Mechanisms of Soluble Cytokine Receptor 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 Why The JI? Submit online. http://www.jimmunol.org/ • Rapid Reviews! 30 days* from submission to initial decision • No Triage! Every submission reviewed by practicing scientists • Fast Publication! 4 weeks from acceptance to publication *average by guest on September 28, 2021 Subscription Information about subscribing to The Journal of Immunology is online at: http://jimmunol.org/subscription Permissions Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html Email Alerts Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts 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 Cytokine Receptor 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 proteins, 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 genes 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 protein (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 cytokines. 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, decoy receptor 3; L, The costs of publication of this article were defrayed in part by the payment of page charges. ligand; 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 G protein-coupled 6R␣/IL-6 complexes regulates the expression of CXC and CC receptors, such as the protease-activated receptor 1, can induce chemokines 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- growth factor with resultant transactivation of the epidermal 6/sIL-6R␣ trans-signaling enhances lymphocyte trafficking growth factor receptor (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 growth hormone-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,