OSM Receptor Timothy M. Rose* and A. Gregory Bruce Department of Pathobiology, School of Public Health and Community Medicine, University of Washington, Box 357238, Seattle, WA 98195, USA * corresponding author tel: 206 616 2084, fax: 206 543 3873, e-mail:
[email protected] DOI: 10.1006/rwcy.2000.17005.
SUMMARY Oncostatin M (OSM), a member of the IL-6 family of cytokines, interacts with low-affinity receptor subunit monomers and high-affinity heterodimeric receptor complexes composed of members of the class I cytokine receptor family. Important species-specific differences in receptor binding have been identified. OSM binds directly with low-affinity to gp130, which was originally characterized as the signal transducer subunit within the high-affinity IL-6 receptor complex.
BACKGROUND
Discovery High- and low-affinity receptors for oncostatin M were originally detected using binding assays on a wide variety of cell types (Linsley et al., 1989; Horn et al., 1990). Crosslinking studies using 125I-labeled OSM revealed a major binding protein of approximately 160 kDa (Linsley et al., 1989). The nature and identity of these receptors first came to light after the discovery that OSM was structurally and functionally related to leukemia-inhibitory factor (LIF) Rose and Bruce, 1991), and that OSM shared with LIF the ability to bind the high-affinity LIF receptor (Bruce et al., 1992a; Gearing et al., 1992a). The high-affinity LIF receptor is a heterodimeric complex of two receptor subunits, the LIF receptor (LIFR ) which binds LIF directly at low affinity (Gearing et al., 1991) and gp130, a molecule previously shown to be the signaling subunit of the high-affinity interleukin 6 (IL-6) receptor complex (Hibi et al., 1990). Molecular characterization of LIFR and gp130 revealed a close similarity between the two and to the members of a newly described cytokine receptor family which
includes the IL-6 receptor (IL-6R ) (Bazan, 1990). Ligand binding to this class of receptors is characterized by low-affinity binding to an receptor subunit which is converted to high affinity by further association of an additional receptor component or components involved in signal transduction, usually refered to as converting or receptor subunits. Binding studies demonstrated that gp130 is the lowaffinity receptor for OSM (Gearing et al., 1992a; Liu et al., 1992b). Thus, while gp130 is the affinityconverting receptor subunit for the high-affinity receptor complexes for LIF, IL-6 and other members of the IL-6 family of cytokines, it is the receptor subunit for OSM within the high-affinity OSM receptor complex, and, in this context, will be referred to as OSMR (gp130). Previous studies noted the presence of a highaffinity receptor which was specific to OSM and did not bind LIF (Bruce et al., 1992b). While the shared LIF/OSM receptor described above is composed of OSMR (gp130) and LIFR , the OSM-specific receptor is composed of OSMR (gp130) and a previously undescribed receptor subunit closely related to OSMR (gp130), LIFR , and other members of the cytokine receptor family. This receptor subunit converted the receptor binding of OSM to high affinity in the absence of LIFR and was thus termed the OSM receptor (OSMR ) (Mosley et al., 1996). An important note is that studies in mice have shown that murine OSM binds only the OSM-specific receptor with high affinity, as discussed further below.
Alternative names The low-affinity OSM receptor gp130, herein designated as OSMR (gp130), has also been called the IL-6 signal transducer or the IL-6 receptor
1792 Timothy M. Rose and A. Gregory Bruce chain (Hibi et al., 1990). The LIF receptor, which acts as a affinity-converting receptor subunit for the LIF/OSM shared receptor in humans, is variously designated as LIFR, LIFR , LIFR , or differentiation-stimulating factor receptor (Gearing et al., 1991; Gearing et al., 1992b). The affinity-converting receptor for the high-affinity OSM-specific receptor is termed OSMR or OSM receptor subunit in humans (Mosley et al., 1996). In the murine system, only one high-affinity receptor complex exists for murine OSM, which consists of the murine homologs of OSMR (gp130) and OSMR (Ichihara et al., 1997; Lindberg et al., 1998). Binding and crosslinking studies in heterologous cells suggest that murine OSM binds separately to both subunits of this receptor complex at low affinity, although the relative affinities are unknown at this time. As such, the murine homolog of OSMR is referred to as a specific receptor for OSM to denote the fact that it binds
murine OSM directly at low affinity (Lindberg et al., 1998). However, the murine homolog of gp130, which also binds OSM directly at low affinity, has not been termed as such in the literature.
Structure Molecular cloning studies of OSMR (gp130), OSMR , and LIFR have demonstrated a structural relationship between the three receptor subunits which categorizes them as members of the class I cytokine receptor family (Mosley et al., 1996; Taga, 1996; Lindberg et al., 1998). Members of this family contain conserved hematopoietin domains of approximately 200 amino acids in the extracellular portion of the receptor (Bazan, 1990). Within this domain are positioned four conserved cysteine residues and a WSXWS motif, where X is any
Table 1 OSMR (gp130), OSMR , and LIFR gene sequences Accession
Species
Source
Type
Human
Placenta
mRNA, complete
Size (bp)
Reference
OSMR (gp130) M57230
3085
Hibi et al., 1990
a
S80479
Human
Embryo
Alternate splice IF-1 mRNA, partial
150
Sharkey et al., 1995
U58146
Human
Blood cells
Alternate splice IF-2a mRNA, partial
153
Diamant et al., 1997
X62646
Mouse
Macrophage
mRNA, complete
2995
Saito et al., 1992
M92340
Rat
Liver
mRNA, complete
3053
Wang et al., 1992
Human
Placenta/bone marrow/fibroblast
mRNA composite, complete
4171
Mosley et al., 1996
OSMR U60805 AB015978
Mouse
mRNA, complete
4026
Unpublished
AF058805
Mouse
Skeletal muscle
mRNA, complete
4792
Lindberg et al., 1998
X61615
Human
Placenta
mRNA, complete
3591
Gearing et al., 1991
U78628
Human
Placenta
Alternate 50 noncoding exon
224
Unpublished
Not deposited
Human
Liver
3 alternate spliced isoforms
U78104
Human
Placenta
Promoter and partial exon 1
4935
Unpublished
S83362
Human
Placenta
50 region and exon 1
1350
Tomida and Gotoh, 1996
AF018079
Human
Alternate promoter (nonplacental)
681
Unpublished
LIFR
a
IF=isoform designation used within this chapter.
Tomida, 1997
OSM Receptor 1793 amino acid. Additionally, three fibronectin type III modules which are considered to function as ligandbinding pockets are positioned proximal to the transmembrane-spanning domain.
Main activities and pathophysiological roles OSM is a pleiotropic cytokine which regulates cell growth and differentiation in a wide variety of biological systems, including hematopoiesis, neurogenesis, and osteogenesis (Bruce et al., 1992b). However, the elaboration of the biological activities of OSM has been confounded by the presence of different OSM receptor signaling systems in humans and mice. In humans, OSM signals through two different receptors complexes: the LIF/OSM shared receptor (Gearing and Bruce, 1992), which shares high-affinity binding with LIF, an evolutionarily related protein with structural similarity to OSM (Rose and Bruce, 1991; Rose et al., 1993), and the OSM-specific receptor, which binds OSM uniquely (Bruce et al., 1992a). In mice, OSM signals only through the murine homolog of the OSM-specific receptor (Ichihara et al., 1997; Lindberg et al., 1998). To confuse matters, human OSM, used historically for in vitro and in vivo studies in mice, binds uniquely to the murine LIF receptor and thus exhibits only the biological activities of LIF in mice and not those of OSM (Ichihara et al., 1997; Lindberg et al., 1998). Therefore, the biological activities for OSM are derived from signaling through two different receptors and overlap those of LIF in human but not murine systems. Receptor utilization of OSM in other species has not yet been well defined. As such, the literature on OSM should be reviewed with careful consideration of these findings.
GENE
Accession numbers See Table 1.
Sequence The complete mRNA coding sequences for the membrane-bound forms of human and mouse OSMR (gp130), OSMR , and LIFR have been determined (Figure 1, Figure 2, and Figure 3; Table 1).
In addition, alternately spliced mRNAs have been detected for OSMR (gp130) and LIFR (Table 1) which produce different translated products that correspond to soluble forms of the receptor subunits (Figure 4 and Figure 5). An alternate splice of a 50 noncoding exon of the human LIFR has also been identified (Table 1). The gene for human LIFR spans more than 70 kilobases and contains 20 exons (Tomida and Gotoh, 1996).
PROTEIN
Accession numbers See Table 2.
Description of protein A general comparison of the different OSM membrane-bound receptor subunits encoded by the mRNAs for OSMR (gp130) (Figure 1), OSMR (Figure 2), and LIFR (Figure 3) is shown in Figure 6 and Table 3. All contain three fibronectin type III repeats proximal to a hydrophobic transmembrane domain. In addition, all have a hydrophobic signal sequence at the N-terminus and a C-terminal cytoplasmic domain (200±300 amino acids). Conserved hematopoietin domains ( 200 amino acids) containing four positionally conserved cysteine residues in the N-terminal region and a WSXWS motif in the Cterminal region are found in all three receptor subunits. OSMR and LIFR have additional variant hematopoietin domains, with a domain lacking the N-terminal cysteine residues in OSMR and a domain lacking one pair of conserved cysteine residues in LIFR . In the C-terminal cytoplasmic domain of each receptor subunit are conserved sequences corresponding to the box 1, box 2, and box 3 motifs involved in signal transduction (Murakami et al., 1991; Baumann et al., 1994).
Relevant homologies and species differences OSMR (gp130), OSMR , and LIFR are related to each other and to other members of the hematopoietin receptor family. OSMR shares closest similarity to the LIFR, with a 32% amino acid identity, while OSMR (gp130) is less similar (Mosley et al., 1996). Structurally, OSMR and LIFR are very similar,
1794 Timothy M. Rose and A. Gregory Bruce with the exception that the LIFR contains two intact hematopoietin domains, whereas the OSMR has an N-terminal truncated domain lacking the conserved cysteine residues. OSMR is unique among the hematopoietin receptors in this regard,
since all other receptors have domains with both the conserved cysteine residues and the WSXWS motif. OSMR (gp130) contains only one hematopoietin domain but contains an immunoglobulin (Ig)-like domain at its N-terminus (Bazan, 1990).
Figure 1 Nucleotide and encoded amino acid sequence of the transmembrane form of human OSMR (gp130). The hydrophobic signal sequence and transmembrane-spanning domains are shown in bold and the WSXWS hematopoietin motif is boxed. Exon splice junctions yielding alternately spliced mRNAs are indicated, using the exon numbering of the human LIFR gene (Tomida and Gotoh, 1996).
OSM Receptor 1795 Figure 1 (Continued )
Comparison of the human and murine OSM receptor subunits demonstrates a close similarity between the OSMR (gp130) (76% amino acid identity) and OSMR (55% amino acid identity) homologs (Lindberg et al., 1998). Although the mouse OSMR has the same structural domains as the human protein, it contains variant sequences in the WSXWS motifs present in the hematopoietin
domains with a WGNWS sequence in the N-terminal truncated domain and a WSDWT motif in the second complete domain. Whereas the human LIFR forms part of the LIF/OSM shared receptor complex with OSMR (gp130), the murine homolog of LIFR does not participate in binding or signaling of mouse OSM (Ichihara et al., 1997; Lindberg et al., 1998). Many studies examining the biological function of
1796 Timothy M. Rose and A. Gregory Bruce Figure 1
OSM in mice have used human OSM which only mimics mouse LIF by binding and signaling uniquely through the mouse LIF receptor complex (Ichihara et al., 1997; Lindberg et al., 1998).
(Continued )
et al., 1997), which is composed of the murine homologs of OSMR (gp130) and OSMR (Lindberg et al., 1998).
Affinity for ligand(s)
Cell types and tissues expressing the receptor
A summary of low-affinity direct binding for individual receptor subunits is shown in Table 4. Direct binding of OSMR (gp130) to OSM at low affinity has been detected in both human and murine systems (Linsley et al., 1989; Ichihara et al., 1997; Lindberg et al., 1998). Although OSMR can bind OSM directly in the murine system (low-affinity; Lindberg et al., 1998), no evidence for binding is seen in the human system (Mosley, 1997). LIFR binds only LIF directly (low-affinity) and not OSM (Gearing and Bruce, 1992). A summary of binding to high-affinity receptor complexes is shown in Table 5. The shared LIF/OSM receptor complex composed of OSMR (gp130) and LIFR binds both OSM and LIF with high affinity in humans (Gearing and Bruce, 1992; Bruce et al., 1992a). However, the murine homolog of the LIF/OSM receptor complex binds murine and human LIF, as well as human OSM, but does not bind murine OSM (Ichihara et al., 1997). Therefore, in murine cells, human OSM mimics the activities of LIF and does not display the activities of murine OSM. Murine OSM binds with high affinity only to the murine OSM-specific receptor (Ichihara
The OSMR (gp130) receptor is ubiquitously expressed on a wide variety of cell types and tissues (Saito et al., 1992). Distinctive patterns of expression have been demonstrated in the brain (Watanabe et al., 1996). Alternately spliced products are found in embryonic tissues (Sharkey et al., 1995) and in blood mononuclear cells (Diamant et al., 1997). OSMR receptor mRNA is detected in mouse heart, brain, spleen, lung, liver, skeletal muscle, and kidney tissue, but not in testis (Lindberg et al., 1998). Human LIFR is expressed in a variety of cell tissues, including the oocytes, preimplantation embryos and the placenta (Gearing et al., 1991; Kojima et al., 1995; van Eijk et al., 1996). Alternately spliced mRNAs encoding soluble human LIFR have been detected in liver, placenta, and choriocarcinoma cells (Tomida, 1997). Studies on bone marrow stromal/osteoblastic cells have shown the presence of OSMR (gp130), OSMR , and LIFR (Bellido et al., 1996). A number of studies have determined sites of expression of mouse LIFR but the exact correlation with the human situation is not clear, since mouse LIFR , unlike human LIFR , does not participate in OSM signaling. A comparison of the expression of
OSM Receptor 1797 the different human OSM receptor subunits, derived from Mosley et al. (1996) is shown in Table 6.
Regulation of receptor expression Of the OSM receptor subunits, only the promoter region for the hLIFR has been reported. The region
upstream of the transcriptional start site for LIFR has a consensus TATA motif 30 bp upstream of the initiation site and several potential regulatory elements, including AP-2-, SP-1-, and NF-IL6binding sites (Tomida and Gotoh, 1996). An alternate promoter in the LIFR gene with an upstream enhancer which is active in placental tissues has also been characterized (Wang and Melmed, 1997).
Figure 2 Nucleotide and encoded amino acid sequence of the transmembrane form of human OSMR . The hydrophobic signal sequence and transmembrane-spanning domains are shown in bold and the WSXWS hematopoietin motif is boxed.
1798 Timothy M. Rose and A. Gregory Bruce Figure 2
Studies on lung-derived epithelial cells have shown that mRNA levels of OSMR (gp130) and OSMR are upregulated by OSM (Cichy et al., 1998).
Release of soluble receptors Alternately spliced mRNAs encoding two different soluble forms of OSMR (gp130) have been identified
(Continued )
(Sharkey et al., 1995; Diamant et al., 1997) (Figure 4). In addition, alternately spliced mRNAs encoding three different soluble forms of human LIFR have been detected in adult liver (Figure 5) (Tomida, 1997). Interestingly, some of the soluble forms encode new cysteine residues in the C-terminal domain (Figure 4 and Figure 5), suggesting the possibility of lipid linkages to membranes, as is found with the receptor
OSM Receptor 1799 Figure 2
for ciliary neurotropic factor (CNTFR ), which contains a glycosylphosphatidylinositol anchor at a C-terminal cysteine residue. Soluble forms of OSMR (gp130) (50 and 100 kDa) and LIFR have been detected in normal human serum, plasma, and urine (Narzaki et al., 1993; Zhang et al., 1998). Soluble murine OSMR (gp130) has been detected in the ascitic fluid of tumor-bearing mice (Matsuda and Hirano, 1994).
SIGNAL TRANSDUCTION
Associated or intrinsic kinases The OSM receptor subunits OSMR (gp130), OSMR , and LIFR all contain cytoplasmic domains with critical tyrosine residues involved in
(Continued )
signaling. However, these molecules contain no intrinsic kinase activity and are dependent upon members of the JAK (Janus-activated kinase) family of constitutively associated kinases (JAK1, JAK2, JAK3, TYK2) for phosphorylation and subsequent signal transduction (Stahl et al., 1994; reviewed in Nakashima and Taga, 1998). Activation of the JAK kinases does not explain all downstream signaling events, and other pathways involving the Src family tyrosine kinases, Ras, mitogen-activated protein kinases (MAPK), phosphatidylinositol 3-kinase (PI-3 kinase) are also implicated in cytokine signaling (Schiemann et al., 1997; reviewed in Hirano et al., 1997). Signal transduction by OSM in endothelial cells has been shown to involve activation of the p62yes tyrosine kinase (Schieven et al., 1992). Studies have suggested that the OSM-specific receptor signal transduction pathway utilizes the MAPK activation more than the LIF/OSM shared receptor
1800 Timothy M. Rose and A. Gregory Bruce (Amaral et al., 1993; Thoma et al., 1994). OSM activates Raf-1 which leads to the ultimate activation of MAPK. This requires the expression of STAT1 and is mediated through a JAK1-dependent pathway (Stancato et al., 1997, 1998). Phosphorylation
of a 250 kDa protein is apparently a specific consequence of OSM signaling through the OSMspecific receptor in A375 cells which involves the JAK1, JAK2, and TYK2 tyrosine kinases (Auguste et al., 1997).
Figure 3 Nucleotide and encoded amino acid sequence of the transmembrane form of human LIFR . The hydrophobic signal sequence and transmembranespanning domains are shown in bold and the WSXWS hematopoietin motif is boxed. Exon splice junctions yielding alternately spliced mRNAs are indicated, using the exon numbering of the human LIFR gene (Tomida and Gotoh, 1996).
OSM Receptor 1801 Figure 3 (Continued )
Cytoplasmic signaling cascades Signal transduction through OSMR (gp130) has mainly been studied in the context of IL-6 activation, which has become a model for the cytokine system. Binding of ligand to its receptor induces dimerization of OSMR (gp130) which leads to activation of members of the JAK family of tyrosine kinases (reviewed in Heinrich et al., 1998) and subsequent phosphorylation of members of the STAT (signal transducer and activator of transcription) family of transcriptional activators, including STAT1, STAT3, and STAT5 (Darnell et al., 1994; Schindler and
Darnell, 1995). Phosphorylated STATs dimerize and are translocated to the nucleus where they activate expression of genes containing STAT-recognition sites.
DOWNSTREAM GENE ACTIVATION
Transcription factors activated Signaling through OSM-specific and LIF/OSM shared receptors activates the DNA-binding activity
1802 Timothy M. Rose and A. Gregory Bruce Figure 3
of STAT1, STAT3, and STAT5b (Auguste et al., 1997; Kuropatwinski et al., 1997; Stephens et al., 1998). Although many similarities are seen with the activation by the IL-6 receptor, an increase in the activation of STAT5 over that seen with IL-6 suggests that differences in biological activity could result from differential activation of the various STATs (Kuropatwinski et al., 1997). In addition to tyrosine phosphorylation of STATs, phosphorylation
(Continued )
on serine residues is also important, especially for binding to low-affinity sites where homodimerization of the STATs is essential (reviewed in Hirano et al., 1997).
Genes induced Table 7 summarizes the gene expression induced by activation of the OSM receptors.
OSM Receptor 1803 Figure 4 Comparison of the alternately spliced isoforms of human OSMR (gp130). (a) The hydrophobic signal peptide (SP) sequence and transmembrane (TM) domain are blue. In the extracellular (EC) domain, the hematopoietin domains with conserved cysteine residues and WSXWS motifs are shown. The fibronectin (FN) type III repeats are colored green. The C-terminal alternately spliced domains are indicated with striped boxes and the presence of a new cysteine residue in these domains is indicated with a C. The intracellular (IC) domain of the membrane form is shown. (b) The exon origins of the alternately spliced mRNAs are shown for the extracellular membrane-form (ECM) and the two putative soluble isoforms (IF-1 and IF-2). Variations in splicing results in the use of different reading frames within the same exon. (c) The encoded amino acid sequence for the C-terminus of each form is shown. The positions of the splice junctions are indicated by bold type and underlining using the exon numbering of the human LIFR gene (Tomida and Gotoh, 1996). The C-terminal cysteine residues (C) are boxed. (Full colour figure can be viewed online.)
Promoter regions involved STAT-recognition sites, including the types I and II IL-6 response elements (IL-6RE), have been identified in a variety of genes induced by IL-6. Subsequently, genes activated by OSM have also
been shown to contain these recognition sites (Kordula et al., 1998). In addition, OSM-responsive elements have been detected in other genes induced by OSM, including tissue inhibitor of matrix metalloproteinase 1 (TIMP-1) and matrix metalloproteinase 1 (MMP1) (Korzus et al., 1997).
1804 Timothy M. Rose and A. Gregory Bruce Figure 5 Comparison of the alternately spliced isoforms of LIFR . (a) The hydrophobic signal peptide (SP) sequence and transmembrane (TM) domain are blue. In the extracellular (EC) domain, the hematopoietin domains with conserved cysteine residues and WSXWS motifs are shown. The fibronectin (FN) type III repeats are colored green. The C-terminal alternately spliced domains are indicated with striped boxes and the presence of a new cysteine residue in these domains is indicated with a C. The intracellular (IC) domain of the membrane form is shown. (b) The exon origins of the alternately spliced mRNAs are shown for the extracellular membrane-form (ECM) and the three putative soluble isoforms (IF-1, IF-2, and IF-3). The exon numbering is derived from that of the human LIFR (Tomida and Gotoh, 1996). The amino acids which are not capitalized are derived from the adjacent intron. (c) The encoded amino acid sequence for the C-terminus of each form is shown. The positions of the splice junctions are indicated by bold type and underlining. The C-terminal cysteine residue (C) is boxed.
OSM Receptor 1805 Table 2 OSMR (gp130), OSMR , and LIFR protein sequences Accession
Species
Source
Type
Size (amino acids)
Reference
106982
Human
Placenta
Complete
918
Hibi et al., 1990
1246098
Human
Embryo
Alternate splice soluble IF-1a, partial
49
Sharkey et al., 1995
2253598
Human
Blood cells
Alternate splice soluble IF-2a, partial
47
Diamant et al., 1997
3660079
Human
Binding domain A, partial
214
Bravo et al., 1998
3660080
Human
Binding domain B, partial
215
Bravo et al., 1998
2137360
Mouse
Macrophage
Complete
917
Saito et al., 1992
729835
Rat
Liver
Complete
918
Wang et al., 1992
1794211
Human
Placenta/bone marrow/fibroblast
Complete (composite)
979
Mosley et al., 1998
3721860
Mouse
Complete
970
Unpublished
3153816
Mouse
Muscle
Complete
971
Lindbergh et al., 1998
1170784
Human
Placenta
Complete
1097
Gearing et al., 1991
258656
Human
Complete
1078
Gearing et al., 1992b
OSMR (gp130)
OSMR
LIFR
a
IF=isoform designation used within this chapter.
Figure 6 Comparison of the membrane-bound forms of the different OSM receptor subunits. The membranespanning domains are colored blue and the relative positions of the receptors with respect to the cellular membrane are indicated. The hematopoietin domains with conserved cysteine residues and the WSXWS motifs are shown. The fibronectin type III repeats (FN) are colored green. (Full colour figure can be viewed online.)
Table 3 Protein properties of OSM receptor subunits OSMR (gp130)
OSMR
Memb. Human
Soluble Mouse
Memb.
Human IF1
LIFR
Mouse
Human
Mouse
Memb.
Soluble
Human
Human
IF2
IF1
IF2
IF3
Number of amino acids Precursor
918
917
658
646
979
970
1097
692
780
847
Signal peptide domain
22
22
22
22
23
23
44
44
44
44
Mature protein
896
895
636
624
956
947
1053
648
736
803
Extracellular domain
597
595
716
712
789
Transmembrane domain
22
22
22
21
25
Cytoplasmic domain
277
278
218
214
221
N-Glycosylation sites
14
12
20
21
20
17
19
20
11
10
Memb., membrane-bound form; IF=isoform designation for this chapter.
Table 4
Low-affinity (direct) receptor subunit±ligand binding OSM
LIF
Human
Murine
Human
Murine
Yesa,b Yesf
Noc Yesc,g
Yesd, Noe ND
ND Nog
Noe Noc
ND Yesc
Noe ND
ND ND
Noe Noh
ND Nog
Yese Yesd,h
ND Yesi
OSMR (gp130) Human Murine OSMR Human Murine LIFR Human Murine a
Modrell et al., 1994; bGearing et al., 1992b; cLindberg et al., 1998; dZhang et al., 1997; eMosley et al., 1996; Liu et al., 1994; gIchihara et al., 1997; hGearing et al., 1992a; iGearing and Bruce, 1992; ND, no data.
f
Table 5 High-affinity receptor complex±ligand binding OSM Human
LIF Murine
Human
Murine
OSMR (gp130)/LIFR Human Murine
Yes Yes
a b,c,d
No No
b b,e
Yes Yes
a
No No
a,c
b,c
ND Yes b,e
OSMR (gp130)/OSMR Human Murine a
Yes a,c,d No b
ND Yes b,e
b
ND No b,e
Mosley et al., 1996; bLindberg et al., 1998; Gearing et al., 1992a; dBruce et al., 1992a; eIchihara et al., 1997; ND, no data.
OSM Receptor 1807 Table 6 Expression profile of the different OSM receptor subunits Tissue type
Cell line
Relative mRNA expression level OSMR (gp130)
OSMR
LIFR
Bone marrow
0
0
0
Brain (fetal)
25
5
68
Monocyte
15
0
0
Muscle (smooth)
224
129
57
Peripheral blood T cells
61
0
0
Placenta
124
107
142
Primary cells
Skin
44
46
84
Tonsil B cells
0
0
0
Tonsil T cells
92
0
0
0
0
0
Pre-B cell lines
JM-1 Nalm 6
0
0
0
B cell lines
CESS
4
1
0
Raji
2
0
0
Umbilical vein
HUVE
53
17
39
Uterine, mesodermal tumor
SK-UT-1
14
25
0
Cervical carcinoma
HeLa
91
52
38
Epidermal carcinoma
KB
81
43
93
Foreskin
HFF
114
94
41
Lung, adult
LL97A
116
116
79
Lung, embryonic
WI26 VA4
32
36
7
HepG2
21
47
18
Hep3B
15
0
0
SK Hep
30
36
17
HL-60
39
0
0
THP-1
37
6
2
U937
5
0
0
Astrocytoma
CCF STT G1
49
28
41
Glioblastoma
A172
52
82
83
Medulloblastoma
Daoy
29
30
26
Neuroblastoma
SK-N-SH
25
72
67
T cell lines
clone 22
8
0
0
Jurkat
8
1
0
Endothelial cell lines
Epithelial cell lines
Fibroblast cell lines
Liver Hepatocarcinoma
Monocytic cell lines Acute monocytic leukemia
Neural cell lines
1808 Timothy M. Rose and A. Gregory Bruce Table 6 (Continued ) Tissue type
Cell line
Relative mRNA expression level OSMR (gp130)
OSMR
LIFR
Other Bone marrow stromal
IMTLH
42
42
7
Leiosarcoma
SK-LMS
70
23
5
Megakaryocyte
Mo7E
8
0
0
Melanoma, malignant
A375
59
47
73
Pancreatic tumor
HPT
35
29
8
Placental choriocarcinoma
JAR
22
0
26
Promonocyte
TF-1
7
0
0
Rhabdomyosarcoma
A673
17
22
38
Modified with data from Mosley et al. (1996).
Table 7 Gene expression induced by activation of the OSM receptors Affected gene
Cell type
Species
Reference
1-Antichymotrypsin
HepG2 cells
Human
Richards et al., 1992
1-Antichymotrypsin
Astrocytes
Human
Kordula et al., 1998
1-Proteinase inhibitor
Epithelial
Human
Sallenave et al., 1997
Basic fibroblast growth factor
Endothelial
Bovine
Wijelath et al., 1997
EGR-1, c-jun, c-myc
Fibroblasts
Human
Liu et al., 1992a
Haptoglobin
HepG2 cells
Human
Richards et al., 1992
IL-6
Endothelial
Human
Brown et al., 1991
Matrix metalloproteinase 1
Fibroblasts
Human
Korzus et al., 1997
P21 kinase inhibitor
Osteoblasts
Human
Bellido et al., 1998
P-Selectin
Endothelial
Human
Yao et al., 1996
TIMP-1 (tissue inhibitor of metalloproteinase 1)
Cartilage
Human
Nemoto et al., 1996
TIMP-1
Synovial
Human
Gatsios et al., 1996
TIMP-1
Fibroblasts
Mouse
Richards et al., 1997
TIMP-1
Fibroblasts
Human
Korzus et al., 1997
Urokinase-type plasminogen activator
Fibroblasts
Human
Hamilton et al., 1991
BIOLOGICAL CONSEQUENCES OF ACTIVATING OR INHIBITING RECEPTOR AND PATHOPHYSIOLOGY
Unique biological effects of activating the receptors Although most of the biological effects of activating the OSM receptors are similar to other receptor
complexes with shared receptor subunits, some effects appear to be specific to the OSM-specific receptors. OSM-specific receptor appears specifically to inhibit the growth of normal and malignant mammary epithelial cells (Liu et al., 1998), stimulate expression of the tissue inhibitor of metalloproteinase 1 (TIMP-1) (Richards et al., 1997), and induce the synthesis of 1-antichymotrypsin and 1-antiproteinase inhibitor (Cichy et al., 1998; Kordula et al., 1998).
OSM Receptor 1809
Phenotypes of receptor knockouts and receptor overexpression mice Both receptor knockouts and receptor overexpression in mice have been used to study the biological effects of OSMR (gp130). Because of the ubiquitous use of OSMR (gp130) as a signaling subunit in the receptor complexes for the entire IL-6 family of cytokines, the elimination of this gene has dire consequences in embryonic development, including hematological disorders, hypoplasia of the myocardium, structural and function defects in the placenta and reduction of bone mass (Yoshida et al., 1996; reviewed in Nakashima and Taga, 1998). Inducible inactivation of OSMR (gp130) postnatally results in neurological, cardiac, hematopoietic, immunological, hepatic, and pulmonary defects in mice (Betz et al., 1998). Mice expressing a dominant-negative form of OSMR (gp130) with a truncated signaling domain demonstrated the necessity for OSMR (gp130) in antigen-specific antibody production (Kumanogoh et al., 1997). Targeted disruption of the LIFR in mice causes placental, skeletal, neural, and metabolic defects and results in perinatal death (Ware et al., 1995; Koblar et al., 1998). Since OSM utilizes receptor complexes containing LIFR in humans, but not in mice, generalizing the murine knockout studies to the functions of OSM-induced LIFR signaling through the LIF/OSM shared receptor in humans should be done with some caution. The biological effects of OSMR knockouts or overexpressors are not yet known.
THERAPEUTIC UTILITY
Effect of treatment with soluble receptor domain Although soluble forms of OSMR (gp130) and LIFR act as antagonists of members of the IL-6 family of cytokines in vitro (Layton et al., 1992; Yamaguchi-Yamamoto et al., 1993; Montero-Julian et al., 1997), their function in vivo is unknown.
Effects of inhibitors (antibodies) to receptors Monoclonal antibodies to OSMR (gp130) have been derived that specifically inhibit the growth of
OSM-dependent cell lines (Liu et al., 1992b; Taga et al., 1992; Gu et al., 1996). Although monoclonal antibodies to LIFR have been derived that specifically block the biological activity of LIF (Pitard et al., 1997), it is unknown whether they also block the activity of OSM binding to the LIF/ OSM shared receptor in humans. Mutants of LIF have been derived which antagonize OSM signaling through the LIF/OSM shared receptor (Vernallis et al., 1997).
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