Mechanisms of Soluble Generation Stewart J. Levine This information is current as J Immunol 2004; 173:5343-5348; ; of September 28, 2021. doi: 10.4049/jimmunol.173.9.5343 http://www.jimmunol.org/content/173/9/5343 Downloaded from References This article cites 113 articles, 70 of which you can access for free at: http://www.jimmunol.org/content/173/9/5343.full#ref-list-1

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The Journal of Immunology is published twice each month by The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 2004 by The American Association of Immunologists All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. THE

JOURNAL OF IMMUNOLOGY

BRIEF REVIEWS

Mechanisms of Soluble Generation Stewart J. Levine1

Soluble cytokine receptors regulate inflammatory and im- biomarker of T cell activation and tumor burden in IL-2R␣- mune events by functioning as agonists or antagonists of expressing lymphoid neoplasms (3, 4). cytokine signaling. As such, they act within complex recep- Agonistic and antagonistic modulation of cytokine activity by soluble tor systems that include signaling receptors, nonsignaling cytokine receptors decoy receptors, receptor-associated , and soluble The IL-1 and IL-6 receptor systems are paradigms for soluble receptor antagonists. Soluble cytokine receptors can be cytokine receptors that mediate antagonistic and agonistic ef- generated by several mechanisms, which include proteo- fects. Both systems are complex and are regulated by multiple lytic cleavage of receptor ectodomains, alternative splicing cell-associated and soluble receptors, as well as receptor-associ- Downloaded from of mRNA transcripts, transcription of distinct that ated proteins. encode soluble cytokine-binding proteins, release of full- Multiple endogenous regulatory mechanisms exist to prevent length receptors within the context of exosome-like vesicles, excessive, proinflammatory IL-1 signaling. The functional and cleavage of GPI-anchored receptors. Furthermore, the IL-1R is a complex comprising the type I IL-1R (IL-1RI), the important role of soluble cytokine receptors in regulating IL-1R accessory (IL-1RAcP),2 and IL-1␣ or IL-1␤ (5). host defense mechanisms is evidenced by viruses that en- In contrast, the 60-kDa type II IL-1R (IL-1RII) is a nonsignal- http://www.jimmunol.org/ code soluble homologues of mammalian receptors and ing decoy receptor, because its short 29-aa cytoplasmic domain thereby evade innate host immune responses via the se- lacks a Toll-IL-1R domain (6, 7). IL-1RII can also form a non- questration of essential . The Journal of Immu- signaling trimeric complex with IL-1 and IL-1RAcP, which se- nology, 2004, 173: 5343–5348. questers essential components of the IL-1RI signaling complex (8, 9). Soluble type II IL-1 receptors (sIL-1RII), which are gen- erated primarily by proteolytic cleavage in response to a variety oluble cytokine receptors, which either attenuate or of stimuli (10), can attenuate excessive IL-1 bioactivity by pref- promote cytokine signaling, are important regulators of erentially binding IL-1␤ (11). Furthermore, the ability of sIL- by guest on September 28, 2021 inflammation and immunity. The key role that soluble S 1RII to bind IL-1␣ and IL-1␤ and inhibit IL-1 signaling is en- cytokine receptors play in preventing excessive inflammatory hanced ϳ100-fold by soluble IL-1RAcP, which is generated by responses is illustrated by the autosomal dominant, autoinflam- alternative splicing rather than by ectodomain cleavage (12). In matory, TNF receptor-associated periodic syndrome (TRAPS), addition, sIL-1RII can bind to and inhibit the processing of which was initially identified in patients with mutations in pro-IL-1␤ precursor to its mature form by the IL-1-converting the extracellular domain of the 55-kDa, type I TNFR enzyme (caspase-1) (13). Thus, multiple regulatory mecha- (TNFRSF1A, TNFR1) that impaired receptor shedding (1). nisms, including the generation of sIL-1RII and sIL-1RAcP, ex- Additional pathophysiologic mechanisms may also exist, as not ist by which excessive IL-1 signaling can be attenuated. all TRAPS-related TNFRSF1A mutations are associated with In contrast to the antagonistic effect of sIL-1RII on IL-1 sig- defective receptor shedding. Patients manifest recurrent epi- naling, soluble IL-6 receptors (sIL-6R␣) are an important sodes of fever, myalgia, rash, abdominal pain, and conjunctivi- mechanism by which IL-6 signaling is amplified. Soluble IL-6 tis that may be attenuated by anti-TNF therapy with a recom- receptors can be generated by two distinct pathways: proteolytic binant soluble human TNFR2-Ig fusion protein (1). Similarly, cleavage that sheds the membrane-bound IL-6R ectodomain or administration of a recombinant soluble human TNFR2-Ig fu- alternative mRNA splicing, with resulting synthesis of an IL- sion protein has been used to modify TNF biological activity 6R␣ that lacks the transmembrane domain (14, 15). Soluble and disease severity in patients with inflammatory arthritides IL-6 receptors bind IL-6 with an affinity similar to the mem- and psoriasis (2). Furthermore, the role of soluble cytokine re- brane IL-6R, thereby prolonging the IL-6 half-life (16). Fur- ceptors in modulating immune events is exemplified by the sol- thermore, binding of the sIL-6R␣/IL-6 complex to the ubiqui- uble IL-2R␣ (IL2R␣, CD25, Tac), which has been used as a tously expressed membrane-bound gp130 confers IL-6

Pulmonary-Critical Care Medicine Branch, National Heart, Lung, and Blood Institute, of Health, Building 10, Room 6D03, MSC 1590, Bethesda, MD 20892-1590. E-mail National Institutes of Health, Bethesda, MD 20892 address: [email protected] Received for publication July 20, 2004. Accepted for publication August 20, 2004. 2 Abbreviations used in this paper: IL-1RAcP, IL-1R accessory protein; s, soluble; TACE, TNF-␣-converting enzyme; MMP, matrix metalloprotease; DcR3, ; L, The costs of publication of this article were defrayed in part by the payment of page charges. ; Crm, cytokine response modifying; MT, membrane type. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. 1 Address correspondence and reprint requests to Dr. Stewart J. Levine, Pulmonary-Crit- ical Care Medicine Branch, National Heart, Lung, and Blood Institute, National Institutes

Copyright © 2004 by The American Association of Immunologists, Inc. 0022-1767/04/$02.00 5344 BRIEF REVIEW: MECHANISMS OF SOLUBLE CYTOKINE RECEPTOR GENERATION signaling capability to cells that do not express IL-6R␣ via a tion of the cysteine thiol group in the cysteine-switch domain process termed “trans-signaling” (17). Trans-signaling via sIL- (42, 43). Second, endogenous signaling via -coupled 6R␣/IL-6 complexes regulates the expression of CXC and CC receptors, such as the protease-activated receptor 1, can induce and terminates neutrophil recruitment in the set- the TACE-mediated cleavage of the heparin-binding epidermal ting of bacterial infection (18). Furthermore, gp130-linked IL- with resultant transactivation of the epidermal 6/sIL-6R␣ trans-signaling enhances lymphocyte trafficking (23, 44, 45). Third, TACE catalytic ac- during febrile inflammatory responses via activation of L-selec- tivity may be regulated via protein-protein interactions with the tin-mediated adhesion (19). Importantly, the trans-signaling TACE intracytoplasmic domain. The mitogen-activated pro- function of the sIL-6R␣-IL-6 complex can be abrogated by the tein kinase ERK, in response to phorbol ester stimulation, phos- soluble form of gp130 (sgp130), which competes with mem- phorylates threonine 735 of the TACE intracytoplasmic tail, brane gp130 for binding of the sIL-6R-IL-6 complex (20). whereas serine 819 undergoes -induced phos- phorylation, which may regulate proteolytic activity (46, 47). Generation of soluble cytokine receptors by the proteolytic cleavage of The protein tyrosine phosphatase PTPH1 may negatively reg- ectodomains ulate TACE activity through an interaction between its PDZ Proteolytic cleavage of cell surface receptors is typically cata- domain and the carboxyl terminus of TACE (48). The mitotic lyzed by zinc metalloproteases of the ADAM (a disintegrin and arrest-deficient 2 protein and the scaffolding protein synapse- metalloprotease) family. ADAMs are a large family of type I associated protein 97 have also been identified as potentially transmembrane proteins, with at least 34 named mammalian regulating TACE activity via binding to the TACE intracyto- Downloaded from genes that contain multiple domains, including a prodomain plasmic domain (49, 50). Fourth, TACE undergoes stimula- (that maintains the enzyme in an inactive state via a cysteine- tion-dependent internalization, which may down-regulate cat- switch mechanism), a zinc-dependent catalytic domain, a dis- alytic activity at the plasma membrane (51). Furthermore, the integrin-cysteine-rich domain, an epidermal growth factor-like induction of TACE-mediated shedding in response to PMA repeat, a transmembrane domain, and an intracytoplasmic tail stimulation reflects increased enzymatic activity that is inde- ␣ http://www.jimmunol.org/ (21–23). ADAM17 or TNF- -converting enzyme (TACE) is pendent of the intracytoplasmic domain and is not associated the prototypical receptor sheddase that was identified via its with an increase in cell surface TACE levels (27, 52). Fifth, ability to cleave membrane-bound TNF to its soluble form (24, membrane lipid composition may regulate TACE activity (23). 25). Furthermore, TACE is a key regulator of normal embry- Cholesterol depletion enhances TACE- and ADAM10-cata- onic development, as mice expressing a catalytically inactive ␣ ␣ lyzed IL-6R shedding and TACE-catalyzed CD30 shedding TACE cannot generate soluble TGF- , with resultant defects through a mechanism which may involve dissolution of lipid in epithelial cell maturation and organization (26). rafts, since TACE is localized to non-raft fractions, while CD30 TACE has been implicated in the ectodomain cleavage and is partially localized to lipid raft microdomains (53, 54). Lastly, shedding of cytokine receptors belonging to several distinct cy- by guest on September 28, 2021 the mechanisms underlying substrate recognition by TACE are tokine receptor superfamilies, including the TNFR family (75- complex and remain incompletely defined, as multiple sub- kDa, type II TNFR (TNFRSF1B, TNFR2) (26), TNFR1 (27), strates with variable cleavage sites may be cleaved by TACE CD30 (TNFRSF8) (28), and CD40 (TNFRSF5) (29); the IL- (21). Determinants of substrate specificity may include the sub- 1/TLR family (IL-1RII (27)); the fam- strate cleavage site and juxtamembrane stalk sequences, as well ily (IL-6R ␣-chain (30)); and the IL-15R ␣-chain (31). TACE as the structures of the TACE catalytic and disintegrin/cysteine- has also been reported to mediate the constitutive and inducible rich domains (27, 30, 55). cleavage of the receptor (c-, CD117) (32) and the macrophage CSF receptor (33), as well as the cleavage of Important functions have been identified for other ADAM receptors that regulate growth, differentiation, and survival, family members in the proteolytic cleavage and shedding of cell such as the epidermal growth factor receptor family (erbB4/ surface receptors and ligands. ADAM8 can physically associate HER4) (34), the neurotrophin receptor family (p75 neurotro- with and catalyze the proteolytic cleavage of CD23 (the low- phin receptor) (35), and the growth (36). affinity IgE receptor), whereas ADAM15 and ADAM28 Furthermore, TACE may modulate innate immune responses (MDC-L) have also been implicated in CD23 shedding (56). by regulating the ectodomain cleavage of adhesion molecules, Soluble CD23 ectodomains may then up-regulate IgE produc- such as L-selectin (26), VCAM-1(37), and CX3CL1 (fracta- tion and generate proinflammatory cytokines (56). ADAM10 ␣ lkine) (38, 39), which is an adhesion molecule in its membrane- catalyzes the constitutive and inducible shedding of IL-6R bound form, whereas the soluble form mediates chemotactic (54), as well as that of the constitutive shedding of CXCL16, ␤ activity via binding to its receptor, CX3CR1. Although TACE epidermal growth factor, and -cellulin (57–59). Furthermore, is responsible for the inducible cleavage of CX3CL1, constitu- ADAM10 and TACE have been reported to catalyze the pro- tive shedding is mediated by ADAM10 (40). TACE has also teolytic cleavage of CD44, the for hyaluro- been implicated in the processing of membrane-bound TN- nan, which may contribute to tumor cell migration and inva- FSF11 (TNF-related activation-induced cytokine, osteoclast sion (60, 61). differentiation factor, RANK ligand, osteoprotegrin ligand), Matrix metalloproteinases (MMP) may also possess receptor another TNF family member, to its soluble form (41). sheddase activity. MMP-12 (macrophage metalloelastase) has TACE activity may be regulated at several levels. First, the been implicated as a sheddase for the amino-terminal domain TACE prodomain maintains the zinc metalloprotease catalytic (D1) of the urokinase-type plasminogen receptor (62). Mem- domain in an inactive state via a cysteine-switch mechanism. brane-type 1(MT)-MMP has been implicated in CD44 cleav- Reactive oxygen species and NO, which may be generated dur- age, releasing it into the medium as a soluble 70-kDa fragment ing inflammatory responses, may activate TACE via modifica- (63), while MT1-MMP and MT3-MMP have been implicated The Journal of Immunology 5345 in the proteolytic cleavage and shedding of the type III membrane-associated FasL can be released from melanoma cells TGF-␤R(T␤R-III) betaglycan (64). in microvesicles, which range in size from 100 to 200 nm, with resultant proapoptotic affects on Fas-sensitive lymphoid cells Transcription of soluble cytokine receptor ectodomains and consequent impaired antitumor responses (e.g., Fas tumor Another major mechanism for the generation of soluble cyto- counterattack) (97). Thus, the release of full-length cytokine kine receptor ectodomains is the synthesis of receptors that con- receptors within the context of exosome-like vesicles may rep- tain signal and lack transmembrane domains and are resent an alternative mechanism for the generation of extracel- therefore secreted, rather than membrane-associated proteins. lular receptors. Soluble cytokine receptors can be generated in this fashion via two distinct pathways. The first involves the alternative splicing Generation of soluble cytokine receptors by release of GPI-linked ectodomains of mRNA transcripts that usually encode membrane-associated receptors, examples of which include members of the following Cleavage of ectodomains from GPI-linked receptors may rep- cytokine receptor superfamilies: class I cytokine receptor super- resent an additional mechanism for the generation of soluble family (IL-4R␣, IL-5R␣, IL-6R␣, IL-7R␣, IL-9R␣, EpoR, G- cytokine receptors. This may be applicable to the ciliary neuro- CSFR, GM-CSFR␣, gp130, and LIFR␣) (65–74), class II cy- trophic factor receptor ␣ (CNTFR␣), which is anchored to cell tokine receptor superfamily (type I IFNR (IFNAR1 and membranes by a GPI-linkage and released by phosphatidylinos- IFNAR2␣)) (75), IL-1/TLR family (IL-1RII, IL-1RAcP) (76, itol-specific phospholipase C (98). This represents a unique

77), TGF-␤ receptor family (T␤R-I, -like ki- mechanism, as CNTFR␣ may be the only growth factor or cy- Downloaded from nase 7) (78, 79), TNFR superfamily (TNFRSF6/Fas/CD95, tokine receptor that is anchored to cell membranes by a GPI- TNFRSF9/4-1BB/CD137) (80, 81), and the IL-17R (82). linkage. Similar to IL-6 trans-signaling, sCNTR␣ may allow The second pathway is via the transcription of distinct genes CNTF to act on cells that are not normally responsive to that share homology with cytokine receptors and therefore en- CNTF (99). code soluble cytokine-binding proteins. Signaling through the TNFR and class II cytokine receptor superfamilies can be reg- Virally encoded soluble cytokine receptors http://www.jimmunol.org/ ulated in this fashion. Decoy receptor 3 (DcR3, TNFRSF6B, The utility of soluble cytokine receptors as highly effective TR6, M68) is a secreted member of the TNFR superfamily that modulators of innate immune responses has been exploited by contains a signal and four tandem cysteine-rich domains, viruses which synthesize soluble homologues of mammalian cy- but lacks a transmembrane domain. DcR3 can bind to tokine receptors as a mechanism to evade host defenses. This is (L) (TNFSF6) (83), LIGHT (TNFSF14) (84), and TL1A (endo- consistent with the important role of soluble cytokine receptors thelial cell-derived TNF-like factor) (85), thereby inhibiting apo- in modulating the activity of proinflammatory cytokines. Pox- ptosis by preventing ligand association with Fas, ␤ viruses, such as cowpox, variola, myxoma, and Shope fibroma receptor (TNFRSF3), and (86). Biological pro- viruses, encode homologues of the TNFR superfamily (100). by guest on September 28, 2021 cesses that are modulated by DcR3 include angiogenesis (87), heart The first viral TNFR to be identified was the T2 protein of the allograft rejection (88), autoimmune-mediated islet cell destruc- Shope fibroma virus, which is structurally similar to TNFR2, tion (86), tumor cell evasion of FasL-dependent immune- but lacks a transmembrane domain and is secreted from virally cytotoxic attack (83), and T cell costimulation (85) and chemo- infected cells to function as a TNF-binding protein (101); a taxis (89). (TNFRSF11B), another TNFR similar T2 protein is encoded by the myxoma virus (102). Four superfamily member, is also generated as a secreted, soluble protein additional poxvirus TNFR homologues, the cytokine response that binds TNFSF11 and inhibits osteoclast differentiation (90). modifying (Crm) proteins, which display different ligand spec- IL-22RA2 (IL-22R␣ 2), a member of the human class II cytokine ificities, have been identified, with CrmB and CrmD binding receptor family, lacks a transmembrane domain and functions as a both TNF and lymphotoxin ␣, whereas CrmC and CrmE bind naturally occurring soluble cytokine binding protein that antago- only TNF (103–106). The poxviruses, cowpox and ectromelia nizes IL-22, an IL-10 homologue (91–93). IL-18-binding protein, (mousepox), also encode a soluble, secreted homologue of which shares limited homology with IL-1RII, is another soluble CD30, which can bind CD30L with high affinity, preventing cytokine-binding protein that lacks a transmembrane domain and its receptor binding and thereby inhibiting Th2-mediated in- functions as an IL-18 inhibitor (94). flammation in vivo (107, 108). Soluble viral homologues of the type 1 IFN receptor (109, 110), the IFN-␥ receptor (111), Release of exosome-like vesicles as an alternative mechanism for IL-1RII (112, 113), and IL-18 binding protein (94) have also generation of soluble cytokine receptors been identified. Exosomes are small membrane-enclosed vesicles that corre- spond to the internal vesicles of multivesicular bodies and are Conclusion released from cells via exocytic fusion with the plasma mem- Goals of future investigations will be to determine further the brane (95). It was recently reported that full-length TNFR1 can mechanisms that operate and regulate the shedding processes, be constitutively released from human vascular endothelial cells as well as the specific interactions between receptor sheddases into the extracellular milieu as a constituent of exosome-like and target receptor ectodomains. Molecular interactions that vesicles of 20–50 nm in diameter (96). The HUVEC-derived initiate, mediate, and terminate the release of soluble cytokine TNFR1 exosome-like vesicles do not appear to possess intrinsic receptors need to be clarified further, as do the roles of regula- signaling capabilities based upon the presence of silencer of tory and adaptor proteins that participate in soluble cytokine death domains and the absence of an active TNFR1 signaling receptor generation. Furthermore, the biological functions of complex I (TNFR-associated death domain protein, receptor- soluble cytokine receptors in regulating key inflammatory and interacting protein, and TNFR-associated factor 2). Similarly, immune responses need to be elucidated. These studies should 5346 BRIEF REVIEW: MECHANISMS OF SOLUBLE CYTOKINE RECEPTOR GENERATION provide new insights into disease pathogenesis and generate 25. Moss, M. L., S. L. Jin, M. E. Milla, D. M. Bickett, W. Burkhart, H. L. Carter, W. J. Chen, W. C. Clay, J. R. Didsbury, D. Hassler, et al. 1997. Cloning of a disin- novel therapeutic approaches. tegrin metalloproteinase that processes precursor tumour-necrosis factor-␣. Nature 385:733. 26. Peschon, J. J., J. L. Slack, P. Reddy, K. L. Stocking, S. W. Sunnarborg, D. C. Lee, Acknowledgments W. E. Russell, B. J. Castner, R. S. Johnson, J. N. Fitzner, et al. 1998. An essential role I thank Drs. 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