al., 1992). Preliminary crystallographic analysis showed that the crystals belong to space group P2(1)2(1)2(1) and have unit cell dimensions of a=42.7 AÊ, b=59.3 AÊ, and c=100.3 AÊ. The molecular mass of the protein and volume of the unit cell suggest that there are four monomers in the asymmetric unit. A data set to 2.3 AÊ has been collected, and the selfrotation function identifies the presence of a noncrystallographic 2-fold axis. This structure can be accessed at www.imb-jena.de/cgi-bin/ImgLib.pl? CODE=1mi2.
Important homologies There are two MGSA/GRO homologs in mouse: KC and macrophage inflammatory protein 2 (MIP-2)
Figure 2 Amino acid sequences of the human, hamster, mouse, rat, rabbit, and chick forms of MGSA/GRO. Reprinted with modification from page 270 of ``Human Cytokines, Handbook for Basic and Clinical Research III'' (Shattuck and Richmond, 1998) with permission.
MGSA/GRO 1031
1032 Dingzhi Wang and Ann Richmond (Oquendo et al., 1989; Tekamp-Olson et al., 1990). KC was initially identified as a platelet-derived growth factor (PDGF)-inducible immediate early response gene. The amino acid sequence of MIP-2 is more closely related to human MGSA/GRO (62%) than to the amino acid sequence for mouse KC (59%). In rat, the MGSA/GRO gene is named cytokine-induced neutrophil chemoattractant (CINC). The four CINC isoforms (CINC1, 2 , 2 or 3) have been purified from NRK-49F cells and granulation tissue (Huang et al., 1992a; Watanabe et al., 1992; Konishi et al., 1993; Zagorski and Delarco, 1993; Nakagawa et al., 1994). The amino acid sequence of the mature CINC peptide is 91.7% identical to KC and 69.4% identical to human MGSA/GRO. The difference in amino acid sequence between CINC-2 and CINC-2 consists of only three C-terminal residues. Rat CINC-2 and CINC-3 are 63% and 67% identical to CINC-1. There is one MGSA/GRO chicken homolog (named 9E3 or pCEF-4) cloned from a chick embryo fibroblast (CEF) cDNA library or from RSV-transformed fibroblasts (Martins-Green et al., 1992). The pCEF-4 was identical at the amino acid sequence level to 9E3 with only one exception in the signal peptide (Bedard et al., 1987; Sugano et al., 1987). There are two in rabbit (RabGRO and RBF2) (Jose et al., 1991; Johnson et al., 1994) (Figure 2). The bovine MGSA/ GRO , and (GROA_BOVIN, GROB_BOVIN and GROG_BOVIN), sheep MGSA/GRO (GRO), and pig MGSA/GRO (GRO) have also been sequenced (Modi et al., 1998).
Posttranslational modifications The mRNA for MGSA/GRO encodes a 107 amino acid precursor that includes a 34 amino acid signal peptide (Anisowicz et al., 1987; Richmond et al., 1988). Cleavage occurs on the N-terminal side of the ASVA sequence based upon the sequence analysis of MGSA/GRO protein isolated from melanoma culture medium (Richmond and Thomas, 1988). The mature MGSA/GRO protein has been purified from culture medium conditioned by osteosarcoma cells and demonstrated to have an N-terminal sequence of ASVVTELRCQC, indicating a signal peptide cleavage pattern similar to that of the isoform (Proost et al., 1993). It has been suggested that signal peptide for the isoform is cleaved in the same position (Tekamp-Olson et al., 1990; Perlman and Halvorson, 1983; von Heijne, 1984, 1986). There is no evidence to support N- or O-linked glycosylation of MGSA/GRO (Balentien et al., 1990).
CELLULAR SOURCES AND TISSUE EXPRESSION
Cellular sources that produce MGSA/GRO proteins are produced by a variety of cell types in vivo and in vitro (Table 3). This includes not only malignant melanoma cells, but also keratinocytes, macrophages, neutrophils, and lymphocytes, and activated endothelial cells, fibroblasts, and hepatocytes.
Eliciting and inhibitory stimuli, including exogenous and endogenous modulators Cytokines and growth factors upregulate the expression of MGSA/GRO and a number of repressors have also been identified (Table 4). It is noted that IFN , IFN , and IFN are potent inhibitors of the production of monocyte-derived IL-8, MGSA/ GRO , and ENA-78. However, IFN , IFN , and IFN upregulate IP-10 and MIG (non-ELR) from a variety of cells. These data suggest that interferons may shift the biological balance toward a preponderance of non-ELR CXC chemokines.
RECEPTOR UTILIZATION Three human receptors and two viral receptors have been cloned which bind MGSA/GRO ligands: CXCR1, CXCR2, Duffy antigen receptor for chemokines (DARC), Kaposi's sarcoma human herpesvirus 8 G protein-coupled receptor (GPCR) and the herpesvirus saimiri receptor (HSV-ECRF3). Two mouse receptors for KC and MIP-2 have been cloned. One receptor is most closely related to the human CXCR2 receptor. The second murine receptor for KC and MIP-2 is mDARC. The rabbit receptor, rb F3R, has been cloned and is equivalent to the human CXCR1 receptor regarding ligand-binding specificity. The rabbit homolog of the DARC receptor has also been cloned recently (Peiper et al., 1995). These receptors are members of the G proteincoupled, seven transmembrane domain receptor family (Table 5). The receptor's sequence for CINC in rat and 9E3/pCEF4 in chick has not yet been reported. The binding of MGSA/GRO to the CXCR2 receptor effects a series of immediate and secondary
MGSA/GRO 1033 Table 3 Sources of MGSA/GRO Cell type
Human
Mouse
Rat
Epithelial cells Retinal pigmented
Jaffe et al., 1993
Melanocytes
Bordoni et al., 1990
Nasal
Becker et al., 1994a
Yamamoto, 1998
Lung
Leikauf et al., 1995
Driscoll et al., 1993
Renal
Pawar et al., 1995
Watanabe et al., 1989
Mammary
Stampfer and Yaswen, 1993; Anisowicz et al., 1988a
Fibroblasts Epidermal
Stoeckle, 1991
Synovial
Hogan et al., 1994; Golds et al., 1989; Bedard and Golds, 1993
Lung Gingival
Cochran et al.,1983
Crippes et al., 1993 Dolecki and Delarco, 1994
Huang et al., 1992a
Huang et al., 1992a, 1992b
Odake, 1993
Endothelial cells Umbilical vein
Introna et al., 1993; Wen et al., 1989
Hemangioma
Bussolino et al., 1991
Keratinocytes
Venner et al., 1995; De Haan et al., 1994
Ovarian stromal cells, granulosa-lutein
Oral et al., 1997
Virally transformed
Knop and Enk, 1995
Sipes et al., 1990
Hepatocytes
Maher, 1995; Takada et al., 1995
Mesangial cells
Feng et al., 1994
Muscle cells Myoblasts
Steiner et al., 1991
Ventricular myocytes
Massey et al., 1995
Epidermal Langerhans cells
Heufler et al., 1992
Hematopoietic cells Monocytes
Hosaka et al., 1994
Neutrophils
Haskill et al., 1990
Macrophages
Haskill et al., 1990
Alveolar
Becker et al., 1994
Ohmori et al., 1995; Roach et al., 1994
Farone et al., 1995; Xing et al., 1994; Al-Mokdad et al., 1998
Peripheral, peritoneal
Yamamoto et al., 1995
Ohmori and Hamilton, 1994
Al-Mokdad et al., 1998
Bone marrow-derived
Isaacs et al., 1992
Seebach et al., 1995
T lymphocytes
Zipfel et al., 1991; Skerka et al., 1993
Articular chondrocytes
Recklies and Golds, 1992
Astrocytoma cells
Legoux et al., 1992
1034 Dingzhi Wang and Ann Richmond Table 3 (Continued) Cell type
Human
Mouse
Rat
Transformed cells Melanoma
Chenevix-Trench et al., 1990; Rodeck et al., 1991;a Bordoni et al., 1990a
Colon carcinoma
Cuenca et al., 1992a Sonouchi et al., 1994a
Renal cell carcinoma Bladder carcinoma Transformed fibroblasts
Anisowicz et al., 1988a Anisowicz et al., 1987a
Crippes et al., 1993a Yamada et al., 1995a
Mammary carcinoma Psoriatic plaques
Kojima et al., 1993;a Schroder et al., 1992a
Renal cortex
Safirstein et al., 1991
Glomeruli
Wu et al., 1994
Uvea
DeVos et al., 1994
Lung
Huang, 1992a, 1992b; Driscoll et al., 1993
Retina
de Vos et al., 1994
Liver Epidermis
Ohmori, 1988 Nanney et al., 1995
Kayama et al., 1995
Enk, 1991
Cerebral cortex Anterior pituitary gland
Liu et al., 1993; Koike et al., 1994
a
These cells or tissues have been noted to constitutively express MGSA/GRO. Reprinted with modification from page 272 of ``Human Cytokines, Handbook for Basic and Clinical Research III'' (Shattuck and Richmond, 1998) with permission.
signal transduction events. MGSA/GRO induces G i protein coupling, calcium mobilization, receptor phosphorylation, activation of serine/tyrosine kinases, activation of MAP kinase, increased expression of fMLP receptors, induction of neutrophil exocytosis, and actin polymerization (Geiser et al., 1993; Metzner et al., 1994; Mueller et al., 1994, 1995; Jones et al., 1995) (Table 6).
IN VITRO ACTIVITIES
In vitro findings Numerous investigations have shown that MGSA/ GRO plays an important role in chemotaxis, growth regulation, angiogenesis, tumorigenesis, wound healing, and apoptosis (Table 7).
Regulatory molecules: Inhibitors and enhancers See Table 8.
Bioassays used Chemotaxis: the biological activity for MGSA/GRO as a chemoattractant for neutrophils and fibroblasts can be assayed as described previously (Geiser et al., 1993; Ben-Baruch et al., 1995). DNA synthesis, cell number assays, and colorimetric cell number assay: Hs294T melanoma cells are used for this assay as described previously (Richmond et al., 1986; Balentien et al., 1990). Soft-agar assay: melanocytes or melanoma cells are cultured in soft agar using a procedure described previously (Richmond et al., 1985; Balentien et al., 1991).
MGSA/GRO 1035 Table 4 Inducers and repressors Inducers
Cytokines and growth factors IL-1 , IL-1
a
TNF
a
PDGF
Cochran et al., 1983; Bordoni et al., 1989
MGSA
Bordoni et al.,1989
EGF
Stampfer and Yaswen, 1993
Thrombin
Wen et al., 1989; Murakami et al., 1995; Vaingankar and Martins-Green, 1998
IL-2
Sonouchi et al., 1994
LPS
a
PHA/PMA
Rodeck et al., 1991; Zipfel et al., 1991
Con A
Himi et al., 1997
1,3-glucan
Crippen et al., 1998
Infectious agents Entamoeba histolytica
Eckmann et al., 1995
Listeria monocytogenes
Seebach et al., 1995
Mycobacterium tuberculosis
Riedel and Kaufmann, 1997
Porphyromonas gingivalis
Murakami et al., 1994
HTLV Tax gene
Yamada et al., 1995
Borrelia burgdorferi
Sprenger et al., 1997
Salmonella dublin
Yang et al., 1997a
Escherichia coli endotoxin
Goodman et al., 1998
Herpes simplex virus
Yan et al., 1998
Wounding UVB
Repressors
Fahey et al., 1990; Pawar et al., 1995
Ozone
Venner et al., 1995
Osmosis
Driscoll et al., 1993, Koto et al., 1997; Koike et al., 1998
Cyclosporin A
Koijima et al., 1993
Staurosporine
Murakami et al., 1995
IFN
Ohmori and Hamilton, 1994
IL-10
Greenberger et al., 1995; Kasama et al., 1995
Glucocorticoids
Villard et al., 1995
Rapamycin
Wieder et al., 1993
TRK-530
Tanahashi et al., 1998
Dexamethasone
Al-Mokdad et al., 1998; Yamamoto et al., 1998
Influenza A virus
Hofmann et al., 1997
Reprinted with modification from page 275 of ``Human Cytokines, Handbook for Basic and Clinical Research III'' (Shattuck and Richmond, 1998) with permission. a
These references are too numerous to list. Many of the references are listed in Table 3.
1036 Dingzhi Wang and Ann Richmond Table 5 MGSA/GRO receptors Receptor
Other ligands
Human CXCR2
IL-8, NAP-2, ENA-78, GCP-2
Murphy and Tiffany, 1991
DARC
IL-8, NAP-2, RANTES, MCP-1
Horuk et al., 1996; Neote et al., 1993
HSV-ECRF3
IL-8, NAP-2
Ahuja and Murphy, 1993; Ahuja et al., 1994a, 1994b
HHV8-GPCR
IL-8, NAP-2, RANTES, I-309
Arvanitakis et al., 1997; Bais et al., 1998; Gershengorn et al., 1998
KC, MIP-2
Cacalano et al., 1994; Harada et al., 1994
Murine mCXCR2 mDARC
Luo et al., 1997; Tang et al., 1998
Rabbit rbF3R
Beckmann et al., 1991; Thomas et al., 1991, 1994; Norgauer et al., 1994; Prado et al., 1994
Table 6 Signal transduction pathway mediated through CXCR2 Events
References
G i coupling
Kupper et al., 1992, Yang et al., 1997b
Calcium mobilization
Walz et al., 1991; Ahuja et al., 1996; Damaj et al., 1996
Receptor phosphorylation
Mueller et al., 1994, 1995, 1997; Ben-Baruch et al., 1997; Richardson et al., 1998
Activation of serine kinases
Mueller et al., 1994, 1995
Activation of tyrosine kinases
Cheng et al., 1992; Schraw and Richmond, 1995
Inhibition of adenylyl cyclase
Shyamala et al., 1998
Activation of PI-3 kinase
Knall et al., 1997
PLC
Norgauer et al., 1996; Richardson et al., 1998
Activation of MAP-kinase
Knall et al., 1997
Heterologous desensitization of other GPCRs
Richardson et al., 1995; Kitayama et al., 1997; Mueller et al., 1997; Ben-Baruch et al., 1997
IN VIVO BIOLOGICAL ACTIVITIES OF LIGANDS IN ANIMAL MODELS
Normal physiological roles MGSA/GRO plays a major role in recruitment of neutrophils and lymphocytes during inflammation, angiogenesis, and tumorigenesis, in addition to facilitating cutaneous wound repair (Table 9). The details of the wound healing model will be given here, since the other models are fully described in the references in Table 9.
The Wound Healing Model A recent study assessed the temporal sequence and distribution for immunoreactive MGSA/GRO and its receptor (CXCR2) in margins of partial thickness and full-thickness burn wounds during the first 12 days of wound repair. The expression of both ligand and receptor, as well as their modulation, were observed during this time period, suggesting an involvement for this ligand±receptor interaction in healing of burn wounds (Nanney et al., 1995). The receptor is localized in the basal and the suprabasal layers of keratinocytes, while the ligand is only in the suprabasal keratinocytes. The latter study also
MGSA/GRO 1037 Table 7 MGSA/GRO biological functions in vitro
Table 8 Endogenous inhibitors and enhancers
In vitro findings
Enhancers
No reports
Inhibitors
Smith-Kline CXCR2a inhibitor, Leukinate
White et al., 1998
IP-10, MIG, I-TACa
Neville et al., 1997; Farber, 1997; Cole, 1998
Neutralizing antibodies to MGSA/GRO , ,
Owen et al., 1997
Neutralizing antibodies to CXCR2
Keane et al., 1999
References
Chemoattractant properties Neutrophils
Geiser et al., 1993; Kurdowska et al., 1994; Van Damme et al., 1997; Zagorski and Wahl, 1997
Basophils
Geiser et al., 1993
Eosinophils
Erger and Casale, 1995
Monocytes
Schwartz et al., 1994
Smooth muscle cells
Yue et al., 1994
Lymphocytes
Jinquan et al., 1997; Loetscher et al., 1994; Youngs et al., 1997
Breast carcinoma cells
Normal melanocytes
Richmond et al., 1986
Nevocytes
Richmond et al., 1986
Melanoma cells
Pichon and Lagarde, 1989; Schadendorf et al., 1993; Singh et al., 1994
Myeloid progenitor cell line 32D
Robinson et al., 1998 Sanchez et al., 1998
Angiogenesis Lung cancer Melanocytes
Work at both in vivo and in vitro level.
Richmond et al., 1986
Growth regulatory properties
Oligodendrocyte precursors
a
Smith et al., 1994; Strieter et al., 1995a, 1995b; Arenberg et al., 1997 Owen et al., 1997
Wound healing
Kemeny et al., 1994; Nanney et al., 1995; Tanaka et al., 1997; Tsuruta et al., 1997; Rennekampff et al., 1997
Tumorigenesis
Richmond et al., 1986; Richmond and Thomas, 1988; Balentien et al., 1991; Moser et al., 1993; Mattei et al., 1994; Luan et al., 1997; Owen et al., 1997
Apoptosis
Kettritz et al., 1998
Other biological functions Regulation of hormone secretion
Koike et al., 1994; Sawada et al., 1994a
Regulation of IL-6 production
Sawada et al., 1994a, 1994b
Respiratory burst
Magazin et al., 1992
noted immunoreactivity for CXCR2 in endothelial cells undergoing neovascularization. There is strong expression of receptor in the migrating margins of epidermis during the healing process, which subsides once the epidermis is fully hypertrophied. IL-8 has been associated with chemical inflammation of the skin in a wound healing model (Wilmer et al., 1994). Rennekampff et al. studied the effects of MGSA/ GRO on proliferation and migration of primary human keratinocytes and modulation of their integrin expression. They found that there is a high level of MGSA/GRO in burn blister and donor site wound fluids and MGSA/GRO stimulated a maximum (2.6fold) proliferation of keratinocytes and enhanced the mean fluorescence intensity for integrin 6 (Rennekampff et al., 1997). Chesney et al. described a novel population of blood-borne CD34 fibrocytes that rapidly enter sites of tissue and contribute to scar formation. They found that these cells produced chemokines, including IL-8 and MGSA/GRO , in response to IL-1 , which is a critical mediator in wound healing (Chesney et al., 1998). These studies localizing MGSA/GRO ligand and receptor in burn wounds suggest that MGSA/ GRO is also available for participation in this wound healing event. The chicken model for wound healing has implicated 9E3/pCEF-4. This protein was normally expressed in connective tissue, and injury was associated with increased expression, especially in sites undergoing neovascularization (Martins-Green and Bissell, 1990; Martins-Green et al., 1991, 1992). The expression of the CINC gene in the rat subcutaneous air pouch model has shown that LPS injection changes the concentration of CINC/GRO, and with this change in chemokine, there is enhanced
1038 Dingzhi Wang and Ann Richmond Table 9 Disease models associated with MGSA/GRO increases Inflammatory
Neoplastic
Injury
Endotoxin-induced uveitis
de Vos et al., 1994
Air pouch-type allergic inflammation
Iida et al., 1992
Monosodium urate pleurisy
Aihara et al., 1995
Antiglomerular basement membrane (GBM) glomerulonephritis
Wu et al., 1994
LPS-induced endotoxemia
Standiford et al., 1995
Type II collagen-induced arthritis
Kasama et al., 1995
Bacterial meningitis
Seebach et al., 1995
Experimental allergic encephalomyelitis
Godiska et al., 1995; Glabinski et al., 1998
Acute lung inflammation
Xing et al., 1994
Lung model
Blackwell et al., 1994; Fan et al., 1998
Helicobacter pylori infection
Bodger and Crabtree, 1998; Suzuki et al., 1998; Yamaoka et al., 1998; Kusugami et al., 1997; Shimoyama and Crabtree, 1997
Intraamniotic infection
Hsu et al., 1998
Chlamydia infection
Rasmussen et al., 1997
Psoriatic disease
Schroder et al., 1992; Tettlebach et al., 1993; Gillitzer et al., 1996; Santamaria Babi et al., 1996
HSV-1
Yan et al., 1998
Arthritis model
Tanahashi et al., 1998
Melanoma
Balentien et al., 1991; Luan et al., 1997; Owen et al., 1997
HTLV T cell leukemia
Yamada et al., 1995
Angiogenesis
Cao et al., 1995; Arenberg et al., 1997
Ischemia (cerebral and renal)
Liu et al., 1993; Safirstein et al., 1991
Hepatotoxicity (ethanol, cadmium)
Kayama et al., 1995, Shiratori et al., 1993, 1994a, 1994b
Liver injury
Maher et al., 1998; Ohkubo et al., 1998
Acute lung inflammatory injury
Shanley et al., 1997
Traumatic injury in spinal cord
McTigue et al., 1998
Surgical trauma
Shijo et al., 1998
Wound healing
Tanaka et al., 1997; Tsuruta et al., 1997; Rennekampff et al., 1997
Reprinted with modification from page 295 of ``Human Cytokines, Handbook for Basic and Clinical Research III'' (Shattuck and Richmond, 1998) with permission.
neutrophil infiltration. These data showed a functional role for CINC in rat inflammation (Iida et al., 1992). MIP-2 has also been implicated in wound healing in the mouse (Fahey et al., 1990).
Species differences Species differences/comparisons have been discussed throughout the above sections.
MGSA/GRO 1039
Knockout mouse phenotypes No ligand (KC or MIP-2) knockout mice have been developed.
Transgenic overexpression In a transgenic model where KC was overexpressed in the thymus or epidermis, there was no evidence of hyperproliferation of epidermal cells (Lira et al., 1994). However, using a Clara cell-specific lung promoter to direct expression of KC in transgenic mice with a B6D2 background enhanced resistance to Klebsiella pneumoniae in mice (Tsai et al., 1998). Improved survival correlated with enhanced clearance of bacteria due to increased neutrophil recruitment. When transgenic mice were developed using the myelin basic protein (MBP) promoter to direct expression of KC to the central nervous system, neurological symptoms developed at 40 days of age, including postural instability and rigidity (Tani et al., 1996). Offspring from one founder exhibited high early mortality, frequently accompanied by clearly evident neurological symptoms. Characteristically there was activation of microglia and disruption of the blood±brain barrier without dysmyelination. Since it is now understood that both CXCR2 and mDARC are widely expressed in the brain, it can be speculated that these neurological symptoms result from a complex neuronal and immunological response.
Endogenous inhibitors and enhancers See Table 8.
PATHOPHYSIOLOGICAL ROLES IN NORMAL HUMANS AND DISEASE STATES AND DIAGNOSTIC UTILITY
Normal levels and effects The chemokines have been demonstrated to be expressed in the epidermis of normal and psoriatic skin, as well as a variety of human skin lesions exhibiting proliferative and/or differentiative disorders (Richmond and Thomas, 1988; Nickoloff et al., 1991; Schroder et al., 1992; Kojima et al., 1993; Tettlebach
et al., 1993; Boorsma et al., 1994; Garner et al., 1994). Both IL-8 and MGSA/GRO proteins have been localized to the spinous layer of the epidermis of nonlesional skin (Sticherling et al., 1991). A number of laboratories have demonstrated that the CXCR2 receptor for MGSA/GRO and IL-8 is expressed in keratinocytes of normal skin and psoriatic skin, further supporting this hypothesis (Schulz et al., 1993; Kemeny et al., 1994; Mueller et al., 1994).
Role in experiments of nature and disease states When expression of MGSA/GRO becomes disregulated resulting in chronic overexpression, tissue damage, angiogenesis, tumor growth, and other disease can occur. There are several disease models where MGSA/GRO proteins are overexpressed and these models provide important inferences about the biological roles of this chemokine. These models include tumorigenesis, angiogenesis, psoriasis, inflammatory bowel disease, viral infection, and autoimmune disease (Table 9).
References Ahuja, S. K., and Murphy, P. M. (1993). Molecular piracy of mammalian interleukin-8 receptor type B by herpesvirus saimiri. J. Biol. Chem. 268, 20691±20694. Ahuja, S. K., Gao, J. L., and Murphy, P. M. (1994a). Chemokine receptors and molecular mimicry. Immunol. Today 15, 281±287. Ahuja, S. K., Shetty, A., Tiffany, H. L., and Murphy, P. M. (1994b). Comparison of the genomic organization and promoter function for human interleukin-8 receptors A and B. J. Biol. Chem. 269, 26381±26389. Ahuja, S. K., Lee, J. C., and Murphy, P. M. (1996). CXC chemokines bind to unique sets of selectivity determinants that can function independently and are broadly distributed on multiple domains of human interleukin-8 receptor B. Determinants of high affinity binding and receptor activation are distinct. J. Biol. Chem. 271, 225±232. Aihara, S., Murakami, N., Tomita, T., Naruse, T., and Namba, K. (1995). Inhibitory action of indomethacin on neutrophil infiltration in monosodium urate-induced pleurisy in rats. Jpn J. Pharmacol. 68, 271±277. Al-Mokdad, M., Shibata, F., Takano, K., and Nakagawa, H. (1998). Differential production of chemokines by phagocytosing rat neutrophils and macrophages. Inflammation 22, 145±159. Anisowicz, A., Bardwell, L., and Sager, R. (1987). Constitutive overexpression of a growth-regulated gene in transformed Chinese hamster and human cells. Proc. Natl Acad. Sci. USA 84, 7188±7192. Anisowicz, A., Zajchowski, D., Stenman, G., and Sager, R. (1988). Functional diversity of gro gene expression in human fibroblasts and mammary epithelial cells. Proc. Natl Acad. Sci. USA 85, 9645±9649.
1040 Dingzhi Wang and Ann Richmond Anisowicz, A., Messineo, M., Lee, S. W., and Sager, R. (1991). An NF-kappa/B-like transcription factor mediates IL-1/TNF- induction of gro in human fibroblasts. J. Immunol. 147, 520±527. Arenberg, D. A., Polverini, P. J., Kunkel, S., Shanafelt, A., Hesselgesser, J. R., and Strieter, M. (1997). The role of CXC chemokines in the regulation of angiogenesis in non-small cell lung cancer. J. Leukoc. Biol. 62, 554±562. Arvanitakis, L., Geras-Raaka, E., Varma, A., Gershengorn, M. C., and Cesarman, E. (1997). Human herpesvirus KSHV encodes a constitutively active G-protein-coupled receptor linked to cell proliferation. Nature 385, 347±349. Baggiolini, M., Dewald, B., and Moser, B. (1994). Interleukin-8 and related chemotactic cytokines ± CXC and CC chemokines. Adv. Immunol. 55, 97±179. Bais, C., Santomasso, B., Coso, O., Arvanitakis. L., Raaka, E. G., Gutkind, J. S., Asch, A. S., Cesarman, E., Gershengorn, M. C., Mesri, E. A., and Gerhengorn, M. C. (1998). G-protein-coupled receptor of Kaposi's sarcoma-associated herpesvirus is a viral oncogene and angiogenesis activator. Nature 391, 86±89. Baker, N. E., Kucera, G., and Richmond, A. (1990). Nucleotide sequence of the human melanoma growth stimulatory activity (MGSA) gene. Nucleic Acids Res. 8, 6453. Balentien, E., Han, J. H., Thomas, H. G., Wen, D. Z., Samantha, A. K., Zachariae, C. O., Griffin, P. R., Brachmann, R., Wong, W. L., and Matsushima, K. (1990). Recombinant expression, biochemical characterization, and biological activities of the human MGSA/gro protein. Biochemistry 29, 10225±10233. Balentien, E., Mufson, B., Shattuck, R., Derynck, R., and Richmond, A. (1991). Effects of MGSA/GRO on melanocyte transformation. Oncogene 6, 1115±1124. Baly, D. L., Horuk, R., Yansura, D. G., Simmons, L. C., Fairbrother, W. J., Kotts, C., Wirth, C. M., Gillece-Castro, B. L., Toy, K., Hesselgesser, J., and Allison, D. E. (1998). A His19 to Ala mutant of melanoma growth-stimulating activity is a partial antagonist of the CXCR2 receptor. J. Immunol. 161, 4944±4949. Becker, S., Quay, J., Koren, H. S., and Haskill, J. S. (1994). Constitutive and stimulated MCP-1, GRO , , and gamma expression in human airway epithelium and bronchoalveolar macrophages. Am. J. Physiol. Lung Cell. Mol. Physiol. 266, L278±L286. Beckmann, P. M., Munger, W. E., Kozlosky, C., VandenBos, T., Price, V., Lyman, S., Gerard, N. P., Gerard, C., and Cerretti, D. P. (1991). Molecular characterization of the interleukin-8 receptor. Biochem. Biophys. Res. Commun. 179, 784±789. Bedard, P. A., and Golds, E. E. (1993). Cytokine-induced expression of mRNAs for chemotactic factors in human synovial cells and fibroblasts. J. Cell. Physiol. 154, 433±441. Bedard, P. A., Alcorta, D., Simmons, D. L., Luk, K. C., and Erikson, R. L. (1987). Constitutive expression of a gene encoding a polypeptide homologous to biologically active human platelet protein in Rous sarcoma virus-transformed fibroblasts. Proc. Natl Acad. Sci. USA 84, 6715±6719. Ben-Baruch, A., Xu, L. L., Young, P. P., Bengali, K., Oppenheim, J. J., and Wang, J. M. (1995). Monocyte chemotactic protein-3 (MCP3) interacts with multiple leukocyte receptor±C-C CKR1, a receptor for macrophage inflammatory protein-1Alpha/Rantes, is also a functional receptor for MCP3. J. Biol. Chem. 270, 22123±22128. Ben-Baruch, A., Grimm, M., Bengali, K., Evans, G. A., Chertov, O., Wang, J. M., Howard, O. M., Mukaida, N., Matsushima, K., and Oppenheim, J. J. (1997). The differential ability of IL-8 and neutrophil-activating peptide-2 to induce attenuation of chemotaxis is mediated by their divergent
capabilities to phosphorylate CXCR2 (IL-8 receptor B). J. Immunol. 158, 5927±5933. Blackwell, T. S., Holden, E. P., Blackwell, T. R., Delarco, J. E., and Christman, J. W. (1994). Cytokine-induced neutrophil chemoattractant mediates neutrophilic alveolitis in rats: association with nuclear factor kappa B activation. Am. J. Respir. Cell. Mol. Biol. 11, 464±472. Bodger, K., and Crabtree, J. E. (1998). Helicobacter pylori and gastric inflammation. Br. Med. Bull. 54, 139±150. Boorsma, D. M., deHaan, P., Willemze, R., and Stoof, T. J. (1994). Human growth factor (huGRO), interleukin-8 (IL-8) and interferon-gamma-inducible protein (gamma-IP-10) gene expression in cultured normal human keratinocytes. Arch. Dermatol. Res. 26, 475. Bordoni, R., Thomas, G., and Richmond, A. (1989). Growth factor modulation of melanoma growth stimulatory activity mRNA expression in human malignant melanoma cells correlates with cell growth. J. Cell. Biochem. 39, 421±428. Bordoni, R., Fine, R., Murray, D., and Richmond, A. (1990). Characterization of the role of melanoma growth stimulatory activity (MGSA) in the growth of normal melanocytes, nevocytes, and malignant melanocytes. J. Cell. Biochem. 44, 207±219. Bussolino, F., De Rossi, M., Sica, A., Colotta, F., Wang, J. M., Bocchietto, E., Padura, I. M., Bosia, A., DeJana, E., and Mantovani, A. (1991). Murine endothelioma cell lines transformed by polyoma middle T oncogene as target for and producers of cytokines. J. Immunol. 147, 2122±2129. Cacalano, G., Lee, J., Kikly, K., Ryan, A. M., Pitts-Meek, S., Hultgren, B., Wood, W. I., and Moore, M. W. (1994). Neutrophil and B cell expansion in mice that lack the murine IL-8 receptor homolog. Science 265, 682±684. Cao, Y., Chen, C., Weatherbee, J. A., Tsang, M., and Folkman, J. (1995). Gro-beta, a CXC chemokine, is an angiogenesis inhibitor that suppresses the growth of lewis lung carcinoma in mice. J. Exp. Med. 182, 2069±2077. Casola, A., Estes, M. K., Crawford, S. E., Ogra, P. L., Ernst, P. B., Garofalo, R. P., and Crowe, S. E. (1998). Rotavirus infection of cultured intestinal epithelial cells induces secretion of CXC and CC chemokines. Gastroenterology 114, 947±955. Chenevix-Trench, G., Martin, N. G., and Ellem, K. A. O. (1990). Gene expression in melanoma cell lines and cultured melanocytes: correlation between levels of c-src-1, c-myc and p53. Oncogene 5, 1187±1193. Cheng, Q. C., Han, J. H., Thomas, H. G., Balentien, E., and Richmond, A. (1992). The melanoma growth stimulatory activity receptor consists of two proteins. Ligand binding results in enhanced tyrosine phosphorylation. J. Immunol. 148, 451±456. Chesney, J., Metz, C., Stavitsky, A. B., Bacher, M., and Bucala R. (1998). Regulated production of type I collagen and inflammatory cytokines by peripheral blood fibrocytes. J. Immunol. 160, 419±425. Clark-Lewis, I., Schumacher, C., Baggiolini, M., and Moser, B. (1991). Structure-activity relationships of interleukin-8 determined using chemically synthesized analogs. Critical role of NH2-terminal residues and evidence for uncoupling of neutrophil chemotaxis, exocytosis, and receptor binding activities. J. Biol. Chem. 266, 23128±23134. Clark-Lewis, I., Dewald, B., Geiser, T., Moser, B., and Baggiolini, M. (1993). Platelet factor 4 binds to interleukin 8 receptors and activates neutrophils when its N terminus is modified with Glu-Leu-Arg. Proc. Natl. Acad. Sci. USA 90, 3574± 3577. Clark-Lewis, I., Dewald, B., Loetscher, M., Moser, B., and Baggiolini, M. (1994). Structural requirements for interleukin-8
MGSA/GRO 1041 function identified by design of analogs and CXC chemokine hybrids. J. Biol. Chem. 269, 16075±16081. Clark-Lewis, I., Kim, K. S., Rajarathnam, K., Gong, J. H., Dewald, B., Moser, B., Baggiolini, M., and Sykes, B. D. (1995). Structure-activity relationships of chemokines. J. Leukoc. Biol. 57, 703±711. Clore, G. M., and Gronenborn, A. M. (1995). Three-dimensional structures of alpha and beta chemokines. FASEB J. 9, 57±62. Clore, G. M., Appella, E., Yamada, M., Matsushima, K., and Gronenborn, A. M. (1989). Determination of the secondary structure of interleukin-8 by nuclear magnetic resonance spectroscopy. J. Biol. Chem. 264, 18907±18911. Clubb, R. T., Omichinski, J. G., Clore, G. M., and Gronenborn, A. M. (1994). Mapping the binding surface of interleukin-8 complexes with an N-terminal fragment of the type 1 human interleukin-8 receptor. FEBS Lett. 338, 93±97. Cochran, B. H., Reffel, A. C., and Stiles, C. D. (1983). Molecular cloning of gene sequences regulated by platelet-derived growth factor. Cell 32, 939±947. Cole, K. E., Strick, C. A., Paradis, T. J., Ogborne, K. T., Loetscher, M., Gladue, R. P., Lin, W., Boyd, J. G., Moser, B., Wood, D. E., Sahagan, B. G., and Neote, K. (1998). Interferoninducible T cell alpha activity on activated T cells through selective high affinity binding to CXCR3. J. Exp. Med. 187, 2009± 2021. Crippen, T. L., Riches, D. W., and Hyde, D. M. (1998). Differential regulation of the expression of cytokine-induced neutrophil chemoattractant by mouse macrophages. Pathobiology 66, 24±32. Crippes, B. A., Zagorski, J., Carr, L. S., Wittwer, A. J., Dolecki, G. J., and De Larco, J. E. (1993). Investigation of possible autocrine functions for rat GRO/CINC (cytokineinduced neutrophil chemoattractant). J. Cell. Physiol. 156, 412±420. Cuenca, R. E., Azizkhan, R. G., and Haskill, S. (1992). Characterization of GRO alpha, beta and gamma expression in human colonic tumours: potential significance of cytokine involvement [published erratum appears in Surg. Oncol. 1992; 1, 417] Surg. Oncol. 1, 323±329. Damaj, B. B., McColl, S. R., Neote, K., Hebert, C. A., and Naccache, P. H. (1996). Diverging signal transduction pathways activated by interleukin 8 (IL-8) and related chemokines in human neutrophils. IL-8 and Gro-alpha differentially stimulate calcium influx through IL-8 receptors A and B. J. Biol. Chem. 271, 20540±20544. De Haan, P., Sampat, S., van der, Raaj E. M., Bruynzeel, I., Boorsma, D. M., Willemze, R., and Stoof, T. J. (1994). Effect of calcitriol on growth, differentiation, chemokine mRNA expression of cultured keratinocytes and on keratinocyte-T cell binding. Acta Derm. Venereol. Suppl. (Stockh.) 186, 52±54. Devalaraja, M. N., Wang, D. Z., Ballard, D. W., and Richmond, A. (1999). Elevated constitutive IB kinase activity and IB- phosphorylation in Hs294T melanoma cells lead to increased basal MGSA/GRO- transcription. Cancer Res. 59, 1372±1377. De Vos, A. F., Klaren, V. N., and Kijlstra, A. (1994). Expression of multiple cytokines and IL-1RA in the uvea and retina during endotoxin-induced uveitis in the rat. Invest. Ophthalmol. Vis. Sci. 35, 3873±3883. Dezube, B. J., Pardee, A. B., Beckett, L. A., Ahlers, C. M., Ecto, L., Allen-Ryan, J., Anisowicz, A., Sager, R., and Crumpacker, C. S. (1992). Cytokine dysregulation in AIDS: in vivo overexpression of mRNA of tumor necrosis factoralpha and its correlation with that of the inflammatory cytokine GRO. J. Acquir. Immune. Defic. Syndr. 5, 1099±1104.
Dolecki, G. J., and Delarco, J. E. (1994). Regulation of cytokineinduced neutrophil chemoattractant (CINC) mRNA production in cultured rat cells. DNA Cell. Biol. 13, 883±889. Driscoll, K. E., Hassenbein, D. G., and Carter, J. (1993). Macrophage inflammatory proteins 1 and 2: expression by rat alveolar macrophages, fibroblasts, and epithelial cells and in rat lung after mineral dust exposure. Am. J. Respir. Cell. Mol. Biol. 8, 311±318. Eckmann, L., Reed, S. L., Smith, J. R., and Kagnoff, M. F. (1995). Entamoeba histolytica trophozoites induce an inflammatory cytokine response by cultured human cells through the paracrine action of cytolytically released interleukin-1 alpha. J. Clin. Invest. 96, 1269±1279. Erger, R. A., and Casale, T. B. (1995). Interleukin-8 is a potent mediator of eosinophil chemotaxis through endothelium and epithelium. Am. J. Physiol. 268, L117±L122. Fahey, T. J., Sherry, B., Tracey, K. J., Paez, X., Davatelis, G., Fahey, T., Sherry, B., Cerami, A., and Myers, R. D. (1990). Cytokine production in a model of wound healing: the appearance of MIP-1, MIP-2, cachectin/TNF and IL-1. Cytokine 2, 92±99. Fairbrother, W. J., Reilly, D., Colby, T., and Horuk, R. (1993). 1H assignment and secondary structure determination of human melanoma growth stimulating activity (MGSA) by NMR spectroscopy. FEBS Lett. 330, 302±306. Fairbrother, W. J., Reilly, D., Colby, T. J., Hesselgesser, J., and Horuk, R. (1994). The solution structure of melanoma growth stimulating activity. J. Mol. Biol. 242, 252±270. Fan, J., Marshall, J. C., Jimenez, M., Shek, P. N., Zagorski, J., and Rotstein, O. D. (1998). Hemorrhagic shock primes for increased expression of cytokine-induced neutrophil chemoattractant in the lung: role in pulmonary inflammation following lipopolysaccharide. J. Immunol. 161, 440±447. Farber, J. M. (1997). Mig and IP-10: CXC chemokines that target lymphocytes. J. Leukoc. Biol. 61, 246±257. Farone, A., Huang, S., Paulauskis, J., and Kobzik, L. (1995). Airway neutrophilia and chemokine mRNA expression in sulfur dioxide-induced bronchitis. Am. J. Respir. Cell Mol. Biol. 12, 345±350. Feng, L., Xia, Y., Kreisberg, J. I., and Wilson, C. B. (1994). Interleukin-1 alpha stimulates KC synthesis in rat mesangial cells: glucocorticoids inhibit KC induction by IL-1. Am. J. Physiol. 266, F713±722. Freter, R. R., Irminger, J. C., Parter, J. A., Jones, S. D., and Stiles, C. D. (1992). A novel of nucleotide motif located in 30 untranslated sequences of the immediate-early gene set mediates platelet-derived growth induction of the JE gene. Mol. Cell. Biol. 12, 5288±5300. Garner, W. L., Rodriguez, J. L., Miller, C. G., Till, G. O., Rees, R. S., Smith, D. J., and Remick, D. G. (1994). Acute skin injury releases neutrophil chemoattractants. Surgery 116, 42±48. Geiser, T., Dewald, B., Ehrengruber, M. U., Clark-Lewis, I., and Baggiolini, M. (1993). The interleukin-8-related chemotactic cytokines GRO , GRO , and GRO activate human neutrophil and basophil leukocytes. J. Biol. Chem. 268, 15419±15424. Gershengorn, M. C., Geras-Raaka, E., Varma, A., and ClarkLewis, I. (1998). Chemokines activate Kaposi's sarcoma-associated herpesvirus G protein-coupled receptor in mammalian cells in culture J. Clin. Invest. 102, 1469±1472. Gillitzer, R., Ritter, U., Spandau, U., Goebeler, M., and Brocker, E. B. (1996). Differential expression of gro-alpha and IL-8 mrna in psoriasis ± a model for neutrophil migration and accumulation in vivo. J. Invest. Dermatol. 107, 778±782.
1042 Dingzhi Wang and Ann Richmond Glabinski, A. R., Tuohy, V. K., and Ransohoff, R. M. (1998). Expression of chemokines RANTES, MIP-1alpha and GROalpha correlates with inflammation in acute experimental autoimmune encephalomyelitis. Neuroimmunomodulation 5, 166±171. Godiska, R., Chantry, D., Dietsch, G. N., and Gray, P. W. (1995). Chemokine expression in murine experimental allergic encephalomyelitis. J. Neuroimmunol. 58, 167±176. Golds, E. E., Mason, P., and Nyirkos, P. (1989). Inflammatory cytokines induce synthesis and secretion of gro protein and a neutrophil chemotactic factor but not beta 2-microglobulin in human synovial cells and fibroblasts. Biochem. J. 259, 585±588. Goodman, R. B., Strieter, R. M., Frevert, C. W., Cummings, C. J., Tekamp-Olson, P., Kunkel, S. L., Walz, A., and Martin, T. R. (1998). Quantitative comparison of C-X-C chemokines produced by endotoxin-stimulated human alveolar macrophages. Am. J. Physiol. 275, L87±95. Greenberger, M. J., Strieter, R. M., Kunkel, S. L., Danforth, J. M., Goodman, R. E., and Standiford, T. J. (1995). Neutralization of IL-10 increases survival in a murine model of Klebsiella pneumonia. J. Immunol. 155, 722±729. Grundy, J. E., Lawson, K. M., MacCormac, L. P., Fletcher, J. M., and Yong, K. L. (1998). Cytomegalovirus-infected endothelial cells recruit neutrophils by the secretion of C-X-C chemokines and transmit virus by direct neutrophil-endothelial cell contact and during neutrophil transendothelial migration. J. Infect. Dis. 177, 1465±1474. Hanzawa, H., Haruyama, H., Konishi, K., Watanabe, K., and Tsurufuji, S. (1997). Subunit association and monomer structure of CINC/Gro revealed by 1H-NMR. J. Biochem. 121, 835± 841. Hanzawa, H., Haruyama, H., Konishi, K., Watanabe, K., and Tsurufuji, S. (1998). Solution structure of CINC/Gro investigated by heteronuclear NMR. J. Biochem. 123, 62±70. Harada, A., Kuno, K., Nomura, H., Mukaida, N., Murakami, S., and Matsushima, K. (1994). Cloning of a cDNA encoding a mouse homolog of the interleukin-8 receptor. Gene 142, 297± 300. Haskill, S., Peace, A., Morris, J., Morris, J., Sporn, S. A., Anisowicz, A., Lee, S. W., Smith, T., Martin, G., Ralph, P., and Sager, R. (1990). Identification of three related human GRO genes encoding cytokine functions. Proc. Natl Acad. Sci. USA 87, 7732±7736. HeÂbert, C. A., Vitangcol, R. V., and Baker, J. B. (1991). Scanning mutagenesis of interleukin-8 identifies a cluster of residues required for receptor binding. J. Biol. Chem. 266, 18989±18994. Hellerbrand, C., Jobin, C., Licato, L. L., Sartor, R. B., and Brenner, D. A. (1998). Cytokines induce NF-kappaB in activated but not in quiescent rat hepatic stellate cells. Am. J. Physiol. 275, G269±278. Heufler, C., Topar, G., Koch, F., Trockenbacher, B., Kampgen, E., Romani, N., and Schuler, G. (1992). Cytokine gene expression in murine epidermal cell suspensions: interleukin 1 beta and macrophage inflammatory protein 1 alpha are selectively expressed in Langerhans cells but are differentially regulated in culture. J. Exp. Med. 176, 1221±1226. Himi, T., Yoshioka, I., and Kataura, A. (1997). Production and gene expression of IL-8-like cytokine GRO/CINC-1 in rat nasal mucosa. Acta Oto-Laryngol. 117, 123±127. Hofmann, P., Sprenger, H., Kaufmann, A., Bender, A., Hasse, C., Nain, M., and Gemsa, D. (1997). Susceptibility of mononuclear phagocytes to influenza A virus infection and possible role in the antiviral response. J. Leukoc. Biol. 61, 408±414. Hogan, M., Sherry, B., Ritchlin, C., Fabre, M., Winchester, R., Cerami, A., and Bucala, R. (1994). Differential expression of
the small inducible cytokines GRO alpha and GRO beta by synovial fibroblasts in chronic arthritis: possible role in growth regulation. Cytokine 6, 61±69. Horuk, R., Martin, A., Hesselgesser, J., Hadley, T., Lu, Z. H., Wang, Z. X., and Peiper S. C. (1996). The Duffy antigen receptor for chemokines: structural analysis and expression in the brain. J. Leukoc. Biol. 59, 29±38. Hosaka, S., Akahoshi, T., Wada, C., and Kondo, H. (1994). Expression of the chemokine superfamily in rheumatoid arthritis. Clin. Exp. Immunol. 97, 451±457. Hsu, C. D., Meaddough, E., Aversa, K., and Copel, J. A. (1998). The role of amniotic fluid L-selectin, GRO-alpha, and interleukin-8 in the pathogenesis of intraamniotic infection. Am. J. Obstet. Gynecol. 178, 428±432. Huang, S., Paulauskis, J. D., and Kobzik, L. (1992a). Rat KC cDNA cloning and mRNA expression in lung macrophages and fibroblasts. Biochem. Biophys. Res. Commun. 184, 922±929. Huang, S., Paulauskis, J. D., Godleski, J. J., and Kobzik, L. (1992b). Expression of macrophage inflammatory protein-2 and KC mRNA in pulmonary inflammation. Am. J. Pathol. 141, 981±988. Iida, N., and Grotendorst, G. R. (1990). Cloning and sequencing of a new gro transcript from activated human monocytes: expression in leukocytes and wound tissue. Mol. Cell. Biol. 10, 5596±5599. Iida, M., Watanabe, K., Tsurufuji, M., Takaishi, K., Iizuka, Y., and Tsurufuji, S. (1992). Level of neutrophil chemotactic factor CINC/gro, a member of the interleukin-8 family, associated with lipopolysaccharide-induced inflammation in rats. Infect. Immun. 60, 1268±1272. Introna, M., Breviario, F., d'Aniello, E. M., Golay, J., Dejana, E., and Mantovani, A. (1993). IL-1 inducible genes in human umbilical vein endothelial cells. Eur. Heart J. 14, SupplK78±81. Isaacs, K. L., Sartor, R. B., and Haskill, S. (1992). Cytokine messenger RNA profiles in inflammatory bowel disease mucosa detected by polymerase chain reaction amplification. Gastroenterology 103, 1587±1595. Jaffe, G. J., Richmond, A., Van Le, L., Shattuck, R. L., Cheng, Q. C., Wong, F., and Roberts, W. (1993). Expression of three forms of melanoma growth stimulating activity (MGSA)/gro in human retinal pigment epithelial cells. Invest. Ophthalmol. Vis. Sci. 34, 2776±2785. Jinquan, T., Moller, B., Storgaard, M., Mukaida, N., Bonde, J., Grunnet, N., Black, F. T., Larsen, C. G., Matsushima, K., and Thestrup-Pedersen, K. (1997). Chemotaxis and IL-8 receptor expression in B cells from normal and HIV-infected subjects. J. Immunol. 158, 475±484. Jones, S. A., Moser, B., and Thelen, M. A. (1995). A comparison of post-receptor signal transduction events in Jurkat cells transfected with either IL-8R1 or IL-8R2: chemokine mediated activation of p42/p44 MAP-kinase (ERK-2). FEBS Lett. 364, 211±214. Johnson, M. C., Goodman, R. B., Kajikawa, O., Wong, V. A., Mongovin, S. M., and Martin, T. R. (1994). Cloning of two rabbit GRO homologues and their expression in alveolar macrophages. Gene 151, 16075±16081. Jose, P. J., Collins, P. D., Perkins, J. A., Beaubien, B. C., Totty, N. F., Waterfield, M. D., Hsuan, J., and Williams, T. J. (1991). Identification of a second neutrophil-chemoattractant cytokine generated during an inflammatory reaction in the rabbit peritoneal cavity in vivo. Purification, partial amino acid sequence and structural relationship to melanoma-growth-stimulatory activity. Biochem. J. 278, 493±497. Kasama, T., Strieter, R. M., Lukacs, N. W., Lincoln, P. M., Burdick, M. D., and Kunkel, S. L. (1995). Interleukin-10
MGSA/GRO 1043 expression and chemokine regulation during the evolution of murine type II collagen-induced arthritis. J. Clin. Invest. 95, 2868±2876. Kayama, F., Yoshida, T., Elwell, M. R., and Luster, M. I. (1995). Role of tumor necrosis factor-alpha in cadmium-induced hepatotoxicity. Toxicol. Appl. Pharmacol. 131, 224±234. Keane, M. P., Belperio, J. A., Moore, T. A., Moore, B. B., Arenberg, D. A., Smith, R. E., Burdick, M. D., Kunkel, S. L., and Strieter, R. M. (1999). Neutralization of the CXC chemokine, macrophage inflammatory protein-2, attenuates bleomycin-induced pulmonary fibrosis. J. Immunol. 162, 5511±5518. Kemeny, L., Ruzicka, T., Dobozy, A., and Michel, G. (1994). Role of interleukin-8 receptor in skin. Int. Arch. Allergy Immunol. 104, 317±322. Kettritz, R., Gaido, M. L., Haller, H., Luft, F. C., Jennette, C. J., and Falk, R. J. (1998). Interleukin-8 delays spontaneous and tumor necrosis factor-alpha-mediated apoptosis of human neutrophils. Kidney Int. 53, 84±91. Kim, K. S., Clark-Lewis, I., and Sykes, B. D. (1994). Solution structure of GRO/melanoma growth stimulatory activity determined by 1H NMR spectroscopy. J. Biol. Chem. 269, 32909± 32915. Kitayama, J., Carr, M. W., Roth, S. J., Buccola, J., and Springer, T. A. (1997). Contrasting responses to multiple chemotactic stimuli in transendothelial migration: heterologous desensitization in neutrophils and augmentation of migration in eosinophils. J. Immunol. 158, 2340±2349. Knall, C., Worthen, G. S., and Johnson, G. L. (1997). Interleukin 8-stimulated phosphatidylinositol-3-kinase activity regulates the migration of human neutrophils independent of extracellular signal-regulated kinase and p38 mitogen-activated protein kinases. Proc. Natl Acad. Sci. USA 94, 3052±3057. Koch,A.E.,Kunkel, S.L.,Shah,M. R., Hosaka,S.,Halloran, M. M., Haines, G. K., Burdick, M. D., Pope, R. M., and Strieter, R. M. (1995). Growth-related gene product alpha. A chemotactic cytokine for neutrophils in rheumatoid arthritis. J. Immunol. 155, 3660±3666. Koike, K., Sakamoto, Y., Sawada, T., Ohmichi, M., Kanda, Y., Nohara, A., Hirota, K., Kiyama, H., and Miyake, A. (1994). The production of CINC/gro, a member of the interleukin-8 family, in rat anterior pituitary gland. Biochem. Biophys. Res. Commun. 202, 161±167. Koike, K., Sakamoto, Y., Kiyama, H., Masuhara, K., Miyake, A., and Inoue, M. (1998). Cytokine-induced neutrophil chemoattractant gene expression in the rat hypothalamus by osmotic stimulation. Brain Res. Mol. Brain Res. 52, 326±329. Kojima, T., Cromie, M. A., Fisher, G. J., Voorhees, J. J., and Elder, J. T. (1993). GRO-alpha mRNA is selectively overexpressed in psoriatic epidermis and is reduced by cyclosporin A in vivo, but not in cultured keratinocytes. J. Invest. Dermatol. 101, 767±772. Konishi, K., Takata, Y., Yamamoto, M., Yomogida, K., Watanabe, K., Tsurufuji, S., and Fujioka, M. (1993). Structure of the gene encoding rat neutrophil chemo-attractant Gro. Gene 126, 285±286. Knop, J., and Enk, A. H. (1995). Cellular and molecular mechanisms in the induction phase of contact sensitivity. Int. Arch. Allergy Immunol. 107, 231±232. Koto, H., Salmon, M., Haddad, el-B., Huang, T. J., Zagorski, J., and Chung, K. F. (1997). Role of cytokine-induced neutrophil chemoattractant (CINC) in ozone-induced airway inflammation and hyperresponsiveness. Am. J. Respir. Crit. Care Med. 156, 234±239. Kupper, R. W., Dewald, B., Jakobs, K. H., Baggiolini, M., and Gierschik, P. (1992). G-protein activation by interleukin 8 and
related cytokines in human neutrophil plasma membranes. Biochem. J. 282, 429±434. Kurdowska, A., Cohen, A. B., Carr, F. K., Stevens, M. D., Miller, E. J., Mullenbach, G., and Tekamp-Olson, P. (1994). Biological and kinetic characterization of recombinant human macrophage inflammatory peptides 2 alpha and beta and comparison with the neutrophil activating peptide 2 and interleukin 8. Cytokine 6, 124±134. Kusugami, K., Ando, T., Ohsuga, M., Imada, A., Shinoda, M., Konagaya, T., Ina, K., Kasuga, N., Fukatsu, A., Ichiyama, S., Nada, T., and Ohta, M. (1997). Mucosal chemokine activity in Helicobacter pylori infection. J. Clin. Gastroenterol. 25, S203±210. Legoux, P., Minty, C., Delpech, B., Minty, A. J., and Shire, D. (1992). Simultaneous quantitation of cytokine mRNAs in interleukin-1 beta stimulated U373 human astrocytoma cells by a polymerisation chain reaction method involving co-amplification with an internal multi-specific control. Eur. Cytokine Netw. 3, 553±563. Leikauf, G. D., Fink, S. P., Miller, M. L., Lockey, J. E., and Driscoll, K.E (1995). Refractory ceramic fibers activate alveolar macrophage eicosanoid and cytokine release. J. Appl. Physiol. 78, 164±171. Lira, S. A., Zalamea, P., Heinrich, J. N., Fuentes, M. E., Carrasco, D., Lewin, A. C., Barton, D. S., Durham, S., and Bravo, R. (1994). Expression of the chemokine N51/KC in the thymus and epidermis of transgenic mice results in marked infiltration of a single class of inflammatory cells. J. Exp. Med. 180, 2039±2048. Liu, T., Young, P. R., McDonnell, P. C., White, R. F., Barone, F. C., and Feuerstein, G. Z. (1993). Cytokine-induced neutrophil chemoattractant mRNA expressed in cerebral ischemia. Neurosci. Lett. 164, 125±128. Loetscher, P., Seitz, M., Clark-Lewis, I., Baggiolini, M., and Moser, B. (1994). Both interleukin-8 receptors independently mediate chemotaxis. Jurkat cells transfected with IL-8R1 or IL-8R2 migrate in response to IL-8, GRO alpha and NAP-2. FEBS Lett. 341, 187±192. Lolis, E., Sweet, R. M., Cousens, L. S., Tekamp-Olson, P., and Sherry, B. A. (1992). Preliminary crystallographic analysis of murine macrophage inflammatory protein 2. J. Mol. Biol. 225, 913±915. Luan, J., Shattuck-Brandt, R., Haghnegahdar, H., Owen, J. D., Strieter, R., Burdick, M., Nirodi, C., Beauchamp, D., Johnson, K. N., and Richmond, A. (1997). Mechanism and biological significance of constitutive expression of MGSA/ GRO chemokines in malignant melanoma tumor progression. J. Leukoc. Biol. 62, 588±597. Luo, H., Chaudhuri, A., Johnson, D. R., Neote, K., Zbrzezna, V., He, Y., and Pogo, A. O. (1997). Cloning, characterization, and mapping of a murine promiscuous chemokine receptor gene-homolog of the human duffy gene. Genome Res. 7, 932± 941. McTigue, D. M., Tani, M., Krivacic, K., Chernosky, A., Kelner, G. S., Maciejewski, D., Maki, R., Ransohoff, R. M., and Stokes, B. T. (1998). Selective chemokine mRNA accumulation in the rat spinal cord after contusion injury. J. Neurosci. Res. 53, 368±376. Magazin, M., Vita, N., Cavrois, E., Lefort, S., Guillemot, J. C., and Ferrara, P. (1992). The biological activities of gro beta and IL-8 on human neutrophils are overlapping but not identical. Eur. Cytokine Netw. 3, 461±467. Maher, J. J. (1995). Rat hepatocytes and Kupffer cells interact to produce interleukin-8 (CINC) in the setting of ethanol. Am. J. Physiol. 269, G518±523.
1044 Dingzhi Wang and Ann Richmond Maher, J. J., Lozier, J. S., and Scott, M. K. (1998). Rat hepatic stellate cells produce cytokine-induced neutrophil chemoattractant in culture and in vivo. Am. J. Physiol. 275, G847±853. Martins-Green, M., and Bissell, M. J. (1990). Localization of 9E3/ CEF-4 in avian tissues: expression is absent in Rous sarcoma virus-induced tumors but is stimulated by injury. J. Cell. Biol. 110, 581±595. Martins-Green, M., Tilley, C., Schwarz, R., Hatier, C., and Bissell, M. J. (1991). Wound-factor-induced and cell cycle phase-dependent expression of 9E3/CEF4, the avian gro gene. Cell. Regul. 2, 739±752. Martins-Green, M., Aotaki-Keen, A., Hjelmeland, L. M., and Bissell, M. J. (1992). The 9E3 protein: immunolocalization in vivo and evidence for multiple forms in culture. J. Cell. Sci. 101, 701±707. Massey, K. D., Strieter, R. M., Kunkel, S. L., Danforth, J. M., and Standiford, T. J. (1995). Cardiac myocytes release leukocyte-stimulating factors. Am. J. Physiol. 269, H980±987. Matsushima, K., Morishita, K., Yoshimura, T., Lavu, S., Kobayashi, Y., Lew, W., Appella, E., Kung, H. F., Leonard, E. J., and Oppenheim, J. J. (1988). Molecular cloning of a human monocyte-derived neutrophil chemotactic factor (MDNCF) and the induction of MDNCF mRNA by interleukin 1 and tumor necrosis factor. J. Exp. Med. 167, 1883±1893. Mattei, S., Colombo, M. P., Melani, C., Silvani, A., Parmiani, G., and Herlyn, M. (1994). Expression of cytokine/growth factors and their receptors in human melanoma and melanocytes. Int. J. Cancer 56, 853±857. Metzner, B., Elsner, J., Dobos, G., Kownatzki, E., Parlow, F., Schraufstatter, I., and Norgauer, J. (1994). [Ca2]I-transients and actin polymerization in human neutrophils under stimulation with GRO alpha and complement fragment C5a. Agents Actions 42, 101±106. Miller, M. D., and Krangel, M. S. (1992). Biology and biochemistry of the chemokines: a family of chemotactic and inflammatory cytokines. Crit. Rev. Immunol. 12, 17±46. Modi, W. S., Amarante, M. R., Hanson, M., Womack, J. E., and Chidambaram A. (1998). Assignment of the mouse and cow CXC chemokine genes. Cytogenet. Cell. Genet. 81, 213±216. Moser, B., Barella, L., Mattei, S., Schumacher, C., Boulay, F., Colombo, M. P., and Baggiolini, M. (1993). Expression of transcripts for two interleukin 8 receptors in human phagocytes, lymphocytes and melanoma cells. Biochem. J. 294, 285±292. Mueller, S. G., Schraw, W. P., and Richmond, A. (1994). Melanoma growth stimulatory activity enhances the phosphorylation of the class II interleukin-8 receptor in non-hematopoietic cells. J. Biol. Chem. 269, 1973±1980. Mueller, S. G., Schraw, W. P., and Richmond, A. (1995). Activation of protein kinase C enhances the phosphorylation of the type B interleukin-8 receptor and stimulates its degradation in non-hematopoietic cells. J. Biol. Chem. 270, 10439± 10448. Mueller, S. G., White, J. R., Schraw, W. P., Lam, V., and Richmond, A. (1997). Ligand induced desensitization of human CXC chemokine receptor-2 is modulated by multiple serine residues in the carboxyl-terminal domain of the receptor. J. Biol. Chem. 272, 8207±8214. Murakami, Y., Hanazawa, S., Watanabe, A., Naganuma, K., Iwasaka, H., Kawakami, K., and Kitano, S. (1994). Porphyromonas gingivalis fimbriae induce a 68-kilodalton phosphorylated protein in macrophages. Infect. Immun. 62, 5242± 5246. Murakami, K., Ueno, A., Yamanouchi, K., and Kondo, T. (1995). Thrombin induces GRO alpha/MGSA production in human umbilical vein endothelial cells. Thromb. Res. 79, 387±394.
Murphy, P. M., and Tiffany, H. L. (1991). Cloning of complementary DNA encoding a functional human interleukin-8 receptor. Science 253, 1280±1283. Nakagawa, H., Komorita, N., Shibata, F., Ikesue, A., Konishi, K., Fujioka, M., and Kato, H. (1994). Identification of cytokine-induced neutrophil chemoattractants (CINC), rat GRO/CINC-2 alpha and CINC-2beta, produced by granulation tissue in culture: purification, complete amino acid sequences and characterization. Biochem. J. 301, 545±550. Nanney, L. B., Mueller, S. G., Bueno, R., Peiper, S. C., and Richmond, A. (1995). Distributions of melanoma growth stimulatory activity or growth-regulated gene and the interleukin-8 receptor B in human wound repair. Am. J. Pathol. 47, 1248± 1260. Neote, K., Darbonne, W., Ogez, J., Horuk, R., and Schall, T. J. (1993). Identification of a promiscuous inflammatory peptide receptor on the surface of red blood cells. J. Biol. Chem. 268, 12247±12249. Neville, L. F., Mathiak, G., and Bagasra, O. (1997). The immunobiology of interferon-gamma inducible protein 10 kD (IP-10): a novel, pleiotropic member of the C-X-C chemokine superfamily. Cytokine Growth Factor Rev. 8, 207±219. Nickoloff, B. J., Karabin, G. D., Barker, J. N., Griffiths, C. E., Sarma, V., Mitra, R. S., Elder, J. T., Kunkel, S. L., and Dixit, V. M. (1991). Cellular localization of interleukin-8 and its inducer, tumor necrosis factor-alpha in psoriasis. Am. J. Pathol. 138, 129±140. Norgauer, J., Krutmann, J., Dobos, G. J., Traynor-Kaplan, A. E., Oades, Z. G., and SchraufstaÈtter, I. U. (1994). Actin polymerization, calcium-transients, and phospholipid metabolism in human neutrophils after stimulation with interleukin-8 and Nformyl peptide. J. Invest. Dermatol. 102, 310±314. Norgauer, J., Metzner, B., Czech, W., and Schraufstatter, I. (1996). Reconstitution of chemokine-induced actin polymerization in undifferentiated human leukemia cells (HL-60) by heterologous expression of interleukin-8 receptors. Inflamm. Res. 45, 127±131. Odake, H., Koizumi, F., Hatakeyama, S., Furuta, I., and Nakagawa, H. (1993). Production of cytokines belonging to the interleukin-8 family by human gingival fibroblasts stimulated with interleukin-1 beta in culture. Exp. Mol. Pathol. 58, 14±24. Ohkubo, K., Masumoto, T., Horiike, N., and Onji, M. (1998). Induction of CINC (interleukin-8) production in rat liver by non-parenchymal cells. J. Gastroenterol. Hepatol. 13, 696±702. Ohmori, Y., and Hamilton, T. A. (1994). Cell type and stimulus specific regulation of chemokine gene expression. Biochem. Biophys. Res. Commun. 198, 590±596. Ohmori, Y., Fukumoto, S., and Hamilton, T. A. (1995). Two structurally distinct kappa B sequence motifs cooperatively control LPS-induced KC gene transcription in mouse macrophages. J. Immunol 155, 3593±3600. Oral, E., Seli, E., Bahtiyar, M. O., Jones, E. E., and Arici, A. (1997). Growth-regulated alpha expression in human preovulatory follicles and ovarian cells. Am. J. Reprod. Immunol. 38, 19±25. Oquendo, P., Alberta, J., Wen, D. Z., Graycar, J. L., Derynck, R., and Stiles, C. D. (1989). The platelet-derived growth factorinducible KC gene encodes a secretory protein related to platelet -granule proteins. J. Biol. Chem. 264, 4133±4137. Owen, J. D., Strieter, R., Burdick, M., Haghnegahdar, H., Nanney, L., Ahattuckbrandt, R., and Richmond, A. (1997). Enhanced tumor-forming capacity for immortalized melanocytes expressing melanoma growth stimulatory activity/ growth-regulated cytokine beta and gamma proteins. Int. J. Cancer. 73, 94±103.
MGSA/GRO 1045 Pawar, S., Kartha, S., and Toback, F. G. (1995). Differential gene expression in migrating renal epithelial cells after wounding. J. Cell. Physiol. 165, 556±565. Peiper, S. C., Wang, Z., Neote, K., Martin, A. W., Showell, H. J., Conklyn, M. J., Ogborne, K., Hadley, T. J., Lu, Z. H., and Hesselgesser, J. (1995). The duffy antigen/receptor for chemokines (DARC) is expressed in endothelial cells of duffy negative individuals, who lack the erythrocyte receptor. J. Exp. Med. 181, 1311±1317. Perlman, D., and Halvorson, H. O. (1983). A putative signal peptidase recognition site and sequence in eukaryotic and prokaryotic signal peptides. J. Mol. Biol. 167, 391±409. Pichon, F., and Lagarde, A. E. (1989). Autoregulation of MeWo metastatic melanoma cell growth: characterization of intracellular (FGF, MGSA) and secreted (PDGF) growth factors. J. Cell. Physiol. 140, 344±358. Prado, G. N., Thomas, K. M., Suzuki, H., LaRosa, G. J., Wilkinson, N., Folco, E., and Navarro, J. (1994). Molecular characterization of a novel rabbit interleukin-8 receptor isotype. J. Biol. Chem. 269, 12391±12394. Proost, P., De Wolf-Peeters, C., Conings, R., Opdenakker, G., Billiau, A., and Van Damme, J. (1993). Identification of a novel granulocyte chemotactic protein (GCP-2) from human tumor cells. In vitro and in vivo comparison with natural forms of GRO, IP-10, and IL-8. J. Immunol. 150, 1000±1010. Rajarathnam, K., Clark-Lewis, I., and Sykes, B. D. (1994). 1H NMR studies of interleukin 8 analogs: characterization of the domains essential for function. Biochemistry 33, 6623±6630. Rasmussen, S. J., Eckmann, L., Quayle, A. J., Shen, L., Zhang, Y. X., Anderson, D. J., Fierer, J., Stephens, R. S., and Kagnoff, M. F. (1997). Secretion of proinflammatory cytokines by epithelial cells in response to Chlamydia infection suggests a central role for epithelial cells in chlamydial pathogenesis. J. Clin. Invest. 99, 77±87. Recklies, A. D., and Golds, E. E. (1992). Induction of synthesis and release of interleukin-8 from human articular chondrocytes and cartilage explants. Arthritis Rheum. 35, 1510±1519. Rennekampff, H. O., Hansbrough, J. F., Woods, V., Dore, C., Kiessig, V., and Schroder, J. M. (1997). Role of melanoma growth stimulatory activity (MGSA/gro) on keratinocytes function in wound healing. Arch. Dermatol. Res. 289, 204±212. Richardson, R. M., Ali, H., Tomhave, E. D., Haribabu, B., and Snyderman, R. (1995). Cross-desensitization of chemoattractant receptors occurs at multiple levels. Evidence for a role for inhibition of phospholipase C activity. J. Biol. Chem. 270, 27829±27833. Richardson, R. M., Pridgen, B. C., Haribabu, B., Ali, H., and Snyderman, R. (1998). Differential cross-regulation of the human chemokine receptors CXCR1 and CXCR2. Evidence for time-dependent signal generation. J. Biol. Chem. 273, 23830±23836. Richmond, A., and Shattuck, R. L. (1996). In ``Chemoattractant Ligands and their Receptors'' (ed R. Horuk), Melanoma growth stimulatory activity: physiology biology, structure/function, and role in disease, pp. 87±124. CRC Press, Boca Raton. Richmond, A., and Thomas, H. G. (1986). Purification of melanoma growth stimulatory activity. J. Cell. Physiol. 129, 375±384. Richmond, A., and Thomas, H. G. (1988). Melanoma growth stimulatory activity: isolation from human melanoma tumors and characterization of tissue distribution. J. Cell. Biochem. 36, 185±198. Richmond, A., Lawson, D. H., and Nixon, D. W. (1982). Release of an autostimulatory growth activity by human malignant melanoma cells. Cold Spring Harbor Conf. Cell Prolif. 9, 885± 887.
Richmond, A., Lawson, D. H., Stevens, J. S., Chawla, R. K., and Nixon, D. W. (1983). Extraction of a melanoma growth-stimulatory activity from culture medium conditioned by the Hs0294 human melanoma cell line. Cancer Res. 43, 2106±2112. Richmond, A., Lawson, D. H., Nixon, D. W., and Chawla, R. K. (1985). Characterization of autostimulatory and transforming growth factors from human melanoma cells. Cancer Res. 45, 6390±6394. Richmond, A., Fine, R., Murray, D., Lawson, D. H., and Priest, J. A. (1986). Growth factor and cytogenetic abnormalities in cultured nevi and malignant melanomas. J. Invest. Dermatol. 86, 295±302. Richmond, A., Balentien, E., Thomas, H. G., Flaggs, G., Barton, D. E., Spiess, J., Bordoni, R., Francke, U., and Derynck, R. (1988). Molecular characterization of melanoma growth stimulatory activity, a growth factor structurally related to -thromboglobulin. EMBO J. 7, 2025±2033. Riedel, D. D., and Kaufmann, S. H. (1997). Chemokine secretion by human polymorphonuclear granulocytes after stimulation with Mycobacterium tuberculosis and lipoarabinomannan. Infect. Immun. 65, 4620±4623. Roach, T. I., Chatterjee, D., and Blackwell, J. M. (1994). Induction of early-response genes KC and JE by mycobacterial lipoarabinomannans: regulation of KC expression in murine macrophages by Lsh/Ity/Bcg (candidate Nramp). Infect. Immun. 62, 1176±1184. Robinson, S., Tani, M., Strieter, R. M., Ransohoff, R. M., and Miller, R. H. (1998). The chemokine growth-regulated oncogene-alpha promote spinal cord oligodendrocyte precursor proliferation. J. Neurosci. 18, 10457±10463. Roby, P., and Page, M. (1995). Cell-binding and growth-stimulating activities of the C-terminal part of human MGSA/Gro alpha. Biochem. Biophys. Res. Commun. 206, 792±798. Rodeck, U., Melber, K., Kath, R., Menssen, H. D., Varello, M., Atkinson, B., and Herlyn, M. (1991). Constitutive expression of multiple growth factor genes by melanoma cells but not normal melanocytes. J. Invest. Dermatol. 97, 20±26. Safirstein, R., Megyesi, J., Saggi, S. J., Price, P. M., Poon, M., Rollins, B. J., and Taubman, M. B. (1991). Expression of cytokine-like genes JE and KC is increased during renal ischemia. Am. J. Physiol. 261, F1095±1101. Sanchez, X., Suetomi, K., Cousins-Hodges, B., Horton, J. K., and Navarro, J. (1998). CXC chemokines suppress proliferation of myeloid progenitor cells by activation of the CXC chemokine receptor 2. J. Immunol. 160, 906±910. Santamaria Babi, L. F., Moser, B., Perez Soler, M. T., Moser, R., Loetscher, P., Villiger, B., Blaser, K., and Hauser, C. (1996). The interleukin-8 receptor B and CXC chemokines can mediate transendothelial migration of human skin homing T cells. Eur. J. Immunol. 26, 2056±2061. Sawada, T., Koike, K., Kanda, Y., Sakamoto, Y., Nohara, A., Ohmichi, M., Hirota, K., and Miyake, A. (1994a). In vitro effects of CINC/gro, a member of the interleukin-8 family, on hormone secretion by rat anterior pituitary cells. Biochem. Biophys. Res. Commun. 202, 155±160. Sawada, T., Koike, K., Sakamoto, Y., Nohara, A., Kanda, Y., Zhang, Z. X., Ohmichi, M., Yamaguchi, M., Hirota, K., and Miyake, A. (1994b). In vitro effects of CINC/gro, a member of the interleukin-8 family, on interleukin-6 secretion by rat posterior pituitary cells. Biochem. Biophys. Res. Commun. 200, 742±748. Schadendorf, D., Moller, A., Algermissen, B., Worm, M., Sticherling, M., and Czarnetzki, B. M. (1993). IL-8 produced by human malignant melanoma cells in vitro is an essential autocrine growth factor. J. Immunol. 151, 2667±2675.
1046 Dingzhi Wang and Ann Richmond Schraw, W., and Richmond, A. (1995). Melanoma growth stimulatory activity signaling through the class II interleukin-8 receptor enhances the tyrosine phosphorylation of Crk-associated substrate, p130 and a 70 kilodalton protein. Biochemistry 34, 13760±13767. Schroder, J. M., Gregory, H., Young, J., and Christophers, E. (1992). Neutrophil-activating proteins in psoriasis. J. Invest. Dermatol. 98, 241±247. Schulz, B. S., Michel, G., Wagner, S., Suss, R., Beetz, A., Peter, R. U., Kemeny, L., and Ruzicka, T. (1993). Increased expression of epidermal IL-8 receptor in psoriasis. Down-regulation by FK-506 in vitro. J. Immunol. 151, 4399±4406. Schwartz, D., Andalibi, A., Chaverri-Almada, L., Berliner, J. A., Kirchgessner, T., Fang, Z. T., Tekamp-Olson, P., Lusis, A. J., Gallegos, C., and Fogelman, A. M. (1994). Role of the GRO family of chemokines in monocyte adhesion to MM-LDL-stimulated endothelium. J. Clin. Invest. 94, 1968±1973. Seebach, J., Bartholdi, D., Frei, K., Spanaus, K. S., Ferrero, E., Widmer, U., Isenmann, S., Strieter, R. M., Schwab, M., and Pfister, H. (1995). Experimental Listeria meningoencephalitis. Macrophage inflammatory protein-1 alpha and -2 are produced intrathecally and mediate chemotactic activity in cerebrospinal fluid of infected mice. J. Immunol. 155, 4367±4375. Seldin, M. F., Martinez, L., Howard, T. A., Naylor, S. L., and Sakaguchi, A. Y. (1990). Localization of mouse melanoma growth stimulatory activity gene (MGSA) between Afp and Gus on chromosome 5 using interspecific backcross mice. Cytogenet. Cell. Genet. 54, 68±70. Shanley, T. P., Schmal, H., Warner, R. L., Schmid, E., Friedl, H. P., and Ward, P. A. (1997). Requirement for C-XC chemokines (macrophage inflammatory protein-2 and cytokine-induced neutrophil chemoattractant) in IgG immune complex-induced lung. J. Immunol. 158, 3439±3448. Shao, W., Jerva, L. F., West, J., and Lolis, E. (1998). Solution structure of murine macrophage inflammatory protein-2. Biochemistry 37, 8303±8313. Shattuck, R. L., and Richmond, A. (1998). In ``Human Cytokines, Handbook for Basic and Clinical Research III'' (ed B. B. Aggarwal), Melanoma growth stimulatory activity, pp. 266±313. Blackwell Science, Malden, MA. Shattuck-Brandt, R. L., and Richmond, A. (1997). Enhanced degradation of I-B contributes to endogenous activation of NF-B in HS294T melanoma cells. Cancer Res. 57, 3032± 3039. Shattuck-Brandt, R. L., Wood, L. D., Jaffe, G. J., and Richmond, A. (1994). MGSA/GRO transcription is differentially regulated in normal retinal pigment epithelial and melanoma cells. Mol. Cell. Biol. 14, 791±802. Shattuck-Brandt, R. L., Wood, L. D., and Richmond, A. (1997). Identification and characterization of an MGSA/GRO pseudogene. DNA Seq. 7, 379±386. Shibata, F., Konishi, K., and Nakagawa, H. (1998). Gene structure, cDNA cloning, and expression of the rat cytokineinduced neutrophil chemoattractant-2 (CINC-2) gene. Cytokine 10, 169±174. Shijo, H., Iwabuchi, K., Hosoda, S., Watanabe, H., Nagaoka, I., and Sakakibara, N. (1998). Evaluation of neutrophil functions after experimental abdominal surgical trauma. Inflamm. Res. 47, 67±74. Shimoyama, T., and Crabtree, J. E. (1997). Mucosal chemokines in Helicobacter pylori infection. J. Physiol. Pharmacol. 48, 315±323. Shiratori, Y., Takada, H., Hikiba, Y., Okano, K., Niwa, Y., Matsumura, M., Komatsu, Y., and Omata, M. (1993). Increased release of KC/gro protein, intercrine cytokine family,
from hepatocytes of the chronically ethanol fed rats. Biochem. Biophys. Res. Commun. 197, 319±325. Shiratori, Y., Hikiba, Y., Mawet, E., Niwa, Y., Matsumura, M., Kato, N., Shiina, S., Tada, M., Komatsu, Y., and Kawabe, T. (1994a). Modulation of KC/gro protein (interleukin-8 related protein in rodents) release from hepatocytes by biologically active mediators. Biochem. Biophys. Res. Commun. 203, 1398± 1403. Shiratori, Y., Takada, H., Hai, K., Kiriyama, H., Mawet, E., Komatsu, Y., Niwa, Y., Matsumura, M., Shiina, S., and Kawase, T. (1994b). Effect of anti-allergic agents on chemotaxis of neutrophils by stimulation of chemotactic factor released from hepatocytes exposed to ethanol. Dig. Dis. Sci. 39, 1569±1575. Shirozu, M., Nakano, T., Inazawa, J., Tashiro, K., Tada, H., Shinohara, T., and Honjo, T. (1995). Structure and chromosomal localization of the human stromal cell-derived factor 1 (SDF1) gene. Genomics 28, 495±500. Shyamala, V., Khoja, H., and Moghadam, M. (1998). Inhibition of adenylyl cyclase by alpha chemokines IL-8 and GRO-alpha in Chinese hanster ovary cells expressing R1 and R2receptors. J. Interferon Cytokine Res. 18, 235±239. Singh, R. K., Gutman, M., Radinsky, R., Bucana, C. D., and Fidler, I. J. (1994). Expression of interleukin 8 correlates with the metastatic potential of human melanoma cells in nude mice. Cancer Res. 54, 3242±3247. Sipes, N. J., Lyons, R. M., and Moses, H. L. (1990). Isolation and characterization of Kirsten murine sarcoma virus-transformed mouse keratinocytes resistant to transforming growth factor beta. Mol. Carcinog. 3, 12±19. Sirenko, O. I., Lofquist, A. K., DeMaria, C. T., Morris, J. S., Brewer, G., and Haskill, J. S. (1997). Adhesion-dependent regulation of an AU-rich element-binding activity associated with AUF1. Mol. Cell. Biol. 17, 3898±3906. Skerka, C., Irving, S. G., Bialonski, A., and Zipfel, P. F. (1993). Cell type specific expression of members of the IL-8/NAP-1 gene family. Cytokine 5, 112±116. Smith, D. R., Polverini, P. J., Kunkel, S. L., Orringer, M. B., Whyte, R. I., Burdick, M., Wilke, C. A., and Strieter, R. M. (1994). Inhibition of interleukin 8 attenuates angiogenesis in bronchogenic carcinoma. J. Exp. Med. 179, 1409±1415. Sonouchi, K., Hamilton, T. A., Tannenbaum, C. S., Tubbs, R. R., Bukowski, R., and Finke, J. H. (1994). Chemokine gene expression in the murine renal cell carcinoma, RENCA, following treatment in vivo with interferon-alpha and interleukin-2. Am. J. Pathol. 144, 747±755. Sprenger, H., Krause, A., Kaufmann, A., Priem, S., Fabian, D., Burmester, G. R., Gemsa, D., and Rittig, M. G. (1997). Borrelia burgdorferi induces chemokines in human monocytes. Infect. Immun. 65, 4384±4388. Stampfer, M. R., and Yaswen, P. (1993). Culture systems for study of human mammary epithelial cell proliferation, differentiation and transformation. Cancer Surv. 18, 7±34. Standiford, T. J., Strieter, R. M., Lukacs, N. W., and Kunkel, S. L. (1995). Neutralization of IL-10 increases lethality in endotoxemia. Cooperative effects of macrophage inflammatory protein-2 and tumor necrosis factor. J. Immunol. 155, 2222± 2229. Steiner, S. M., Keutzer, J. C., and Hirschhorn, R. R. (1991). Prostaglandin endoperoxide synthase (cyclooxygenase) mRNA and protein production in mouse myoblasts and a differentiation-defective variant. Exp. Cell. Res. 192, 643±646. Sticherling, M., Bornscheuer, E., Schrder, J.-M., and Christophers, E. (1991). Localization of neutrophil-activating peptide-1/interleukin-8-immunoreactivity in normal and psoriatic skin. J. Invest. Dermatol. 96, 26±30.
MGSA/GRO 1047 Stoeckle, M. Y. (1991). Post-transcriptional regulation of gro alpha, gro beta, gro gamma and IL-8 mRNAs by IL-1beta. Nucleic Acids Res. 19, 917±920. Stoeckle, M. Y. (1992). Removal of a 30 non-coding sequence is an initial step in degradation of gro alpha mRNA and is regulated by interleukin-1. Nucleic Acids Res. 20, 1123±1127. Stoeckle, M. Y., and Guan, L. (1993). High-resolution analysis of gro alpha mRNA poly(A) shortening: regulation by interleukin1 beta. Nucleic Acids Res. 21, 1613±1617. Strieter, R. M., Polverini, P. J., Arenberg, D. A., Walz, A., Opdenakker, G., Van Damme, J., and Kunkel, S. L. (1995a). Role of C-X-C chemokines as regulators of angiogenesis in lung cancer. J. Leukoc. Biol. 57, 752±762. Strieter, R. M., Polverini, P. J., Kunkel, S. L., Arenberg, D. A., Burdick, M. D., Kasper, J., Dzuiba, J., Van Damme, J., Walz, A., Marriott, D., Chan, S. Y., Roczniak, S., and Shanafelt, A. B. (1995b). The functional role of the ELR motif in CXC chemokine-mediated angiogenesis. J. Biol. Chem. 270, 348±357. Sugano, S., Stoeckle, M. Y., and Hanafusa, H. (1987). Transformation by rous sarcoma virus induces a novel gene with homology to a mitogenic platelet protein. Cell 49, 321±328. Suzuki, H., Mori, M., Sakaguchi, A. A., Suzuki, M., Miura, S., and Ishii, H. (1998). Enhanced levels of C-X-C chemokine, human GROalpha, in Helicobacter pylori-associated gastric disease. J. Gastroenterol. Hepatol. 13, 516±520. Takada, H., Mawet, E., Shiratori, Y., Hikiba, Y., Nakata, R., Yoshida, H., Okano, K., Kamii, K., and Omata, M. (1995). Chemotactic factors released from hepatocytes exposed to acetaminophen. Dig. Dis. Sci. 40, 1831±1836. Tanahashi, M., Koike, J., Kawabe, N., and NakadateMatsushita, T. (1998). Inhibitory effect of TRK-530 on inflammatory cytokines in bone marrow of rats with adjuvant arthritis. Pharmacology 56, 237±241. Tanaka, F., Dannenberg, A. M., Higuchi, K., Nakamura, M., Pula, P. J., Hugli, T. E., Discipio, R. G., and Kreutzer, D. L. (1997). Chemotactic factors released in culture by intact developing and healing skin lesions produced in rabbits by the irritant sulfur mustard. Inflammation 21, 251±257. Tang, T., Owen, J. D., Du, J., Walker, C. L., and Richmond, A. (1998). Molecular cloning and characterization of a mouse gene with homology to the Duffy-antigen receptor for chemokine. DNA Sequence 8, 1±15. Tani, M., Fuentes, M. E., Peterson, J. W., Trapp, B. D., Durham, S. K., Loy, J. K., Bravo, R., Ransohoff, R. M., and Lira, S. A. (1996). Neutrophil infiltration, glial reaction, and neurological disease in transgenic mice expressing the chemokine N51/KC in oligodendrocytes. J. Clin. Invest. 98, 529±539. Tekamp-Olson, P., Gallegos, C., Bauer, D., McClain, J., Sherry, B., Fabre, M., van Deventer, S., and Cerami, A. (1990). Cloning and characterization of cDNAs for murine macrophage inflammatory protein 2 and its human homologues. J. Exp. Med. 172, 911±919. Tettlebach, W., Nanney, L., Ellis, D., King, L., and Richmond, A. (1993). Localization of MGSA/GRO protein in cutaneous lesions. J. Cutan. Pathol. 20, 259±266. Thomas, H. G., and Richmond, A. (1988). High yield purification of melanoma growth stimulatory activity. Mol. Cell. Endocrinol. 57, 69±76. Thomas, K. M., Taylor, L., and Navarro, J. (1991). The interleukin-8 receptor is encoded by a neutrophil-specific cDNA clone, F3R. J. Biol. Chem. 266, 14839±14841. Thomas, K. M., Taylor, L., Prado, G., Romero, J., Moser, B., Car, B., Walz, A., Baggiolini, M., and Navarro, J. (1994).
Functional and ligand binding specificity of the rabbit neutrophil IL-8 receptor. J. Immunol. 152, 2496±2500. Tsai, W. C., Strieter, R. M., Wilkowski, J. M., Bucknell, K. A., Burdick, M. D., Lira, S. A., and Standiford, T. J. (1998). Lungspecific transgenic expression of KC enhancers resistance to Klebsiella pneumoniae in mice. J. Immunol. 161, 2435±2440. Tsuruta, J., Sugisaki, K., Dannenberg, A. M., Yoshimura, T., Abe, Y., and Mounts, P. (1997). The cytokines NAP-1 (IL-8), MCP-1, IL-1beta, and GRO in rabbit inflammatory skin lesions produced by the chemical irritant sulfur mustard. Inflammation 20, 293±318. Vaingankar, S. M., and Martins-Green, M. (1998). Thrombin activation of the 9E3/CEF4 chemokine involves tyrosine kinases including c-src and the epidermal growth factor receptor. J. Biol. Chem. 27, 5226±5234. Van Damme, J., Wuyts, A., Froyen, G., Van Coillie, E., Struyf, S., Billiau, A., Proost, P., Wang, J. M., and Opdenakker, G. (1997). Granulocyte chemotactic protein-2 and related CXC chemokines: from gene regulation to receptor usage. J. Leukoc. Biol. 62, 563±569. Venner, T. J., Sauder, D. N., Feliciani, C., and Mckenzie, R. C. (1995). Interleukin-8 and melanoma growth-stimulating activity (GRO) are induced by ultraviolet B radiation in human keratinocyte cell lines. Exp. Dermatol. 4, 138±145. Villard, J., Dayer-Pastore, F., Hamacher, J., Aubert, J. D., Schlegel-Haueter, S., and Nicod, L. P. (1995). GRO alpha and interleukin-8 in Pneumocystis carinii or bacterial pneumonia and adult respiratory distress syndrome. Am. J. Respir. Crit. Care. Med. 152, 1549±1554. von Heijne, G. (1984). How signal sequences maintain cleavage specificity. J. Mol. Biol. 173, 243±251. von Heijne, G. (1986). A new method for predicting signal sequence cleavage sites. Nucleic Acids Res. 14, 4683. Walz, A., Meloni, F., Clark-Lewis, I., Von Tscharner, V., and Baggiolini, M. (1991). [Ca2]i changes and respiratory burst in human neutrophils and monocytes induced by NAP-1/interleukin-8, NAP-2, and gro/MGSA. J. Leukoc. Biol. 50, 279±286. Walz, A., Kunkel, S. L., and Strieter, R. M. (1996). In ``Chemokines in Disease'' (ed A. E. Koch and R. M. Strieter), CXC chemokines ± an over-view, pp. 1±26. R. G. Landes & Co., Austin, TX. Watanabe, K., Konishi, K., Fujioka, M., Kinoshita, S., and Nakagawa, H. (1989). The neutrophil chemoattractant produced by the rat kidney epithelioid cell line NRK-52E is a protein related to the KC/gro protein. J. Biol. Chem. 264, 19559±19563. Watanabe, K., Fujioka, M., Yokokawa, H., Konishi, K., Tsurufuji, S., and Nakagawa, H. (1992). Rat gro/melanoma growth-stimulating activity. Assessment of the structure responsible for chemotactic activity by use of its fragments prepared by proteolysis and chemical synthesis. Cytokine 4, 12±17. Wen, D. Z., Rowland, A., and Derynck, R. (1989). Expression and secretion of gro/MGSA by stimulated human endothelial cells. EMBO J. 8, 1761±1766. White, J. R., Lee, J. M., Young, P. R., Hertzberg, R. P., Jurewicz, A. J., Chaikin, M. A., Widdowson, K., Foley, J. J., Martin, L. D., Griswold, D. E., and Sarau, H. M. (1998). Identification of a potent, selective non-peptide CXCR2 antagonist that inhibits interleukin-8-induced neutrophil migration. J. Biol. Chem. 273, 10095±10098. Widmer, U., Manogue, K. R., Cerami, A., and Sherry, B. (1993). Genomic cloning and promoter analysis of macrophage inflammatory protein (MIP)-2, MIP-1 , and MIP-1 , members of the chemokine superfamily of proinflammatory cytokines. J. Immunol. 150, 4996±5012.
1048 Dingzhi Wang and Ann Richmond Wieder, K. J., Hancock, W. W., Schmidbauer, G., Corpier, C. L., Wieder, I., Kobzik, L., Strom, T. B., and KupiecWeglinski, J. W. (1993). Rapamycin treatment depresses intragraft expression of KC/MIP-2, granzyme B, and IFN-gamma in rat recipients of cardiac allografts. J. Immunol. 151, 1158±1166. Wilmer, J. L., Burleson, F. G., Kayama, F., Kanno, J., and Luster, M. I. (1994). Cytokine induction in human epidermal keratinocytes exposed to contact irritants and its relation to chemical-induced inflammation in mouse skin. J. Invest. Dermatol. 102, 915±922. Wood, L. D., and Richmond, A. (1995). Constitutive and cytokine-induced expression of the melanoma growth stimulatory activity/GRO gene requires both NF-B and novel constitutive factors. J. Biol. Chem. 270, 30619±30626. Wood, L. D., Farmer, A. A., and Richmond, A. (1995). HMGI(Y) and Sp1 in addition to NF-B regulate transcription of the MGSA/GRO gene. Nucleic Acids Res. 23, 4210±4219. Wu, X., Wittwer, A. J., Carr, L. S., Crippes, B. A., Delarco, J. E., and Lefkowith, J. B. (1994). Cytokine-induced neutrophil chemoattractant mediates neutrophil influx in immune complex glomerulonephritis in rat. J. Clin. Invest. 94, 337±344. Xing, Z., Jordana, M., Kirpalani, H., Driscoll, K. E., Schall, T. J., and Gauldie, J. (1994). Cytokine expression by neutrophils and macrophages in vivo: endotoxin induces tumor necrosis factoralpha, macrophage inflammatory protein-2, interleukin-1 beta, and interleukin-6 but not RANTES or transforming growth factor-beta 1 mRNA expression in acute lung inflammation [published erratum appears in Am. J. Respir. Cell. Mol. Biol. 1998; 10, following 346]. Am. J. Respir. Cell. Mol. Biol. 10, 148± 153. Yamada, S., Ikeda, H., Yamazaki, H., Shikishima, H., Kikuchi, K., Wakisaka, A., Kasai, N., Shimotohno, K., and Yoshiki, T. (1995). Cytokine-producing mammary carcinomas in transgenic rats carrying the pX gene of human T-lymphotropic virus type I. Cancer Res. 55, 2524±2527. Yamamoto, T., Iyonaga, K., Takeya, M., Saita, N., Suga, M., Ando, M., and Takahashi, K. (1998). Morphological alteration of cultured tracheobronchial epithelial cells is accompanied by the expression of chemokines, MCP-1 and CINC/gro, in rats. Int. J. Exp. Pathol. 79, 81±92. Yamamoto, Y., Retzlaff, C., He, P., Klein, T. W., and Friedman, H. (1995). Quantitative reverse transcription-PCR analysis of Legionella pneumophila-induced cytokine mRNA in different macrophage populations by high-performance liquid chromatography. Clin. Diagn. Lab. Immunol. 2, 18±24.
Yamaoka, Y., Kita, M., Kodama, T., Sawai, N., Tanahashi, T., Kashima, K., and Imanishi, J. (1998). Chemokines in the gastric mucosa in Helicobacter pylori infection. Gut 42, 609±617. Yan, X. T., Tumpey, T. M., Kunkel, S. L., Oakes, J. E., and Lausch, R. N. (1998). Role of MIP-2 in neutrophil migration and tissue injury in the herpes simplex virus-1-infected cornea. Invest. Ophthalmol. Vis. Sci. 39, 1854±1862. Yang, S. K., Eckmann, L., Panja, A., and Kagnoff, M. F. (1997a). Differential and regulated expression of C-X-C, C-C, and Cchemokines by human colon epithelial cells. Gastroenterology 113, 1214±1223. Yang, W., Schraw, W. P., Mueller, S. G., and Richmond, A. (1997b). Interruption of G protein-coupling in CXCR2 does not alter ligand binding, but eliminates ligand±activation of GTP 35S binding, calcium mobilization, and chemotaxis. Biochemistry 36, 15193±15200. Youngs, S. J., Ali, S. A., Taub, D. D., and Rees, R. C. (1997). Chemokines induce migrational responses in human breast carcinoma cell lines. Int. J. Cancer 71, 257±266. Yue, T. L., Wang, X., Sung, C. P., Olson, B., McKenna, P. J., Gu, J. L., and Feuerstein, G. Z. (1994). Interleukin-8: A mitogen and chemoattractant for vascular smooth muscle cells. Circ. Res. 75, 1±7. Zagorski, J., and Delarco, J. E. (1993). Rat CINC (cytokineinduced neutrophil chemoattractant) is the homolog of the human GRO proteins but is encoded by a single gene. Biochem. Biophys. Res. Commun. 190, 104±110. Zagorski, J., and Wahl, S. M. (1997). Inhibition of acute peritoneal inflammation in rats by a cytokine-induced neutrophil chemoattractant receptor antagonist. J. Immunol. 153, 1059±1062. Zipfel, P. F., Bialonski, A., and Skerka, C. (1991). Induction of members of the IL-8/NAP-1 gene family in human T lymphocytes is suppressed by cyclosporin A. Biochem. Biophys. Res. Commun. 27, 179±183.
ACKNOWLEDGEMENTS This work was supported by the Department of Veterans Affairs and by grants from the NCI (CA34590 and CA 56705). We are indebted to Amy Pruitt for her excellent assistance in editing this manuscript.
