Soluble cytokine receptors regulate inflammatory and immune events by functioning as agonists or antagonists of cytokine signaling. As such, they act within complex receptor systems that include signaling receptors, nonsignaling decoy receptors, receptor-associated proteins, and soluble receptor antagonists. Soluble cytokine receptors can be generated by several mechanisms, which include proteolytic cleavage of receptor ectodomains, alternative splicing of mRNA transcripts, transcription of distinct genes that encode soluble cytokine-binding proteins, release of full-length receptors within the context of exosome-like vesicles, and cleavage of GPI-anchored receptors. Furthermore, the important role of soluble cytokine receptors in regulating host defense mechanisms is evidenced by viruses that encode soluble homologues of mammalian receptors and thereby evade innate host immune responses via the sequestration of essential cytokines.

Soluble cytokine receptors, which either attenuate or promote cytokine signaling, are important regulators of inflammation and immunity. The key role that soluble cytokine receptors play in preventing excessive inflammatory responses is illustrated by the autosomal dominant, autoinflammatory, TNF receptor-associated periodic syndrome (TRAPS), which was initially identified in patients with mutations in the extracellular domain of the 55-kDa, type I TNFR (TNFRSF1A, TNFR1) that impaired receptor shedding (1). Additional pathophysiologic mechanisms may also exist, as not all TRAPS-related TNFRSF1A mutations are associated with defective receptor shedding. Patients manifest recurrent episodes of fever, myalgia, rash, abdominal pain, and conjunctivitis that may be attenuated by anti-TNF therapy with a recombinant soluble human TNFR2-Ig fusion protein (1). Similarly, administration of a recombinant soluble human TNFR2-Ig fusion protein has been used to modify TNF biological activity and disease severity in patients with inflammatory arthritides and psoriasis (2). Furthermore, the role of soluble cytokine receptors in modulating immune events is exemplified by the soluble IL-2Rα (IL2Rα, CD25, Tac), which has been used as a biomarker of T cell activation and tumor burden in IL-2Rα-expressing lymphoid neoplasms (3, 4).

The IL-1 and IL-6 receptor systems are paradigms for soluble cytokine receptors that mediate antagonistic and agonistic effects. Both systems are complex and are regulated by multiple cell-associated and soluble receptors, as well as receptor-associated proteins.

Multiple endogenous regulatory mechanisms exist to prevent excessive, proinflammatory IL-1 signaling. The functional IL-1R is a complex comprising the type I IL-1R (IL-1RI), the IL-1R accessory protein (IL-1RAcP),2 and IL-1α or IL-1β (5). In contrast, the 60-kDa type II IL-1R (IL-1RII) is a nonsignaling decoy receptor, because its short 29-aa cytoplasmic domain lacks a Toll-IL-1R domain (6, 7). IL-1RII can also form a nonsignaling trimeric complex with IL-1 and IL-1RAcP, which sequesters essential components of the IL-1RI signaling complex (8, 9). Soluble type II IL-1 receptors (sIL-1RII), which are generated primarily by proteolytic cleavage in response to a variety of stimuli (10), can attenuate excessive IL-1 bioactivity by preferentially binding IL-1β (11). Furthermore, the ability of sIL-1RII to bind IL-1α and IL-1β and inhibit IL-1 signaling is enhanced ∼100-fold by soluble IL-1RAcP, which is generated by alternative splicing rather than by ectodomain cleavage (12). In addition, sIL-1RII can bind to and inhibit the processing of pro-IL-1β precursor to its mature form by the IL-1-converting enzyme (caspase-1) (13). Thus, multiple regulatory mechanisms, including the generation of sIL-1RII and sIL-1RAcP, exist by which excessive IL-1 signaling can be attenuated.

In contrast to the antagonistic effect of sIL-1RII on IL-1 signaling, soluble IL-6 receptors (sIL-6Rα) are an important mechanism by which IL-6 signaling is amplified. Soluble IL-6 receptors can be generated by two distinct pathways: proteolytic cleavage that sheds the membrane-bound IL-6R ectodomain or alternative mRNA splicing, with resulting synthesis of an IL-6Rα that lacks the transmembrane domain (14, 15). Soluble IL-6 receptors bind IL-6 with an affinity similar to the membrane IL-6R, thereby prolonging the IL-6 half-life (16). Furthermore, binding of the sIL-6Rα/IL-6 complex to the ubiquitously expressed membrane-bound gp130 confers IL-6 signaling capability to cells that do not express IL-6Rα via a process termed “trans-signaling” (17). Trans-signaling via sIL-6Rα/IL-6 complexes regulates the expression of CXC and CC chemokines and terminates neutrophil recruitment in the setting of bacterial infection (18). Furthermore, gp130-linked IL-6/sIL-6Rα trans-signaling enhances lymphocyte trafficking during febrile inflammatory responses via activation of L-selectin-mediated adhesion (19). Importantly, the trans-signaling function of the sIL-6Rα-IL-6 complex can be abrogated by the soluble form of gp130 (sgp130), which competes with membrane gp130 for binding of the sIL-6R-IL-6 complex (20).

Proteolytic cleavage of cell surface receptors is typically catalyzed by zinc metalloproteases of the ADAM (a disintegrin and metalloprotease) family. ADAMs are a large family of type I transmembrane proteins, with at least 34 named mammalian genes that contain multiple domains, including a prodomain (that maintains the enzyme in an inactive state via a cysteine-switch mechanism), a zinc-dependent catalytic domain, a disintegrin-cysteine-rich domain, an epidermal growth factor-like repeat, a transmembrane domain, and an intracytoplasmic tail (21, 22, 23). ADAM17 or TNF-α-converting enzyme (TACE) is the prototypical receptor sheddase that was identified via its ability to cleave membrane-bound TNF to its soluble form (24, 25). Furthermore, TACE is a key regulator of normal embryonic development, as mice expressing a catalytically inactive TACE cannot generate soluble TGF-α, with resultant defects in epithelial cell maturation and organization (26).

TACE has been implicated in the ectodomain cleavage and shedding of cytokine receptors belonging to several distinct cytokine receptor superfamilies, including the TNFR family (75-kDa, type II TNFR (TNFRSF1B, TNFR2) (26), TNFR1 (27), CD30 (TNFRSF8) (28), and CD40 (TNFRSF5) (29); the IL-1/TLR family (IL-1RII (27)); the type I cytokine receptor family (IL-6R α-chain (30)); and the IL-15R α-chain (31). TACE has also been reported to mediate the constitutive and inducible cleavage of the stem cell factor receptor (c-kit, CD117) (32) and the macrophage CSF receptor (33), as well as the cleavage of receptors that regulate growth, differentiation, and survival, such as the epidermal growth factor receptor family (erbB4/HER4) (34), the neurotrophin receptor family (p75 neurotrophin receptor) (35), and the growth hormone receptor (36). Furthermore, TACE may modulate innate immune responses by regulating the ectodomain cleavage of adhesion molecules, such as L-selectin (26), VCAM-1(37), and CX3CL1 (fractalkine) (38, 39), which is an adhesion molecule in its membrane-bound form, whereas the soluble form mediates chemotactic activity via binding to its receptor, CX3CR1. Although TACE is responsible for the inducible cleavage of CX3CL1, constitutive shedding is mediated by ADAM10 (40). TACE has also been implicated in the processing of membrane-bound TNFSF11 (TNF-related activation-induced cytokine, osteoclast differentiation factor, RANK ligand, osteoprotegrin ligand), another TNF family member, to its soluble form (41).

TACE activity may be regulated at several levels. First, the TACE prodomain maintains the zinc metalloprotease catalytic domain in an inactive state via a cysteine-switch mechanism. Reactive oxygen species and NO, which may be generated during inflammatory responses, may activate TACE via modification of the cysteine thiol group in the cysteine-switch domain (42, 43). Second, endogenous signaling via G protein-coupled receptors, such as the protease-activated receptor 1, can induce the TACE-mediated cleavage of the heparin-binding epidermal growth factor with resultant transactivation of the epidermal growth factor receptor (23, 44, 45). Third, TACE catalytic activity may be regulated via protein-protein interactions with the TACE intracytoplasmic domain. The mitogen-activated protein kinase ERK, in response to phorbol ester stimulation, phosphorylates threonine 735 of the TACE intracytoplasmic tail, whereas serine 819 undergoes growth hormone-induced phosphorylation, which may regulate proteolytic activity (46, 47). The protein tyrosine phosphatase PTPH1 may negatively regulate TACE activity through an interaction between its PDZ domain and the carboxyl terminus of TACE (48). The mitotic arrest-deficient 2 protein and the scaffolding protein synapse-associated protein 97 have also been identified as potentially regulating TACE activity via binding to the TACE intracytoplasmic domain (49, 50). Fourth, TACE undergoes stimulation-dependent internalization, which may down-regulate catalytic activity at the plasma membrane (51). Furthermore, the induction of TACE-mediated shedding in response to PMA stimulation reflects increased enzymatic activity that is independent of the intracytoplasmic domain and is not associated with an increase in cell surface TACE levels (27, 52). Fifth, membrane lipid composition may regulate TACE activity (23). Cholesterol depletion enhances TACE- and ADAM10-catalyzed IL-6Rα shedding and TACE-catalyzed CD30 shedding through a mechanism which may involve dissolution of lipid rafts, since TACE is localized to non-raft fractions, while CD30 is partially localized to lipid raft microdomains (53, 54). Lastly, the mechanisms underlying substrate recognition by TACE are complex and remain incompletely defined, as multiple substrates with variable cleavage sites may be cleaved by TACE (21). Determinants of substrate specificity may include the substrate cleavage site and juxtamembrane stalk sequences, as well as the structures of the TACE catalytic and disintegrin/cysteine-rich domains (27, 30, 55).

Important functions have been identified for other ADAM family members in the proteolytic cleavage and shedding of cell surface receptors and ligands. ADAM8 can physically associate with and catalyze the proteolytic cleavage of CD23 (the low-affinity IgE receptor), whereas ADAM15 and ADAM28 (MDC-L) have also been implicated in CD23 shedding (56). Soluble CD23 ectodomains may then up-regulate IgE production and generate proinflammatory cytokines (56). ADAM10 catalyzes the constitutive and inducible shedding of IL-6Rα (54), as well as that of the constitutive shedding of CXCL16, epidermal growth factor, and β-cellulin (57, 58, 59). Furthermore, ADAM10 and TACE have been reported to catalyze the proteolytic cleavage of CD44, the cell surface receptor for hyaluronan, which may contribute to tumor cell migration and invasion (60, 61).

Matrix metalloproteinases (MMP) may also possess receptor sheddase activity. MMP-12 (macrophage metalloelastase) has been implicated as a sheddase for the amino-terminal domain (D1) of the urokinase-type plasminogen receptor (62). Membrane-type 1(MT)-MMP has been implicated in CD44 cleavage, releasing it into the medium as a soluble 70-kDa fragment (63), while MT1-MMP and MT3-MMP have been implicated in the proteolytic cleavage and shedding of the type III TGF-βR (TβR-III) betaglycan (64).

Another major mechanism for the generation of soluble cytokine receptor ectodomains is the synthesis of receptors that contain signal peptides and lack transmembrane domains and are therefore secreted, rather than membrane-associated proteins. Soluble cytokine receptors can be generated in this fashion via two distinct pathways. The first involves the alternative splicing of mRNA transcripts that usually encode membrane-associated receptors, examples of which include members of the following cytokine receptor superfamilies: class I cytokine receptor superfamily (IL-4Rα, IL-5Rα, IL-6Rα, IL-7Rα, IL-9Rα, EpoR, G-CSFR, GM-CSFRα, gp130, and LIFRα) (65, 66, 67, 68, 69, 70, 71, 72, 73, 74), class II cytokine receptor superfamily (type I IFNR (IFNAR1 and IFNAR2α)) (75), IL-1/TLR family (IL-1RII, IL-1RAcP) (76, 77), TGF-β receptor family (TβR-I, activin receptor-like kinase 7) (78, 79), TNFR superfamily (TNFRSF6/Fas/CD95, TNFRSF9/4-1BB/CD137) (80, 81), and the IL-17R (82).

The second pathway is via the transcription of distinct genes that share homology with cytokine receptors and therefore encode soluble cytokine-binding proteins. Signaling through the TNFR and class II cytokine receptor superfamilies can be regulated in this fashion. Decoy receptor 3 (DcR3, TNFRSF6B, TR6, M68) is a secreted member of the TNFR superfamily that contains a signal peptide and four tandem cysteine-rich domains, but lacks a transmembrane domain. DcR3 can bind to Fas ligand (L) (TNFSF6) (83), LIGHT (TNFSF14) (84), and TL1A (endothelial cell-derived TNF-like factor) (85), thereby inhibiting apoptosis by preventing ligand association with Fas, lymphotoxin β receptor (TNFRSF3), and death receptor 3 (86). Biological processes that are modulated by DcR3 include angiogenesis (87), heart allograft rejection (88), autoimmune-mediated islet cell destruction (86), tumor cell evasion of FasL-dependent immune-cytotoxic attack (83), and T cell costimulation (85) and chemotaxis (89). Osteoprotegerin (TNFRSF11B), another TNFR superfamily member, is also generated as a secreted, soluble protein that binds TNFSF11 and inhibits osteoclast differentiation (90). IL-22RA2 (IL-22Rα 2), a member of the human class II cytokine receptor family, lacks a transmembrane domain and functions as a naturally occurring soluble cytokine binding protein that antagonizes IL-22, an IL-10 homologue (91, 92, 93). IL-18-binding protein, which shares limited homology with IL-1RII, is another soluble cytokine-binding protein that lacks a transmembrane domain and functions as an IL-18 inhibitor (94).

Exosomes are small membrane-enclosed vesicles that correspond to the internal vesicles of multivesicular bodies and are released from cells via exocytic fusion with the plasma membrane (95). It was recently reported that full-length TNFR1 can be constitutively released from human vascular endothelial cells into the extracellular milieu as a constituent of exosome-like vesicles of 20–50 nm in diameter (96). The HUVEC-derived TNFR1 exosome-like vesicles do not appear to possess intrinsic signaling capabilities based upon the presence of silencer of death domains and the absence of an active TNFR1 signaling complex I (TNFR-associated death domain protein, receptor-interacting protein, and TNFR-associated factor 2). Similarly, membrane-associated FasL can be released from melanoma cells in microvesicles, which range in size from 100 to 200 nm, with resultant proapoptotic affects on Fas-sensitive lymphoid cells and consequent impaired antitumor responses (e.g., Fas tumor counterattack) (97). Thus, the release of full-length cytokine receptors within the context of exosome-like vesicles may represent an alternative mechanism for the generation of extracellular receptors.

Cleavage of ectodomains from GPI-linked receptors may represent an additional mechanism for the generation of soluble cytokine receptors. This may be applicable to the ciliary neurotrophic factor receptor α (CNTFRα), which is anchored to cell membranes by a GPI-linkage and released by phosphatidylinositol-specific phospholipase C (98). This represents a unique mechanism, as CNTFRα may be the only growth factor or cytokine receptor that is anchored to cell membranes by a GPI-linkage. Similar to IL-6 trans-signaling, sCNTRα may allow CNTF to act on cells that are not normally responsive to CNTF (99).

The utility of soluble cytokine receptors as highly effective modulators of innate immune responses has been exploited by viruses which synthesize soluble homologues of mammalian cytokine receptors as a mechanism to evade host defenses. This is consistent with the important role of soluble cytokine receptors in modulating the activity of proinflammatory cytokines. Poxviruses, such as cowpox, variola, myxoma, and Shope fibroma viruses, encode homologues of the TNFR superfamily (100). The first viral TNFR to be identified was the T2 protein of the Shope fibroma virus, which is structurally similar to TNFR2, but lacks a transmembrane domain and is secreted from virally infected cells to function as a TNF-binding protein (101); a similar T2 protein is encoded by the myxoma virus (102). Four additional poxvirus TNFR homologues, the cytokine response modifying (Crm) proteins, which display different ligand specificities, have been identified, with CrmB and CrmD binding both TNF and lymphotoxin α, whereas CrmC and CrmE bind only TNF (103, 104, 105, 106). The poxviruses, cowpox and ectromelia (mousepox), also encode a soluble, secreted homologue of CD30, which can bind CD30L with high affinity, preventing its receptor binding and thereby inhibiting Th2-mediated inflammation in vivo (107, 108). Soluble viral homologues of the type 1 IFN receptor (109, 110), the IFN-γ receptor (111), IL-1RII (112, 113), and IL-18 binding protein (94) have also been identified.

Goals of future investigations will be to determine further the mechanisms that operate and regulate the shedding processes, as well as the specific interactions between receptor sheddases and target receptor ectodomains. Molecular interactions that initiate, mediate, and terminate the release of soluble cytokine receptors need to be clarified further, as do the roles of regulatory and adaptor proteins that participate in soluble cytokine receptor generation. Furthermore, the biological functions of soluble cytokine receptors in regulating key inflammatory and immune responses need to be elucidated. These studies should provide new insights into disease pathogenesis and generate novel therapeutic approaches.

I thank Drs. Martha Vaughan and Joel Moss for their critical review of this manuscript.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

2

Abbreviations used in this paper: IL-1RAcP, IL-1R accessory protein; s, soluble; TACE, TNF-α-converting enzyme; MMP, matrix metalloprotease; DcR3, decoy receptor 3; L, ligand; Crm, cytokine response modifying; MT, membrane type.

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