IL-1 Receptor Type II

IL-1 Receptor Type II Charles A. Dinarello* Department of Infectious Diseases, University of Colorado Health Sciences Center, 4200 East Ninth Avenue, B168, Denver, CO 80262, USA * corresponding author tel: 303-315-3589, fax: 303-315-8054, e-mail: [email protected] DOI: 10.1006/rwcy.2000.15003.

SUMMARY

Structure

The extracellular domains of type II IL-1R are structurally related to those of the type I IL-1R; however, the type II IL-1R is a decoy receptor in that the primary ligand, IL-1 , preferentially binds to this receptor rather than the signaling receptor. As such, in the presence of increasing expression of the type II receptor on the cell surface, less IL-1 signaling takes place. This is because the type II IL-1R lacks a cytoplasmic domain capable of cell signal transduction. The type II IL-1R also exists in a shed form as a soluble receptor. The soluble receptor has a high affinity to bind IL-1 over that of IL-1 or IL-1Ra. The soluble IL-1R type II is ideally suited for clinical use because it has a high affinity for IL-1 and a low affinity for IL-1Ra.

The extracellular domains of the IL-1RII are typical of an Ig-like receptor in the fibroblast growth factor family. The glycoprotein has three Ig-like domains in the extracellular segment, a transmembrane domain, and a short cytoplasmic domain (McMahon et al., 1991).

BACKGROUND

GENE

Discovery

Accession numbers

The discovery of the IL-1 receptor type II (IL-1RII) was made by in 1991 (McMahon et al., 1991). Others also contributed to the discovery of this receptor (Symons et al., 1991, 1993). The ability of IL-1 to preferentially bind to B cells is also probably the binding to the type II receptor (Scapigliati et al., 1989; Ghiara et al., 1991).

The gene for the IL-1RII has been reported (Sims et al., 1995).

Alternative names Another name for the IL-1RII is the IL-1 `decoy' receptor (Colotta et al., 1993, 1994).

Main activities and pathophysiological roles When IL-1 binds to the cell membrane, IL-1RII does not signal. A soluble form of this receptor has been described to act to reduce the biological effects of IL-1 (Dower et al., 1994).

PROTEIN

Description of protein IL-1RII has three Ig-like domains in the extracellular segment, a transmembrane domain, and a short cytoplasmic domain (McMahon et al., 1991). The transmembrane segment is linked to a short cytoplasmic domain. In the rat, this cytoplasmic domain

1612 Charles A. Dinarello is longer (Bristulf et al., 1994) but still does not signal. In the human and mouse, IL-1RII has a short cytosolic domain consisting of 29 amino acids; in the rat, there are an additional six charged amino acids (Bristulf et al., 1994).

Relevant homologies and species differences There is considerable homology between the IL-1 receptor type I and IL-1RII in all species. Limited homology between the IL-18-binding protein (Novick et al., 1999) and the IL-1RII exists. Vaccinia and cowpox virus genes encode for a protein with a high amino acid homology to the type II receptor and this protein binds IL-1 (Alcami and Smith, 1992; Spriggs et al., 1992). These viruses also code for IL-18-binding protein-like molecules.

Affinity for ligand(s) The cell-bound IL-1RII does not appear to form a complex with the IL-1R type I receptor (Slack et al., 1993; Dower et al., 1994) nor does it transduce a signal (Sims et al., 1993, 1994). The rank for the three IL-1 ligands (IL-1, IL-1 , and IL-1Ra) binding to IL-1RII is IL-1 > IL-1 > IL-1Ra (Arend et al., 1994; Dower et al., 1994; Sims et al., 1994). In some cells, there is a discrepancy between the dissociation constant of either form of IL-1 (usually 200±300 pM) and concentrations of IL-1 which can elicit a biological response (10±100 fM). In cells expressing large amounts of IL-1R AcP, the high-affinity binding of the IL-1R/IL-1R AcP complex may explain why two classes of binding have been observed. Human recombinant 17 kDa IL-1 binds to cell surface and soluble type I receptors with approximately the same affinity (200±300 pM); however, binding to surface and soluble type II receptors is nearly 100-fold less (30 and 10 nM, respectively). Of the three members of the IL-1 family, IL-1 has the lowest affinity for the cell-bound form of IL-1RI (500 pM±1 nM). By comparison, IL-1 binds more avidly to the nonsignal transducing type II receptor (100 pM). IL-1 binding to the soluble form of the IL-1RI is lower than that to the cell-bound receptor. However, the most dramatic differences in IL-1 binding can be seen at the level of the soluble form of the type II receptor. Of the three ligands, the most avid binding is that of mature IL-1 (500 pM). IL-1 binding to the soluble IL-1RII is nearly irreversible due to a long dissociation rate (2 hours) (Arend et al.,

1994; Dower et al., 1994; Symons et al., 1994). Moreover, precursor IL-1 also preferentially binds to the soluble form of IL-1RII (Symons et al., 1991, 1993).

Cell types and tissues expressing the receptor The primary cells expressing the IL-1RII are monocytes, macrophages, neutrophils, B lymphocytes, myelomonocytic leukemia cells, and hairy cell leukemic cells.

Regulation of receptor expression Increased surface expression of IL-1RII reduces the biological response to IL-1 (Colotta et al., 1993, 1994). Gene expression of the IL-1RII is under the control of two promoters, each of which controls the usage of a divided first exon (exon 1A or 1B) (Vannier et al., 1995). Early studies using B cells, monocytes, or bone marrow cells (type II receptor-bearing cells) demonstrated that hematopoietic growth factors, dexamethasone, and PGE2 increase the number of IL-1-binding sites. Surface expression of IL-1RII is upregulated on neutrophils exposed to dexamethasone and IL-4 (Colotta et al., 1993) and on monocytes or B cell lines exposed to dexamethasone (Dower et al., 1994). These observations have been confirmed using gene expression in different cell lines (Vannier et al., 1995). A transcription factor called PU.1, which is present in cells of hematopoietic origin, is required for expression of IL-1RII. In patients with bacterial sepsis, elevated IL-1RII expression has been observed on neutrophils (Fasano et al., 1991). Although IL-1 itself downregulates gene and surface expression of IL-1RI, IL-1 upregulates gene and surface expression of the IL-1RII on an insulinoma cell line (Bristulf et al., 1994).

Release of soluble receptors Unlike soluble TNF receptors, it is unknown whether the soluble form of IL-1RII acts as a carrier for IL-1 and prolongs its half-life in the circulation. It is likely that as cell-bound IL-1RII increases, there is a comparable increase in soluble forms (Giri et al., 1990). Similar to soluble receptors for TNF, the extracellular domains of the type II IL-1R are found as `soluble' molecules in the circulation and urine of healthy

IL-1 Receptor Type II 1613 subjects and in inflammatory synovial and other pathologic body fluids (Symons et al., 1993, 1994; Arend et al., 1994; Sims et al., 1994; Barak et al., 1996). In healthy humans, the circulating concentrations of the soluble IL-1RII are 100±200 pM. Elevated levels of the soluble IL-1RII are found in the circulation of patients with sepsis (Giri et al., 1994) and in the synovial fluid of patients with active rheumatoid arthritis (Arend et al., 1994) and in patients with hairy cell leukemia (Barak et al., 1996). In patients undergoing aorta resection, crossclamping of the aorta results in significant ischemia and a dramatic release of soluble IL-1RII (Pruitt et al., 1996). High-dose IL-2 therapy induces soluble IL1RII (Orencole et al., 1995). LPS causes rapid shedding of the IL-1 type II. This effect of LPS is reduced by inhibition of metalloprotease. Following LPS, monocytes exhibited a reduction in steady-state mRNA levels (Penton-Rol et al., 1999). Chemoattractants also cause a rapid release of the extracellular domain of the IL-1RII from myelomonocytic cells within a few minutes following exposure (Mantovani et al., 1998). This induction of release of the decoy receptor suggests an early event in inflammation to limit the cascade. Inhibitors of matrix metalloproteases such as hydroxamic acid inhibit the release of the extracellular domain of IL-1RII (Orlando et al., 1997). These protease inhibitors also reduced the slow release of soluble IL-1RII from monocytes and neutrophils and from cells stimulated with dexamethasone, TNF, chemoattractants, or phorbol myristate acetate (PMA). Inhibitors of other protease classes did not affect release. Inhibitors of serine proteases increased the molecular size of the released form of IL-1RII from 45 to 60 kDa (Orlando et al., 1997).

SIGNAL TRANSDUCTION

Associated or intrinsic kinases Because the IL-1RII has no significant cytoplasmic domain, there are no kinases intrinsic to the receptor. See reveiw of Martin and Falk (1997).

Cytoplasmic signaling cascades The IL-1RII does not signal and serves only to bind IL-1 (preferentially IL-1 ) and prevent signaling by IL-1 binding to the type I receptor (Colotta et al., 1994).

BIOLOGICAL CONSEQUENCES OF ACTIVATING OR INHIBITING RECEPTOR AND PATHOPHYSIOLOGY

Unique biological effects of activating the receptors The type II receptor appears to act as `decoy' molecule, particularly for IL-1 . The receptor binds IL-1 tightly, thus preventing binding to the signaltransducing type I receptor (Colotta et al., 1993). It is the lack of a signal-transducing cytosolic domain that makes the type II receptor a functionally negative receptor. For example, when the extracellular portion of the type II receptor is fused to the cytoplasmic domain of the type I receptor, a biological signal occurs (Heguy et al., 1993). The extracellular portion of the type II receptor is found in body fluids, where it is termed IL-1 soluble receptor type II. A proteolytic cleavage of the extracellular domain of the IL-1RII from the cell surface is the source of the soluble receptor.

Phenotypes of receptor knockouts and receptor overexpression mice Constructs encoding IL-1RII were transfected into U937 cells. Gene transfer resulted in receptor numbers (approximately 103/cell) of the same order of magnitude as that found in normal myelomonocytic cells. Transfer of IL-1RII reduced responsiveness to IL-1 (Penton-Rol et al., 1997). Mice overexpressing IL-1RII or deficient in IL-1RII are not reported to date.

THERAPEUTIC UTILITY

Effect of treatment with soluble receptor domain Because soluble IL-1RII binds IL-1 so avidly, a considerable therapeutic use is likely.

Effects of inhibitors (antibodies) to receptors In general, antibodies to IL-1RI block IL-1-mediated activities in vitro and in vivo, whereas antibodies

1614 Charles A. Dinarello specific for the IL-1RII have no effect. An antibody (ALVA 42) which recognizes  and subunits of HLA-DR (Gayle et al., 1994) also binds to cells expressing type II receptors (Ghiara et al., 1991). The ability of this antibody to inhibit IL-1-mediated effects in vivo may be due to inhibition of IL-1induced production of IL-1. For example, anti-HLADR monoclonal antibodies stimulate the production of IL-1 by macrophages and enhance (or suppress) IL-1 induced by either superantigens or LPS.

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