Molecular Mechanisms of Soluble Cytokine Receptor Generation
2008; Elsevier BV; Volume: 283; Issue: 21 Linguagem: Inglês
10.1074/jbc.r700052200
ISSN1083-351X
Autores Tópico(s)interferon and immune responses
ResumoSoluble cytokine receptors play key roles in regulating cytokine-mediated biological events by binding and modulating the activity of target ligands in either an antagonistic or agonistic fashion. This Minireview will provide an overview of the molecular mechanisms mediating the generation of soluble cytokine receptors, which include sheddase-mediated proteolytic cleavage of cell-surface receptors, generation of soluble receptors by alternative gene splicing, transcription and translation of cytokine-binding genes, and extracellular release of membrane-bound receptors within vesicles such as exosomes. Soluble cytokine receptors play key roles in regulating cytokine-mediated biological events by binding and modulating the activity of target ligands in either an antagonistic or agonistic fashion. This Minireview will provide an overview of the molecular mechanisms mediating the generation of soluble cytokine receptors, which include sheddase-mediated proteolytic cleavage of cell-surface receptors, generation of soluble receptors by alternative gene splicing, transcription and translation of cytokine-binding genes, and extracellular release of membrane-bound receptors within vesicles such as exosomes. Cytokine-mediated biological events such as host defense, immune regulation, cellular proliferation, and apoptosis are tightly controlled to prevent adverse sequelae secondary to dysregulated signaling. An important mechanism by which aberrant cytokine signaling is modulated is the generation of soluble cytokine receptors that bind target cytokines and modify their biological activity in an antagonistic or agonistic fashion. This Minireview will focus on the molecular mechanisms that modulate the generation of soluble cytokine receptors. TACE 2The abbreviations used are: TACE, tumor necrosis factor-α-converting enzyme; EGF, epidermal growth factor; TNF, tumor necrosis factor; TNFR, TNF receptor; IL-1R, interleukin-1 receptor; EGFR, EGF receptor; TGF, transforming growth factor; SH, Src homology; MAPK, mitogen-activated protein kinase; ERK, extracellular signal-regulated kinase; GRP, gastrin-releasing peptide; DcR3, decoy receptor 3; IL-18BP, IL-18-binding protein; IFN-γ, interferon-γ; MVBs, multivesicular bodies. (ADAM17), a member of the ADAM (a disintegrin and metalloproteinase) family of zinc metalloproteinases, is the prototypical sheddase of cytokine ligands and receptors (reviewed in Refs. 1Black R.A. Int. J. Biochem. Cell Biol. 2002; 34: 1-5Crossref PubMed Scopus (294) Google Scholar, 2Blobel C.P. Nat. Rev. Mol. Cell Biol. 2005; 6: 32-43Crossref PubMed Scopus (921) Google Scholar, 3Huovila A.P. Turner A.J. Pelto-Huikko M. Karkkainen I. Ortiz R.M. Trends Biochem. Sci. 2005; 30: 413-422Abstract Full Text Full Text PDF PubMed Scopus (373) Google Scholar, 4Milla M.E. Gonzales P.E. Leonard J.D. Cell Biochem. Biophys. 2006; 44: 342-348Crossref PubMed Scopus (25) Google Scholar, 5Moss M.L. Bartsch J.W. Biochemistry. 2004; 43: 7227-7235Crossref PubMed Scopus (119) Google Scholar). The ADAM family is composed of 40 named genes that encode type I transmembrane proteases containing multiple domains: an N-terminal signal sequence, a prodomain, a zinc metalloproteinase domain, a disintegrin cysteine-rich domain, an EGF-like domain, a transmembrane domain, and a cytoplasmic domain (1Black R.A. Int. J. Biochem. Cell Biol. 2002; 34: 1-5Crossref PubMed Scopus (294) Google Scholar, 2Blobel C.P. Nat. Rev. Mol. Cell Biol. 2005; 6: 32-43Crossref PubMed Scopus (921) Google Scholar, 4Milla M.E. Gonzales P.E. Leonard J.D. Cell Biochem. Biophys. 2006; 44: 342-348Crossref PubMed Scopus (25) Google Scholar, 5Moss M.L. Bartsch J.W. Biochemistry. 2004; 43: 7227-7235Crossref PubMed Scopus (119) Google Scholar). TACE was originally identified by its ability to mediate the cell-surface cleavage and shedding of TNF, which is expressed as a 26-kDa transmembrane protein and proteolytically cleaved to produce the soluble 17-kDa TNF (6Black R.A. Rauch C.T. Kozlosky C.J. Peschon J.J. Slack J.L. Wolfson M.F. Castner B.J. Stocking K.L. Reddy P. Srinivasan S. Nelson N. Boiani N. Schooley K.A. Gerhart M. Davis R. Fitzner J.N. Johnson R.S. Paxton R.J. March C.J. Cerretti D.P. Nature. 1997; 385: 729-733Crossref PubMed Scopus (2705) Google Scholar, 7Moss M.L. Jin S.-L.C. Milla M.E. Burkhart W. Carter H.L. Chen W.-J. Clay W.C. Didsbury J.R. Hassler D. Hoffman C.R. Kost T.A. Lambert M.H. Leesnitzer M.A. McCauley P. McGeehan G. Mitchell J. Moyer M. Pahel G. Rocque W. Overton L.K. Schoenen F. Seaton T. Su J.-L. Warner J. Willard D. Becherer J.D. Nature. 1997; 385: 733-736Crossref PubMed Scopus (1481) Google Scholar). Proteolytic cleavage of cell-surface TNF modulates its activity, as both the soluble and membrane forms of TNF signal and mediate distinct biological functions (2Blobel C.P. Nat. Rev. Mol. Cell Biol. 2005; 6: 32-43Crossref PubMed Scopus (921) Google Scholar). TACE functions as a cytokine receptor sheddase for the TNFR superfamily, the IL-1R/Toll-like receptor superfamily, and the type I cytokine receptor superfamily (supplemental Table 1). TACE also mediates the cleavage of a structurally and functionally diverse set of protein ectodomain substrates, which include cytokines, chemokines, EGFR ligands, growth factor receptors, receptor tyrosine kinases, and Notch1 (reviewed in Refs. 2Blobel C.P. Nat. Rev. Mol. Cell Biol. 2005; 6: 32-43Crossref PubMed Scopus (921) Google Scholar, 3Huovila A.P. Turner A.J. Pelto-Huikko M. Karkkainen I. Ortiz R.M. Trends Biochem. Sci. 2005; 30: 413-422Abstract Full Text Full Text PDF PubMed Scopus (373) Google Scholar, 8Levine S.J. J. Immunol. 2004; 173: 5343-5348Crossref PubMed Scopus (134) Google Scholar, and 9Garton K.J. Gough P.J. Raines E.W. J. Leukocyte Biol. 2006; 79: 1105-1116Crossref PubMed Scopus (189) Google Scholar). Furthermore, mice expressing a catalytically inactive TACE have an embryonic lethal phenotype secondary to impaired TGF-α ectodomain shedding with resultant defects in epithelial cell maturation and organization (10Peschon J.J. Slack J.L. Reddy P. Stocking K.L. Sunnarborg S.W. Lee D.C. Russell W.E. Castner B.J. Johnson R.S. Fitzner J.N. Boyce R.W. Nelson N. Kozlosky C.J. Wolfson M.F. Rauch C.T. Cerretti D.P. Paxton R.J. March C.J. Black R.A. Science. 1998; 282: 1281-1284Crossref PubMed Scopus (1361) Google Scholar). The molecular mechanisms underlying TACE substrate recognition of its varied substrates remain incompletely defined (1Black R.A. Int. J. Biochem. Cell Biol. 2002; 34: 1-5Crossref PubMed Scopus (294) Google Scholar, 3Huovila A.P. Turner A.J. Pelto-Huikko M. Karkkainen I. Ortiz R.M. Trends Biochem. Sci. 2005; 30: 413-422Abstract Full Text Full Text PDF PubMed Scopus (373) Google Scholar, 4Milla M.E. Gonzales P.E. Leonard J.D. Cell Biochem. Biophys. 2006; 44: 342-348Crossref PubMed Scopus (25) Google Scholar). Scissile bond sequence and the length of the juxtamembrane stalk of TACE substrates may contribute to substrate specificity (11Hinkle C.L. Sunnarborg S.W. Loiselle D. Parker C.E. Stevenson M. Russell W.E. Lee D.C. J. Biol. Chem. 2004; 279: 24179-24188Abstract Full Text Full Text PDF PubMed Scopus (125) Google Scholar). For example, a systemic analysis of P1′ and P2′ substrate specificity using a peptide library has shown that TACE prefers lipophilic amino acids at the P1′ position, such as leucine and valine, whereas the P2′ position accommodates basic amino acids, such as arginine and lysine, as well as non-basic amino, acids, such as threonine (12Lambert M.H. Blackburn R.K. Seaton T.D. Kassel D.B. Kinder D.S. Leesnitzer M.A. Bickett D.M. Warner J.R. Andersen M.W. Badiang J.G. Cowan D.J. Gaul M.D. Petrov K.G. Rabinowitz M.H. Wiethe R.W. Becherer J.D. McDougald D.L. Musso D.L. Andrews R.C. Moss M.L. Comb. Chem. High Throughput Screen. 2005; 8: 327-339Crossref PubMed Scopus (24) Google Scholar). Multiple mechanisms exist by which TACE enzymatic activity is regulated. Both the TACE prodomain and TIMP3 (tissue inhibitor of matrix metalloproteinases 3) function as inhibitors of the TACE catalytic site. TACE is synthesized as an inactive zymogen that is processed by proprotein convertases (such as furin) that cleave TACE at a putative KEX-2/furin recognition site, located between the prodomain and the catalytic domain (reviewed in Refs. 2Blobel C.P. Nat. Rev. Mol. Cell Biol. 2005; 6: 32-43Crossref PubMed Scopus (921) Google Scholar and 4Milla M.E. Gonzales P.E. Leonard J.D. Cell Biochem. Biophys. 2006; 44: 342-348Crossref PubMed Scopus (25) Google Scholar). This occurs in the trans-Golgi, followed by transport of the mature enzyme to the plasma membrane (13Borroto A. Ruiz-Paz S. de la Torre T.V. Borrell-Pages M. Merlos-Suarez A. Pandiella A. Blobel C.P. Baselga J. Arribas J. J. Biol. Chem. 2003; 278: 25933-25939Abstract Full Text Full Text PDF PubMed Scopus (40) Google Scholar). The TACE prodomain contains a putative cysteine-switch box, which functions as an inhibitor of catalytic activity in other ADAM proteins and matrix metalloproteinases via ligation of the cysteinyl thiol in the prodomain to the zinc ion in the catalytic site. Although Cys184 in the TACE prodomain ligates the catalytic zinc ion, the cysteine-switch motif is not essential for inhibition of TACE enzymatic activity (14Gonzales P.E. Solomon A. Miller A.B. Leesnitzer M.A. Sagi I. Milla M.E. J. Biol. Chem. 2004; 279: 31638-31645Abstract Full Text Full Text PDF PubMed Scopus (98) Google Scholar). Instead, the TACE prodomain, which exists as a stably folded protein that tightly associates with the catalytic domain, may retain the catalytic domain in an open, inactive, conformational state (15Leonard J.D. Lin F. Milla M.E. Biochem. J. 2005; 387: 797-805Crossref PubMed Scopus (50) Google Scholar). Furthermore, the TACE prodomain may function as an intramolecular chaperone that protects the TACE zymogen from intracellular degradation and facilitates proper intracellular trafficking. Similarly, the cleaved ADAM10 prodomain associates with mature ADAM10 and functions as a specific competitive inhibitor of catalytic activity that does not involve a cysteine-switch mechanism (16Moss M.L. Bomar M. Liu Q. Sage H. Dempsey P. Lenhart P.M. Gillispie P.A. Stoeck A. Wildeboer D. Bartsch J.W. Palmisano R. Zhou P. J. Biol. Chem. 2007; 282: 35712-35721Abstract Full Text Full Text PDF PubMed Scopus (122) Google Scholar). This may represent a unique feature of TACE and ADAM10, as the cysteine switch appears to be required for the prodomains of other ADAM family members (such as ADAM12) to inhibit catalytic activity (4Milla M.E. Gonzales P.E. Leonard J.D. Cell Biochem. Biophys. 2006; 44: 342-348Crossref PubMed Scopus (25) Google Scholar). Attenuation of TACE catalytic activity by TIMP3 is another important regulatory mechanism that controls TNF-mediated inflammation (17Mohammed F.F. Smookler D.S. Taylor S.E. Fingleton B. Kassiri Z. Sanchez O.H. English J.L. Matrisian L.M. Au B. Yeh W.-C. Khokha R. Nat. Genet. 2004; 36: 969-977Crossref PubMed Scopus (237) Google Scholar). TIMP3 is the only TIMP family member that binds and inhibits TACE. TIMP3 knock-out mice display increased constitutive soluble TNF generation in the liver, which is associated with chronic hepatic inflammation. This finding is consistent with a key role for TIMP3 in modulating TACE-mediated TNF shedding and supports the concept of TACE as the main physiological TNF-processing enzyme (18Black R.A. Nat. Genet. 2004; 36: 934-935Crossref PubMed Scopus (66) Google Scholar). The cytoplasmic domain of TACE, which contains SH2 and SH3 domain-binding motifs, also modulates its function (2Blobel C.P. Nat. Rev. Mol. Cell Biol. 2005; 6: 32-43Crossref PubMed Scopus (921) Google Scholar, 4Milla M.E. Gonzales P.E. Leonard J.D. Cell Biochem. Biophys. 2006; 44: 342-348Crossref PubMed Scopus (25) Google Scholar). Although the TACE cytoplasmic domain undergoes inducible phosphorylation, phorbol 12-myristate 13-acetate-mediated TACE catalytic activity can occur independently of the cytoplasmic domain (19Doedens J.R. Mahimkar R.M. Black R.A. Biochem. Biophys. Res. Commun. 2003; 308: 331-338Crossref PubMed Scopus (88) Google Scholar). Instead, the TACE cytoplasmic domain may play an important role in regulating TACE protein trafficking and maturation, which are regulated by MAPKs (20Soond S.M. Everson B. Riches D.W. Murphy G. J. Cell Sci. 2005; 118: 2371-2380Crossref PubMed Scopus (202) Google Scholar). Consistent with this, phorbol 12-myristate 13-acetate stimulates the ERK-mediated phosphorylation of Thr735 in the TACE cytoplasmic domain, which induces the translocation of TACE from the endoplasmic reticulum to the cell surface. Furthermore, the phosphorylation state of the TACE cytoplasmic domain may be regulated by an interaction with the PDZ domain of the protein-tyrosine phosphatase PTPH1. Additional proteins that interact with the TACE cytoplasmic domain and potentially regulate its catalytic activity include MAD2 (mitotic arrest-deficient 2), SAP97 (synapse-associated protein 97), and Eve-1, a SH3 domain-containing protein that potentiates the proteolytic cleavage and shedding of EGFR ligands (8Levine S.J. J. Immunol. 2004; 173: 5343-5348Crossref PubMed Scopus (134) Google Scholar, 21Tanaka M. Nanba D. Mori S. Shiba F. Ishiguro H. Yoshino K. Matsuura N. Higashiyama S. J. Biol. Chem. 2004; 279: 41950-41959Abstract Full Text Full Text PDF PubMed Scopus (70) Google Scholar). FHL2 (four-and-a-half LIM domains 2) also binds the TACE cytoplasmic domain as well as the actin cytoskeleton and may regulate TACE cellular localization and activity (22Canault M. Tellier E. Bonardo B. Mas E. Aumailley M. Juhan-Vague I. Nalbone G. Peiretti F. J. Cell. Physiol. 2006; 208: 363-372Crossref PubMed Scopus (35) Google Scholar). TACE proteolytic activity can be regulated by several additional mechanisms. First, TACE undergoes stimulation-dependent internalization, which down-regulates catalytic activity at the plasma membrane (23Doedens J.R. Black R.A. J. Biol. Chem. 2000; 275: 14598-14607Abstract Full Text Full Text PDF PubMed Scopus (154) Google Scholar). Second, partitioning of TACE and its substrates within lipid raft microdomains may regulate proteolytic cleavage and cell-surface shedding. Both mature TACE and its substrates have been localized to lipid raft microdomains, although sequestration of TACE within lipid rafts has not been a universal finding (24von Tresckow B. Kallen K.J. von Strandmann E.P. Borchmann P. Lange H. Engert A. Hansen H.P. J. Immunol. 2004; 172: 4324-4331Crossref PubMed Scopus (96) Google Scholar, 25Tellier E. Canault M. Rebsomen L. Bonardo B. Juhan-Vague I. Nalbone G. Peiretti F. Exp. Cell Res. 2006; 312: 3969-3980Crossref PubMed Scopus (122) Google Scholar). Disruption of lipid raft microdomains by cholesterol depletion has been associated with the increased release of TACE substrates and may reflect enhanced interactions between substrates in non-raft membrane regions and TACE released from lipid rafts (24von Tresckow B. Kallen K.J. von Strandmann E.P. Borchmann P. Lange H. Engert A. Hansen H.P. J. Immunol. 2004; 172: 4324-4331Crossref PubMed Scopus (96) Google Scholar, 25Tellier E. Canault M. Rebsomen L. Bonardo B. Juhan-Vague I. Nalbone G. Peiretti F. Exp. Cell Res. 2006; 312: 3969-3980Crossref PubMed Scopus (122) Google Scholar, 26Matthews V. Schuster B. Schutze S. Bussmeyer I. Ludwig A. Hundhausen C. Sadowski T. Saftig P. Hartmann D. Kallen K.J. Rose-John S. J. Biol. Chem. 2003; 278: 38829-38839Abstract Full Text Full Text PDF PubMed Scopus (324) Google Scholar). Furthermore, co-localization of TACE and furin within lipid raft microdomains in the Golgi apparatus may be necessary for prodomain processing (25Tellier E. Canault M. Rebsomen L. Bonardo B. Juhan-Vague I. Nalbone G. Peiretti F. Exp. Cell Res. 2006; 312: 3969-3980Crossref PubMed Scopus (122) Google Scholar). Third, nardilysin (N-arginine dibasic convertase), a dibasic selective metalloendopetidase of the M16 family, can form a complex with TACE and enhance TACE-induced cleavage of heparin-binding EGF-like protein via a mechanism that is not dependent upon N-arginine dibasic convertase catalytic activity (27Nishi E. Hiraoka Y. Yoshida K. Okawa K. Kita T. J. Biol. Chem. 2006; 281: 31164-31172Abstract Full Text Full Text PDF PubMed Scopus (58) Google Scholar). Fourth, in the case of CD30 shedding, cysteine-rich domains 2 and 5 of the cleaved ectodomain may serve as a stimulus for enhanced shedding, possibly by ligand-independent aggregation that promotes enzyme binding (28Hansen H.P. Recke A. Reineke U. von Tresckow B. Borchmann P. von Strandmann E.P. Lange H. Lemke H. Engert A. FASEB J. 2004; 18: 893-895Crossref PubMed Scopus (26) Google Scholar). Transactivation of TACE-mediated receptor shedding can also be modulated by cross-talk between G protein-coupled receptors and EGFRs. “Triple membrane-passing signaling” describes the activation of an ADAM by a G protein-coupled receptor, which then cleaves and releases an EGFR ligand that binds and activates its EGFR (reviewed in Ref. 2Blobel C.P. Nat. Rev. Mol. Cell Biol. 2005; 6: 32-43Crossref PubMed Scopus (921) Google Scholar). This allows TACE to function as a molecular switch for EGFR signaling (2Blobel C.P. Nat. Rev. Mol. Cell Biol. 2005; 6: 32-43Crossref PubMed Scopus (921) Google Scholar). Consistent with this concept, a GRP-induced signaling cascade that induces EGFR ligand cleavage has been identified recently (29Zhang Q. Thomas S.M. Lui V.W. Xi S. Siegfried J.M. Fan H. Smithgall T.E. Mills G.B. Grandis J.R. Proc. Natl. Acad. Sci. U. S. A. 2006; 103: 6901-6906Crossref PubMed Scopus (123) Google Scholar). GRP stimulation induces the activation of c-Src, leading to downstream induction of phosphoinositide 3-kinase and PDK1 (phosphoinositide-dependent kinase 1), which mediates phosphorylation and translocation of TACE to the cell surface, EGFR proligand cleavage, and EGFR activation. Furthermore, GRP stimulation enhances the cytoplasmic association between c-Src and TACE, which is followed by their co-translocation to the cell membrane. Similarly, in human airway epithelial cells, neutrophil elastase activates DUOX1 (dual oxidase 1) to produce reactive oxygen species that activate TACE to cleave pro-TGF-α, which induces MUC5AC mucin expression (30Shao M.X. Nadel J.A. Proc. Natl. Acad. Sci. U. S. A. 2005; 102: 767-772Crossref PubMed Scopus (228) Google Scholar). Conversely, EGFR-dependent signaling has been shown to activate TACE in response to stimulation with Staphylococcus aureus protein A and to induce release of soluble TNFR1 (TNFRSF1A, p55 TNFR) (31Gomez M.I. Seaghdha M.O. Prince A.S. EMBO J. 2007; 26: 701-709Crossref PubMed Scopus (81) Google Scholar). Interaction of the IgG-binding domain of protein A with EGFR induces TACE phosphorylation and activation via a c-Src-ERK1/2 pathway. This results in the mobilization of TNFR1 from intracellular stores such as the Golgi apparatus to the cell surface, where it co-localizes with TACE and undergoes ectodomain shedding. Histamine has also been shown to mobilize Golgi-associated TNFR1 via a MEK1-p42/44 MAPK pathway that induces TNFR1 shedding (32Wang J. Al-Lamki R.S. Zhang H. Kirkiles-Smith N. Gaeta M.L. Thiru S. Pober J.S. Bradley J.R. J. Biol. Chem. 2003; 278: 21751-21760Abstract Full Text Full Text PDF PubMed Scopus (76) Google Scholar). Other ADAM family members possess cytokine receptor shedding activity (reviewed in Refs. 3Huovila A.P. Turner A.J. Pelto-Huikko M. Karkkainen I. Ortiz R.M. Trends Biochem. Sci. 2005; 30: 413-422Abstract Full Text Full Text PDF PubMed Scopus (373) Google Scholar and 8Levine S.J. J. Immunol. 2004; 173: 5343-5348Crossref PubMed Scopus (134) Google Scholar). ADAM10 has been identified as the sheddase mediating the calcium-dependent cleavage of CD30 and the constitutive and inducible shedding of IL-6Rα (8Levine S.J. J. Immunol. 2004; 173: 5343-5348Crossref PubMed Scopus (134) Google Scholar, 33Eichenauer D.A. Simhadri V.L. von Strandmann E.P. Ludwig A. Matthews V. Reiners K.S. von Tresckow B. Saftig P. Rose-John S. Engert A. Hansen H.P. Cancer Res. 2007; 67: 332-338Crossref PubMed Scopus (48) Google Scholar). ADAM10 also mediates the constitutive and ionomycin-inducible proteolytic shedding of the chemokine ligands fractalkine (CX3CL1) and CXCL16 (8Levine S.J. J. Immunol. 2004; 173: 5343-5348Crossref PubMed Scopus (134) Google Scholar, 34Hundhausen C. Schulte A. Schulz B. Andrzejewski M.G. Schwarz N. von Hundelshausen P. Winter U. Paliga K. Reiss K. Saftig P. Weber C. Ludwig A. J. Immunol. 2007; 178: 8064-8072Crossref PubMed Scopus (140) Google Scholar). ADAM10 has been identified as the principal sheddase for CD23, the low affinity IgE receptor (35Weskamp G. Ford J.W. Sturgill J. Martin S. Docherty A.J. Swendeman S. Broadway N. Hartmann D. Saftig P. Umland S. Sehara-Fujisawa A. Black R.A. Ludwig A. Becherer J.D. Conrad D.H. Blobel C.P. Nat. Immunol. 2006; 7: 1293-1298Crossref PubMed Scopus (176) Google Scholar). TNF, osteoprotegerin ligand, and Kit ligand 1 have been identified as substrates for ADAM19 (36Kawaguchi N. Horiuchi K. Becherer J.D. Toyama Y. Besmer P. Blobel C.P. J. Cell Sci. 2007; 120: 943-952Crossref PubMed Scopus (51) Google Scholar). Soluble cytokine receptors can also be generated via a mechanism that involves regulated intramembrane proteolysis. Cleavage of the IL-1 type II decoy receptor (IL-1RII) in an α-secretase-like fashion sheds the IL-1RII ectodomain and generates a C-terminal fragment, which undergoesγ-secretase-mediated intramembrane proteolysis (37Kuhn P.H. Marjaux E. Imhof A. De Strooper B. Haass C. Lichtenthaler S.F. J. Biol. Chem. 2007; 282: 11982-11995Abstract Full Text Full Text PDF PubMed Scopus (127) Google Scholar). Furthermore, β-secretases BACE1 and BACE2 can function as IL-1RII sheddases that cleave the IL-1RII ectodomain at a site adjacent to the α-secretase site. The physiological relevance of BACE1 and BACE2 as IL-1RII sheddases is unclear, as IL-1RII shedding remains intact in cells deficient in both BACE1 and BACE2. ADAM10-mediated α-secretase cleavage of fractalkine and CXCL16 may also precede a γ-secretase cleavage that releases intracellular signaling fragments (38Schulte A. Schulz B. Andrzejewski M.G. Hundhausen C. Mletzko S. Achilles J. Reiss K. Paliga K. Weber C. John S.R. Ludwig A. Biochem. Biophys. Res. Commun. 2007; 358: 233-240Crossref PubMed Scopus (80) Google Scholar). MMP9 (matrix metalloproteinase 9) has also been implicated in the shedding of IL-2Rα from activated T cells (39Sheu B.C. Hsu S.M. Ho H.N. Lien H.C. Huang S.C. Lin R.H. Cancer Res. 2001; 61: 237-242PubMed Google Scholar), whereas neutrophil elastase may participate in the shedding of TNFR2 and TNFR1 from neutrophils (40Porteu F. Brockhaus M. Wallach D. Engelmann H. Nathan C.F. J. Biol. Chem. 1991; 266: 18846-18853Abstract Full Text PDF PubMed Google Scholar). Phosphatidylinositol-specific phospholipase C has been identified as a receptor sheddase for the ciliary neurotrophic factor receptor-α, which is anchored to cell membranes by a glycosylphosphatidylinositol linkage (8Levine S.J. J. Immunol. 2004; 173: 5343-5348Crossref PubMed Scopus (134) Google Scholar). The second major mechanism of soluble cytokine receptor generation is the alternative splicing of mRNA transcripts, which deletes the transmembrane domain of membrane-associated receptors. Soluble cytokine receptors that can be generated by alternative splicing include members of the TNFR superfamily, the IL-1R/Toll-like receptor superfamily, class I and II cytokine receptor superfamilies, the TGF-β receptor family, and the IL-17 receptor (supplemental Table 1). Several cytokine receptors such as IL-1RII, IL-6Rα, IL-15Rα, and TNFR2 (TNFRSF1B) can be generated by either proteolytic cleavage of receptor ectodomains or alternative splicing events (8Levine S.J. J. Immunol. 2004; 173: 5343-5348Crossref PubMed Scopus (134) Google Scholar). For example, a soluble, differentially spliced isoform of human TNFR2 that lacks exons 7 and 8, which encode the transmembrane and cytoplasmic domains, has been described recently (41Lainez B. Fernandez-Real J.M. Romero X. Esplugues E. Canete J.D. Ricart W. Engel P. Int. Immunol. 2004; 16: 169-177Crossref PubMed Scopus (47) Google Scholar). Similarly, soluble IL-15Rα can be generated by either TACE-mediated proteolytic cleavage or alternative splicing (8Levine S.J. J. Immunol. 2004; 173: 5343-5348Crossref PubMed Scopus (134) Google Scholar, 42Bulanova E. Budagian V. Duitman E. Orinska Z. Krause H. Ruckert R. Reiling N. Bulfone-Paus S. J. Biol. Chem. 2007; 282: 13167-13179Abstract Full Text Full Text PDF PubMed Scopus (55) Google Scholar). Two closely homologous, alternatively spliced IL-15Rα isoforms that contain only the signal peptide and the exon 2 sushi domain, which mediates cytokine binding, have been identified. Both the proteolytically cleaved full-length IL-15Rα ectodomain and the alternatively spliced soluble IL-15Rα isoforms can form heterocomplexes with IL-15, thereby either inhibiting or promoting IL-15 activity, respectively (42Bulanova E. Budagian V. Duitman E. Orinska Z. Krause H. Ruckert R. Reiling N. Bulfone-Paus S. J. Biol. Chem. 2007; 282: 13167-13179Abstract Full Text Full Text PDF PubMed Scopus (55) Google Scholar, 43Mortier E. Bernard J. Plet A. Jacques Y. J. Immunol. 2004; 173: 1681-1688Crossref PubMed Scopus (116) Google Scholar). Consistent with this, the alternatively spliced IL-15Rα sushi domains have been implicated in trans-presentation, whereby IL-15·IL-15Rα complexes present IL-15 to cells (such as natural killer and CD8+ T cells) that lack IL-15Rα but express the intermediate affinity IL-15βγ complex (42Bulanova E. Budagian V. Duitman E. Orinska Z. Krause H. Ruckert R. Reiling N. Bulfone-Paus S. J. Biol. Chem. 2007; 282: 13167-13179Abstract Full Text Full Text PDF PubMed Scopus (55) Google Scholar). trans-Presentation of IL-15 is an example of cytokine trans-signaling that was initially described for soluble IL-6Rα·IL-6 complexes, which bind ubiquitously expressed membrane-bound gp130 and thereby confer IL-6 signaling capabilities to cells deficient in IL-6Rα (8Levine S.J. J. Immunol. 2004; 173: 5343-5348Crossref PubMed Scopus (134) Google Scholar, 44Rose-John S. Neurath M.F. Immunity. 2004; 20: 2-4Abstract Full Text Full Text PDF PubMed Scopus (81) Google Scholar). trans-Signaling has also been reported for other IL-6 subfamily members such as IL-11 and ciliary neurotrophic factor (45Diveu C. Venereau E. Froger J. Ravon E. Grimaud L. Rousseau F. Chevalier S. Gascan H. J. Biol. Chem. 2006; 281: 36673-36682Abstract Full Text Full Text PDF PubMed Scopus (29) Google Scholar). In contrast, soluble IL-6Rα·IL-6 trans-signaling can be attenuated by the soluble form of gp130, which competes with membrane gp130 for binding of soluble IL-6Rα·IL-6 complexes (46Jostock T. Mullberg J. Ozbek S. Atreya R. Blinn G. Voltz N. Fischer M. Neurath M.F. Rose-John S. Eur. J. Biochem. 2001; 268: 160-167Crossref PubMed Scopus (497) Google Scholar). Similarly, soluble forms of the leukemia inhibitory factor and oncostatin M receptors that can bind and antagonize leukemia inhibitory factor and oncostatin M in association with soluble gp130 have been identified (45Diveu C. Venereau E. Froger J. Ravon E. Grimaud L. Rousseau F. Chevalier S. Gascan H. J. Biol. Chem. 2006; 281: 36673-36682Abstract Full Text Full Text PDF PubMed Scopus (29) Google Scholar, 47Zhang J.G. Zhang Y. Owczarek C.M. Ward L.D. Moritz R.L. Simpson R.J. Yasukawa K. Nicola N.A. J. Biol. Chem. 1998; 273: 10798-10805Abstract Full Text Full Text PDF PubMed Scopus (52) Google Scholar). The third mechanism of soluble cytokine receptor generation involves the transcription and translation of distinct genes that encode secreted cytokine-binding proteins that function as inhibitory decoy receptors. DcR3 (TNFRSF6B, TR6, M68) is a secreted TNFR superfamily member that contains a signal peptide and four tandem cysteine-rich domains, but lacks a transmembrane domain (reviewed in Ref. 8Levine S.J. J. Immunol. 2004; 173: 5343-5348Crossref PubMed Scopus (134) Google Scholar). DcR3 inhibits apoptosis by binding the Fas ligand (TNFSF6) and blocking its interaction with Fas (CD95, TNFRSF6). DcR3 is highly expressed by malignant cells (such as Epstein-Barr virus-positive lymphomas) as a protective mechanism against Fas ligand-dependent immune/cytotoxic attack. Furthermore, the Epstein-Barr virus immediate-early protein Rta directly binds an Rta-responsive element in the DcR3 promoter and functions as a transactivator that increases DcR3 expression in conjunction with recruitment of cAMP-responsive element-binding protein-binding protein (48Ho C.H. Hsu C.F. Fong P.F. Tai S.K. Hsieh S.L. Chen C.J. J. Virol. 2007; 81: 4837-4847Crossref PubMed Scopus (24) Google Scholar). This represents a mechanism by which a viral gene product may up-regulate DcR3 expression and thereby promote viral survival and tumorigenesis. Similarly, DcR3 binds and inhibits the interaction of LIGHT (TNFSF14) with its receptors, herpesvirus entry mediator (TNFRSF14, TR2), and the lymphotoxin β-receptor (TNFRSF3), with the resultant inhibition of LIGHT-mediated tumor cell apoptosis. DcR3 also binds TL1A, an endothelial cell-derived TNF-like factor, and competitively inhibits its interaction with death receptor 3 (TNFRSF25). Thus, DcR3 may function as an angiogenic factor by inhibiting the negative proliferative effects of TL1A on endothelial cells. Osteoprotegerin (TNFRSF11B) is another TNFR superfamily member that lacks a transmembrane domain and is expressed as a soluble decoy receptor that binds osteoprotegerin ligand (RANKL, TNFSF11) and prevents its interaction with RANK (TNFRSF11A), with the resultant inhibition of osteoclast differentiation (8Levine S.J. J. Immunol. 2004; 173: 5343-5348Crossref PubMed Scopus (134) Google Scholar). Osteoprotegerin-de
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