Soluble and Transmembrane Isoforms of Novel Interleukin-17 Receptor-like Protein by RNA Splicing and Expression in Prostate Cancer

Name: Soluble and Transmembrane Isoforms of Novel Interleukin-17 Receptor-like Protein by RNA Splicing and Expression in Prostate Cancer
Uploaded: 2002-02-01

Dominik R. Haudenschild; Timothy A. Moseley; Larry Rose; A. Hari Reddi

Basic Information

ID: W2040831260
Title: Soluble and Transmembrane Isoforms of Novel Interleukin-17 Receptor-like Protein by RNA Splicing and Expression in Prostate Cancer
Abstract: Members of the interleukin-17 cytokine family are present in a variety of tissues (1Li H. Chen J. Huang A. Stinson J. Heldens S. Foster J. Dowd P. Gurney A.L. Wood W.I. Proc. Natl. Acad. Sci. U. S. A. 2000; 97: 773-778Crossref PubMed Scopus (275) Google Scholar, 2Lee J. Ho W.H. Maruoka M. Corpuz R.T. Baldwin D.T. Foster J.S. Goddard A.D. Yansura D.G. Vandlen R.L. Wood W.I. Gurney A.L. J. Biol. Chem. 2001; 276: 1660-1664Abstract Full Text Full Text PDF PubMed Scopus (319) Google Scholar, 3Shi Y. Ullrich S.J. Zhang J. Connolly K. Grzegorzewski K.J. Barber M.C. Wang W. Wathen K. Hodge V. Fisher C.L. Olsen H. Ruben S.M. Knyazev I. Cho Y.H. Kao V. Wilkinson K.A. Carrell J.A. Ebner R. J. Biol. Chem. 2000; 275: 19167-19176Abstract Full Text Full Text PDF PubMed Scopus (181) Google Scholar), although the founding member, interleukin-17, is expressed exclusively in T cells and B cells (4Zhou L. Peng S. Duan J. Zhou J. Wang L. Wang J. Biochem. Mol. Biol. Int. 1998; 45: 1113-1119PubMed Google Scholar, 5Yao Z. Painter S.L. Fanslow W.C. Ulrich D. Macduff B.M. Spriggs M.K. Armitage R.J. J. Immunol. 1995; 155: 5483-5486PubMed Google Scholar, 6Aarvak T. Chabaud M. Miossec P. Natvig J.B. J. Immunol. 1999; 162: 1246-1251PubMed Google Scholar, 7Chabaud M. Durand J.M. Buchs N. Fossiez F. Page G. Frappart L. Miossec P. Arthritis Rheum. 1999; 42: 963-970Crossref PubMed Scopus (806) Google Scholar, 8Albanesi C. Cavani A. Girolomoni G. J. Immunol. 1999; 162: 494-502PubMed Google Scholar). The cloning and characterization of a novel single-pass transmembrane protein with limited homology to the interleukin-17 receptor is reported. High mRNA levels were detected in prostate, cartilage, kidney, liver, heart, and muscle, whereas transcripts were barely detected in thymus and leukocytes. At least 11 RNA splice variants were found, transcribed from 19 exons on human chromosome 3p25.3–3p24.1. Differential exon usage was found in different tissues by quantitative reverse transcriptase-PCR. Predicted proteins range from 186 to 720 amino acids. Soluble secreted proteins lacking transmembrane and intracellular domains are predicted from several splice isoforms and may function as extracellular antagonists to cytokine signaling by functioning as soluble decoy receptors. Using antibodies directed at the cytoplasmic and extracellular domains of this protein, we investigated its localization and found that it was expressed in a variety of normal human tissues including prostate and in prostate cancer. Members of the interleukin-17 cytokine family are present in a variety of tissues (1Li H. Chen J. Huang A. Stinson J. Heldens S. Foster J. Dowd P. Gurney A.L. Wood W.I. Proc. Natl. Acad. Sci. U. S. A. 2000; 97: 773-778Crossref PubMed Scopus (275) Google Scholar, 2Lee J. Ho W.H. Maruoka M. Corpuz R.T. Baldwin D.T. Foster J.S. Goddard A.D. Yansura D.G. Vandlen R.L. Wood W.I. Gurney A.L. J. Biol. Chem. 2001; 276: 1660-1664Abstract Full Text Full Text PDF PubMed Scopus (319) Google Scholar, 3Shi Y. Ullrich S.J. Zhang J. Connolly K. Grzegorzewski K.J. Barber M.C. Wang W. Wathen K. Hodge V. Fisher C.L. Olsen H. Ruben S.M. Knyazev I. Cho Y.H. Kao V. Wilkinson K.A. Carrell J.A. Ebner R. J. Biol. Chem. 2000; 275: 19167-19176Abstract Full Text Full Text PDF PubMed Scopus (181) Google Scholar), although the founding member, interleukin-17, is expressed exclusively in T cells and B cells (4Zhou L. Peng S. Duan J. Zhou J. Wang L. Wang J. Biochem. Mol. Biol. Int. 1998; 45: 1113-1119PubMed Google Scholar, 5Yao Z. Painter S.L. Fanslow W.C. Ulrich D. Macduff B.M. Spriggs M.K. Armitage R.J. J. Immunol. 1995; 155: 5483-5486PubMed Google Scholar, 6Aarvak T. Chabaud M. Miossec P. Natvig J.B. J. Immunol. 1999; 162: 1246-1251PubMed Google Scholar, 7Chabaud M. Durand J.M. Buchs N. Fossiez F. Page G. Frappart L. Miossec P. Arthritis Rheum. 1999; 42: 963-970Crossref PubMed Scopus (806) Google Scholar, 8Albanesi C. Cavani A. Girolomoni G. J. Immunol. 1999; 162: 494-502PubMed Google Scholar). The cloning and characterization of a novel single-pass transmembrane protein with limited homology to the interleukin-17 receptor is reported. High mRNA levels were detected in prostate, cartilage, kidney, liver, heart, and muscle, whereas transcripts were barely detected in thymus and leukocytes. At least 11 RNA splice variants were found, transcribed from 19 exons on human chromosome 3p25.3–3p24.1. Differential exon usage was found in different tissues by quantitative reverse transcriptase-PCR. Predicted proteins range from 186 to 720 amino acids. Soluble secreted proteins lacking transmembrane and intracellular domains are predicted from several splice isoforms and may function as extracellular antagonists to cytokine signaling by functioning as soluble decoy receptors. Using antibodies directed at the cytoplasmic and extracellular domains of this protein, we investigated its localization and found that it was expressed in a variety of normal human tissues including prostate and in prostate cancer. interleukin interleukin-17 receptor-like protein extracellular signal-regulated protein kinase c-jun N-terminal kinases stress-activated protein kinase mitogen-activated protein kinase nuclear factor κ chain transcription in B cells expressed sequence tag extracellular domain, CYTO, cytoplasmic domain reverse transcriptase Interleukins were historically defined as soluble secreted factors expressed in immune cells that mediate interactions between leukocytes. However, this definition has evolved to include cytokines with a spectrum of pleiotropic actions (reviewed in Refs. 9Paul W.E. Seder R.A. Cell. 1994; 76: 241-251Abstract Full Text PDF PubMed Scopus (1687) Google Scholar and 10Arai K.I. Lee F. Miyajima A. Miyatake S. Arai N. Yokota T. Annu. Rev. Biochem. 1990; 59: 783-836Crossref PubMed Scopus (1168) Google Scholar). Interleukin-17 is a recently discovered cytokine that exerts its effect on many different tissues due to the nearly ubiquitous distribution of its receptor (5Yao Z. Painter S.L. Fanslow W.C. Ulrich D. Macduff B.M. Spriggs M.K. Armitage R.J. J. Immunol. 1995; 155: 5483-5486PubMed Google Scholar, 11Spriggs M.K. J. Clin. Immunol. 1997; 17: 366-369Crossref PubMed Scopus (78) Google Scholar, 12Fossiez F. Banchereau J. Murray R. Van Kooten C. Garrone P. Lebecque S. Int. Rev. Immunol. 1998; 16: 541-551Crossref PubMed Scopus (213) Google Scholar, 13Yao Z. Spriggs M.K. Derry J.M. Strockbine L. Park L.S. VandenBos T. Zappone J.D. Painter S.L. Armitage R.J. Cytokine. 1997; 9: 794-800Crossref PubMed Scopus (243) Google Scholar, 14Rouvier E. Luciani M.F. Mattei M.G. Denizot F. Golstein P. J. Immunol. 1993; 150: 5445-5456PubMed Google Scholar, 15Van Bezooijen R.L. Farih-Sips H.C. Papapoulos S.E. Lowik C.W. J. Bone Miner. Res. 1999; 14: 1513-1521Crossref PubMed Scopus (139) Google Scholar). IL-171 is a proinflammatory cytokine that has been implicated in a number of diseases including rheumatoid arthritis (16Chabaud M. Lubberts E. Joosten L. van Den Berg W. Miossec P. Arthritis Res. 2001; 3: 168-177Crossref PubMed Scopus (265) Google Scholar, 17Lubberts E. Joosten L.A. van de Loo F.A. van den Gersselaar L.A. van den Berg W.B. Arthritis Rheum. 2000; 43: 1300-1306Crossref PubMed Scopus (90) Google Scholar, 18Miossec P. Curr. Opin. Rheumatol. 2000; 12: 181-185Crossref PubMed Scopus (33) Google Scholar), allergic skin immune response (19Albanesi C. Scarponi C. Sebastiani S. Cavani A. De Federici M. Pita O. Puddu P. Girolomoni G. J. Immunol. 2000; 165: 1395-1402Crossref PubMed Scopus (99) Google Scholar), organ transplant rejection (20Antonysamy M.A. Fanslow W.C. Fu F. Li W. Qian S. Troutt A.B. Thomson A.W. Transplant. Proc. 1999; 31: 93Crossref PubMed Scopus (50) Google Scholar, 21Antonysamy M.A. Fanslow W.C. Fu F. Li W. Qian S. Troutt A.B. Thomson A.W. J. Immunol. 1999; 162: 577-584PubMed Google Scholar, 22Loong C.C. Lin C.Y. Lui W.Y. Transplant. Proc. 2000; 321773Crossref PubMed Scopus (22) Google Scholar, 23Van Kooten C. Boonstra J.G. Paape M.E. Fossiez F. Banchereau J. Lebecque S. De Bruijn J.A. Fijter J.W. Van Es L.A. Daha M.R. J. Am. Soc. Nephrol. 1998; 9: 1526-1534Crossref PubMed Google Scholar), and multiple sclerosis (24Matusevicius D. Kivisakk P. He B. Kostulas N. Ozenci V. Fredrikson S. Link H. Mult. Scler. 1999; 5: 101-104Crossref PubMed Scopus (619) Google Scholar). Recent work has identified three related proteins, establishing an IL-17 family of cytokines. These new family members, IL-17B, IL-17C, and IL-17E, share 20–30% homology with IL-17 and have four conserved cysteines, and all contain a putative N-terminal signal peptide typically required for secretion (1Li H. Chen J. Huang A. Stinson J. Heldens S. Foster J. Dowd P. Gurney A.L. Wood W.I. Proc. Natl. Acad. Sci. U. S. A. 2000; 97: 773-778Crossref PubMed Scopus (275) Google Scholar, 2Lee J. Ho W.H. Maruoka M. Corpuz R.T. Baldwin D.T. Foster J.S. Goddard A.D. Yansura D.G. Vandlen R.L. Wood W.I. Gurney A.L. J. Biol. Chem. 2001; 276: 1660-1664Abstract Full Text Full Text PDF PubMed Scopus (319) Google Scholar, 3Shi Y. Ullrich S.J. Zhang J. Connolly K. Grzegorzewski K.J. Barber M.C. Wang W. Wathen K. Hodge V. Fisher C.L. Olsen H. Ruben S.M. Knyazev I. Cho Y.H. Kao V. Wilkinson K.A. Carrell J.A. Ebner R. J. Biol. Chem. 2000; 275: 19167-19176Abstract Full Text Full Text PDF PubMed Scopus (181) Google Scholar).The IL-17 signaling pathway is currently being studied. Although it is not a kinase itself, the IL-17 receptor (IL-17R) has been shown to transduce its signal through the activation of ERK, JNK/SAPK, and p38 MAP kinase pathways (25Shalom-Barak T. Quach J. Lotz M. J. Biol. Chem. 1998; 273: 27467-27473Abstract Full Text Full Text PDF PubMed Scopus (345) Google Scholar, 26Subramaniam S.V. Cooper R.S. Adunyah S.E. Biochem. Biophys. Res. Commun. 1999; 262: 14-19Crossref PubMed Scopus (97) Google Scholar, 27Martel-Pelletier J. Mineau F. Di Jovanovic D. Battista J.A. Pelletier J.P. Arthritis Rheum. 1999; 42: 2399-2409Crossref PubMed Scopus (145) Google Scholar). In the presence of IL-17 ligand, these pathways lead to the up-regulation of genes typically associated with inflammation, such as stromelysin, IL-6, and IL-1β, and the activation of NFkB (28Awane M. Andres P.G. Li D.J. Reinecker H.C. J. Immunol. 1999; 162: 5337-5344PubMed Google Scholar, 29Kehlen A. Thiele K. Riemann D. Rainov N. Langner J. J. Neuroimmunol. 1999; 101: 1-6Abstract Full Text Full Text PDF PubMed Scopus (57) Google Scholar, 30Broxmeyer H.E. J. Exp. Med. 1996; 183: 2411-2415Crossref PubMed Scopus (64) Google Scholar). One additional receptor was first identified as a receptor for IL-17B and named IL-17BR (3Shi Y. Ullrich S.J. Zhang J. Connolly K. Grzegorzewski K.J. Barber M.C. Wang W. Wathen K. Hodge V. Fisher C.L. Olsen H. Ruben S.M. Knyazev I. Cho Y.H. Kao V. Wilkinson K.A. Carrell J.A. Ebner R. J. Biol. Chem. 2000; 275: 19167-19176Abstract Full Text Full Text PDF PubMed Scopus (181) Google Scholar). This receptor was subsequently shown to have greater affinity for IL-17E than for IL-17B and was also named IL-17Rh1. This receptor was shown to activate NFkB in an in vitro luciferase assay (2Lee J. Ho W.H. Maruoka M. Corpuz R.T. Baldwin D.T. Foster J.S. Goddard A.D. Yansura D.G. Vandlen R.L. Wood W.I. Gurney A.L. J. Biol. Chem. 2001; 276: 1660-1664Abstract Full Text Full Text PDF PubMed Scopus (319) Google Scholar). However, the signal transduction pathway and the in vivo functions of this receptor are not known.The existence of several IL-17-related proteins led us to explore the existence of additional members of the IL-17 receptor family. With this in mind, we searched human sequences in the GenBankTM data base, and in this report, we describe the cloning of a new IL-17R-related mRNA and elucidation of its genomic structure. We characterize its expression in various tissues and demonstrate differential exon usage in different tissues. We present evidence of splice variants that code for single-pass transmembrane proteins as well as secreted proteins that lack the transmembrane and cytoplasmic domains and may function as soluble decoy receptors. This novel receptor is expressed in human prostate and in prostate cancer.DISCUSSIONPrevious work from our laboratory and others (1Li H. Chen J. Huang A. Stinson J. Heldens S. Foster J. Dowd P. Gurney A.L. Wood W.I. Proc. Natl. Acad. Sci. U. S. A. 2000; 97: 773-778Crossref PubMed Scopus (275) Google Scholar, 2Lee J. Ho W.H. Maruoka M. Corpuz R.T. Baldwin D.T. Foster J.S. Goddard A.D. Yansura D.G. Vandlen R.L. Wood W.I. Gurney A.L. J. Biol. Chem. 2001; 276: 1660-1664Abstract Full Text Full Text PDF PubMed Scopus (319) Google Scholar, 3Shi Y. Ullrich S.J. Zhang J. Connolly K. Grzegorzewski K.J. Barber M.C. Wang W. Wathen K. Hodge V. Fisher C.L. Olsen H. Ruben S.M. Knyazev I. Cho Y.H. Kao V. Wilkinson K.A. Carrell J.A. Ebner R. J. Biol. Chem. 2000; 275: 19167-19176Abstract Full Text Full Text PDF PubMed Scopus (181) Google Scholar) 2L. Rose, personal communication, manuscript in preparation. has identified new members of the IL-17 family of cytokines and implicated them in a variety of normal and disease-related conditions. The number of newly identified IL-17 family cytokines provided an impetus to explore the existence of additional receptors. The aim of the present study was to identify new receptors based on homology to the published IL-17 receptor. To this end, we have searched the public EST data base and identified a cDNA coding for a novel protein related to IL-17R. We named this protein IL17-RL (receptor-like) based on its homology to IL-17R. Its primary sequence suggests that, like IL-17R, it is a single-pass transmembrane protein with an extracellular N terminus. We characterized its expression in a variety of human tissues at the mRNA level, as well as on tissue extracts and histological sections at the protein level. We determined its genomic structure and found evidence of alternative splicing even in the limited number of EST sequences available in the public data bases.The RNA splicing of this gene is of particular interest because a number of the observed splice variants introduce frameshifts and stop codons before the C-terminal transmembrane domain, resulting in the translation of secreted rather than transmembrane protein. We found 12 different splice variants in the 108 ESTs currently in the data base. Exons 7, 12, 14, and 15 were spliced out in several ESTs, and exons 6, 8, 9, 11, 14, 18, and 19 have alternate splice donor or acceptor sites. Some ESTs have combinations of two or more nearby exons spliced out. Additional splice variants with combinations of distant exons are possible, but due to the limited length of sequence available from each EST, we have no direct evidence for this. Also, further splice variations in the 5′ end of the mRNA may have been missed because of the inherent bias toward 3′ ends in the EST data base. The extent of alternative splicing is not immediately evident from Northern blot analysis because many of the exons are of similar size and are relatively small when compared with the overall length of the mRNA. However, we have confirmed the presence of multiple transcripts from single tissues and cell lines using RT-PCR (data not shown).We have demonstrated by quantitative RT-PCR that most of the mRNA does not contain exon 7. Moreover, there is some evidence that exon 7 usage is tissue-specific because it is present less frequently in RNA isolated from the brain than from the liver or heart. This implies that there may be tissue-specific regulatory factors that control the RNA splicing of this gene and also that there may be a functional difference between proteins made from mRNA with and without exon 7. This raises the additional possibility that regulation of splicing may occur in response to the activation of growth factor signaling pathways.The assembled full-length cDNA has a single large open reading frame that is predicted to encode a 720-amino acid single-pass transmembrane protein. Translation of the alternatively spliced mRNAs results in at least eleven additional proteins. Although the open reading frame of downstream exons is not affected by the removal of exons 7, 12, or 15, the removal of most other exons causes a frameshift that introduces in-frame stop codons. An in-frame stop codon before exon 17, which codes for the transmembrane domain, will result in translation of a secreted protein. Therefore, the translation products can be classified into two general categories. Both categories contain the presumed ligand binding extracellular domain. The first category is full-length proteins, which have the ligand binding extracellular domain along with transmembrane and cytoplasmic domains. Since the cytoplasmic domain is predicted to contain several phosphorylation sites, this first category of proteins has the potential both for ligand binding and for subsequent activation of cytosolic signal transduction pathways. The second category is truncated proteins, which contain the extracellular domain but in which a stop codon occurs in or before the transmembrane domain. This category consists of either membrane-associated or soluble secreted proteins. Presumably these proteins retain the ligand binding activity but without the capacity for activation of signal transduction pathways. It is likely that the soluble receptor isoforms may thus function as signaling antagonists or decoy receptors.Analysis by immunoblotting confirms that multiple proteins with different molecular weights are detected in homogenates of a single tissue, presumably from translations of alternatively spliced mRNA. Immunohistochemical analysis also indicates that multiple isoforms of the proteins can exist because some tissues bind strongly to antibodies directed against both the extracellular and the cytoplasmic domain, whereas other tissues only bind strongly to antibodies directed against the extracellular domain. Especially noteworthy is the localization in the prostate and prostate cancers. This differential localization of soluble and membrane-bound receptor implies that certain tissues expressing primarily soluble receptor may not respond to the ligand.As there was a strong immunohistochemical localization of the novel IL17-RL in prostate by the antibody directed against the extracellular domain (anti-ECD), it was of interest to also compare the localization in prostate cancers. The results are depicted in Fig. 7. In the normal prostate, IL17-RL was localized in both the epithelial and stromal compartments. In prostate cancers with increasing Gleason grade, there was a progressive loss of staining in the epithelium and increased staining in the stroma. The antibody used is directed against the N-terminal extracellular domain, which is present in both the transmembrane and the soluble decoy isoforms of IL17-RL. Thus, it is possible that in prostate cancer, the redistribution of the receptor from epithelial to stromal compartments signifies a dysregulation of expression or signaling of IL17-RL.With the completion of the human genome project came the realization that the human genome contains far fewer genes than originally predicted (31Lander E.S. Linton L.M. Birren B. Nusbaum C. Zody M.C. Baldwin J. Devon K. Dewar K. Doyle M. FitzHugh W. Funke R. Gage D. Harris K. Heaford A. Howland J. Kann L. Lehoczky J. LeVine R. McEwan P. McKernan K. Meldrim J. Mesirov J.P. Miranda C. Morris W. Naylor J. Raymond C. Rosetti M. Santos R. Sheridan A. Sougnez C. Stange-Thomann N. Stojanovic N. Subramanian A. Wyman D. Rogers J. Sulston J. Ainscough R. Beck S. Bentley D. Burton J. Clee C. Carter N. Coulson A. Deadman R. Deloukas P. Dunham A. Dunham I. Durbin R. French L. Grafham D. Gregory S. Hubbard T. Humphray S. Hunt A. Jones M. Lloyd C. McMurray A. Matthews L. Mercer S. Milne S. Mullikin J.C. Mungall A. Plumb R. Ross M. Shownkeen R. Sims S. Waterston R.H. Wilson R.K. Hillier L.W. McPherson J.D. Marra M.A. Mardis E.R. Fulton L.A. Chinwalla A.T. Pepin K.H. Gish W.R. Chissoe S.L. Wendl M.C. Delehaunty K.D. Miner T.L. Delehaunty A. Kramer J.B. Cook L.L. Fulton R.S. Johnson D.L. Minx P.J. Clifton S.W. Hawkins T. Branscomb E. Predki P. Richardson P. Wenning S. Slezak T. Doggett N. Cheng J.F. Olsen A. Lucas S. Elkin C. Uberbacher E. Frazier M. et al.Nature. 2001; 409: 860-921Crossref PubMed Scopus (17490) Google Scholar, 32Venter J.C. Adams M.D. Myers E.W. Li P.W. Mural R.J. Sutton G.G. Smith H.O. Yandell M. Evans C.A. Holt R.A. Gocayne J.D. Amanatides P. Ballew R.M. Huson D.H. Wortman J.R. Zhang Q. Kodira C.D. Zheng X.H. Chen L. Skupski M. Subramanian G. Thomas P.D. Zhang J. Gabor Miklos G.L. Nelson C. Broder S. Clark A.G. Nadeau J. McKusick V.A. Zinder N. Levine A.J. Roberts R.J. Simon M. Slayman C. Hunkapiller M. Bolanos R. Delcher A. Dew I. Fasulo D. Flanigan M. Florea L. Halpern A. Hannenhalli S. Kravitz S. Levy S. Mobarry C. Reinert K. Remington K. Abu-Threideh J. Beasley E. Biddick K. Bonazzi V. Brandon R. Cargill M. Chandramouliswaran I. Charlab R. Chaturvedi K. Di Deng Z. Francesco V. Dunn P. Eilbeck K. Evangelista C. Gabrielian A.E. Gan W. Ge W. Gong F. Gu Z. Guan P. Heiman T.J. Higgins M.E. Ji R.R. Ke Z. Ketchum K.A. Lai Z. Lei Y. Li Z. Li J. Liang Y. Lin X. Lu F. Merkulov G.V. Milshina N. Moore H.M. Naik A.K. Narayan V.A. Neelam B. Nusskern D. Rusch D.B. Salzberg S. Shao W. Shue B. Sun J. Wang Z. Wang A. Wang X. Wang J. Wei M. Wides R. Xiao C. Yan C. et al.Science. 2001; 291: 1304-1351Crossref PubMed Scopus (10466) Google Scholar). The complexity of the gene we have identified, which has 19 exons and codes for at least 12 different mRNAs and therefore can be translated into several functional isoforms, demonstrates the intricate regulation of function by the transcription and translation of multiple RNAs by RNA splicing. The precise function of the novel receptor IL17-RL and its splice isoforms remains unknown, and understanding its function and regulation are the focus of our laboratory. Interleukins were historically defined as soluble secreted factors expressed in immune cells that mediate interactions between leukocytes. However, this definition has evolved to include cytokines with a spectrum of pleiotropic actions (reviewed in Refs. 9Paul W.E. Seder R.A. Cell. 1994; 76: 241-251Abstract Full Text PDF PubMed Scopus (1687) Google Scholar and 10Arai K.I. Lee F. Miyajima A. Miyatake S. Arai N. Yokota T. Annu. Rev. Biochem. 1990; 59: 783-836Crossref PubMed Scopus (1168) Google Scholar). Interleukin-17 is a recently discovered cytokine that exerts its effect on many different tissues due to the nearly ubiquitous distribution of its receptor (5Yao Z. Painter S.L. Fanslow W.C. Ulrich D. Macduff B.M. Spriggs M.K. Armitage R.J. J. Immunol. 1995; 155: 5483-5486PubMed Google Scholar, 11Spriggs M.K. J. Clin. Immunol. 1997; 17: 366-369Crossref PubMed Scopus (78) Google Scholar, 12Fossiez F. Banchereau J. Murray R. Van Kooten C. Garrone P. Lebecque S. Int. Rev. Immunol. 1998; 16: 541-551Crossref PubMed Scopus (213) Google Scholar, 13Yao Z. Spriggs M.K. Derry J.M. Strockbine L. Park L.S. VandenBos T. Zappone J.D. Painter S.L. Armitage R.J. Cytokine. 1997; 9: 794-800Crossref PubMed Scopus (243) Google Scholar, 14Rouvier E. Luciani M.F. Mattei M.G. Denizot F. Golstein P. J. Immunol. 1993; 150: 5445-5456PubMed Google Scholar, 15Van Bezooijen R.L. Farih-Sips H.C. Papapoulos S.E. Lowik C.W. J. Bone Miner. Res. 1999; 14: 1513-1521Crossref PubMed Scopus (139) Google Scholar). IL-171 is a proinflammatory cytokine that has been implicated in a number of diseases including rheumatoid arthritis (16Chabaud M. Lubberts E. Joosten L. van Den Berg W. Miossec P. Arthritis Res. 2001; 3: 168-177Crossref PubMed Scopus (265) Google Scholar, 17Lubberts E. Joosten L.A. van de Loo F.A. van den Gersselaar L.A. van den Berg W.B. Arthritis Rheum. 2000; 43: 1300-1306Crossref PubMed Scopus (90) Google Scholar, 18Miossec P. Curr. Opin. Rheumatol. 2000; 12: 181-185Crossref PubMed Scopus (33) Google Scholar), allergic skin immune response (19Albanesi C. Scarponi C. Sebastiani S. Cavani A. De Federici M. Pita O. Puddu P. Girolomoni G. J. Immunol. 2000; 165: 1395-1402Crossref PubMed Scopus (99) Google Scholar), organ transplant rejection (20Antonysamy M.A. Fanslow W.C. Fu F. Li W. Qian S. Troutt A.B. Thomson A.W. Transplant. Proc. 1999; 31: 93Crossref PubMed Scopus (50) Google Scholar, 21Antonysamy M.A. Fanslow W.C. Fu F. Li W. Qian S. Troutt A.B. Thomson A.W. J. Immunol. 1999; 162: 577-584PubMed Google Scholar, 22Loong C.C. Lin C.Y. Lui W.Y. Transplant. Proc. 2000; 321773Crossref PubMed Scopus (22) Google Scholar, 23Van Kooten C. Boonstra J.G. Paape M.E. Fossiez F. Banchereau J. Lebecque S. De Bruijn J.A. Fijter J.W. Van Es L.A. Daha M.R. J. Am. Soc. Nephrol. 1998; 9: 1526-1534Crossref PubMed Google Scholar), and multiple sclerosis (24Matusevicius D. Kivisakk P. He B. Kostulas N. Ozenci V. Fredrikson S. Link H. Mult. Scler. 1999; 5: 101-104Crossref PubMed Scopus (619) Google Scholar). Recent work has identified three related proteins, establishing an IL-17 family of cytokines. These new family members, IL-17B, IL-17C, and IL-17E, share 20–30% homology with IL-17 and have four conserved cysteines, and all contain a putative N-terminal signal peptide typically required for secretion (1Li H. Chen J. Huang A. Stinson J. Heldens S. Foster J. Dowd P. Gurney A.L. Wood W.I. Proc. Natl. Acad. Sci. U. S. A. 2000; 97: 773-778Crossref PubMed Scopus (275) Google Scholar, 2Lee J. Ho W.H. Maruoka M. Corpuz R.T. Baldwin D.T. Foster J.S. Goddard A.D. Yansura D.G. Vandlen R.L. Wood W.I. Gurney A.L. J. Biol. Chem. 2001; 276: 1660-1664Abstract Full Text Full Text PDF PubMed Scopus (319) Google Scholar, 3Shi Y. Ullrich S.J. Zhang J. Connolly K. Grzegorzewski K.J. Barber M.C. Wang W. Wathen K. Hodge V. Fisher C.L. Olsen H. Ruben S.M. Knyazev I. Cho Y.H. Kao V. Wilkinson K.A. Carrell J.A. Ebner R. J. Biol. Chem. 2000; 275: 19167-19176Abstract Full Text Full Text PDF PubMed Scopus (181) Google Scholar). The IL-17 signaling pathway is currently being studied. Although it is not a kinase itself, the IL-17 receptor (IL-17R) has been shown to transduce its signal through the activation of ERK, JNK/SAPK, and p38 MAP kinase pathways (25Shalom-Barak T. Quach J. Lotz M. J. Biol. Chem. 1998; 273: 27467-27473Abstract Full Text Full Text PDF PubMed Scopus (345) Google Scholar, 26Subramaniam S.V. Cooper R.S. Adunyah S.E. Biochem. Biophys. Res. Commun. 1999; 262: 14-19Crossref PubMed Scopus (97) Google Scholar, 27Martel-Pelletier J. Mineau F. Di Jovanovic D. Battista J.A. Pelletier J.P. Arthritis Rheum. 1999; 42: 2399-2409Crossref PubMed Scopus (145) Google Scholar). In the presence of IL-17 ligand, these pathways lead to the up-regulation of genes typically associated with inflammation, such as stromelysin, IL-6, and IL-1β, and the activation of NFkB (28Awane M. Andres P.G. Li D.J. Reinecker H.C. J. Immunol. 1999; 162: 5337-5344PubMed Google Scholar, 29Kehlen A. Thiele K. Riemann D. Rainov N. Langner J. J. Neuroimmunol. 1999; 101: 1-6Abstract Full Text Full Text PDF PubMed Scopus (57) Google Scholar, 30Broxmeyer H.E. J. Exp. Med. 1996; 183: 2411-2415Crossref PubMed Scopus (64) Google Scholar). One additional receptor was first identified as a receptor for IL-17B and named IL-17BR (3Shi Y. Ullrich S.J. Zhang J. Connolly K. Grzegorzewski K.J. Barber M.C. Wang W. Wathen K. Hodge V. Fisher C.L. Olsen H. Ruben S.M. Knyazev I. Cho Y.H. Kao V. Wilkinson K.A. Carrell J.A. Ebner R. J. Biol. Chem. 2000; 275: 19167-19176Abstract Full Text Full Text PDF PubMed Scopus (181) Google Scholar). This receptor was subsequently shown to have greater affinity for IL-17E than for IL-17B and was also named IL-17Rh1. This receptor was shown to activate NFkB in an in vitro luciferase assay (2Lee J. Ho W.H. Maruoka M. Corpuz R.T. Baldwin D.T. Foster J.S. Goddard A.D. Yansura D.G. Vandlen R.L. Wood W.I. Gurney A.L. J. Biol. Chem. 2001; 276: 1660-1664Abstract Full Text Full Text PDF PubMed Scopus (319) Google Scholar). However, the signal transduction pathway and the in vivo functions of this receptor are not known. The existence of several IL-17-related proteins led us to explore the existence of additional members of the IL-17 receptor family. With this in mind, we searched human sequences in the GenBankTM data base, and in this report, we describe the cloning of a new IL-17R-related mRNA and elucidation of its genomic structure. We characterize its expression in various tissues and demonstrate differential exon usage in different tissues. We present evidence of splice variants that code for single-pass transmembrane proteins as well as secreted proteins that lack the transmembrane and cytoplasmic domains and may function as soluble decoy receptors. This novel receptor is expressed in human prostate and in prostate cancer. DISCUSSIONPrevious work from our laboratory and others (1Li H. Chen J. Huang A. Stinson J. Heldens S. Foster J. Dowd P. Gurney A.L. Wood W.I. Proc. Natl. Acad. Sci. U. S. A. 2000; 97: 773-778Crossref PubMed Scopus (275) Google Scholar, 2Lee J. Ho W.H. Maruoka M. Corpuz R.T. Baldwin D.T. Foster J.S. Goddard A.D. Yansura D.G. Vandlen R.L. Wood W.I. Gurney A.L. J. Biol. Chem. 2001; 276: 1660-1664Abstract Full Text Full Text PDF PubMed Scopus (319) Google Scholar, 3Shi Y. Ullrich S.J. Zhang J. Connolly K. Grzegorzewski K.J. Barber M.C. Wang W. Wathen K. Hodge V. Fisher C.L. Olsen H. Ruben S.M. Knyazev I. Cho Y.H. Kao V. Wilkinson K.A. Carrell J.A. Ebner R. J. Biol. Chem. 2000; 275: 19167-19176Abstract Full Text Full Text PDF PubMed Scopus (181) Google Scholar) 2L. Rose, personal communication, manuscript in preparation. has identified new members of the IL-17 family of cytokines and implicated them in a variety of normal and disease-related conditions. The number of newly identified IL-17 family cytokines provided an impetus to explore the existence of additional receptors. The aim of the prese
Publication Year: 2002
Publication Date: 2002-02-01
Language: en
Type: article
Indexed In: ['crossref', 'pubmed']

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1794, 1841, 2006, 2035, 2043, 2055, 2065, 2123, 2136, 2152, 2160, 2177, 2187, 2193, 2208, 2213, 2270, 2291, 2295, 2303, 2310, 2330, 2343, 2347, 2353, 2377, 2405, 2409, 2424, 2451, 2463, 2493, 2505, 2516, 2524, 2548, 2560, 2573, 2587, 2599, 2615, 2638, 2651, 2668, 2674, 2686, 2732, 2746, 2749, 2762, 2768, 2771, 2796, 2805, 2811, 2815, 2826, 2839, 2847, 2867, 2873, 2881, 2890, 2893, 2907, 2910, 2926, 2929, 2934, 2937, 3372, 3399, 3405, 3419, 3436, 3531, 4074, 4086, 4158, 4167, 4182, 4376, 4381, 4401, 4407, 4420, 4430, 4477, 4643, 4672, 4680], 'interleukin-17': [3, 259, 389, 645, 773], 'cytokine': [4, 343, 390, 729, 886, 1031, 3520, 3665], 'family': [5, 391, 1269, 1274, 2008, 2028, 3903, 3908, 4645, 4665], 'are': [6, 330, 392, 716, 1753, 2265, 2332, 2337, 2709, 2833, 3435, 4388], 'present': [7, 393, 1823, 2044, 2398, 2887, 4459], 'in': [8, 144, 268, 281, 306, 373, 383, 394, 530, 654, 667, 692, 759, 769, 794, 816, 839, 1036, 1696, 1698, 1747, 1777, 1783, 1789, 1811, 1819, 1858, 1862, 1999, 2014, 2116, 2151, 2159, 2192, 2207, 2212, 2225, 2290, 2309, 2401, 2460, 2498, 2553, 2642, 2648, 2711, 2770, 2808, 2828, 2835, 2845, 2866, 2872, 2888, 2904, 3450, 3473, 3670, 4331, 4333, 4382, 4413, 4419, 4425, 4447, 4455, 4494, 4498, 4636, 4651], 'a': [9, 249, 374, 395, 635, 760, 833, 883, 1029, 1037, 1293, 1436, 1611, 1797, 2015, 2072, 2076, 2103, 2117, 2174, 2436, 2474, 2485, 2531, 2556, 2644, 2714, 2800, 2861, 2918, 3467, 3517, 3663, 3671, 3927, 4071, 4246, 4433, 4652], 'variety': [10, 375, 396, 761, 2016, 2118, 4653], 'tissues': [12, 308, 379, 398, 694, 765, 894, 1813, 2121, 2360, 2738, 2754, 2787, 3528, 4449], '(1Li': [13, 399, 1302, 1871, 3936, 4508], 'H.': [14, 105, 400, 491, 1248, 1303, 1394, 1639, 1872, 1963, 3882, 3937, 4028, 4274, 4509, 4600], 'Chen': [15, 401, 1304, 1873, 3193, 3938, 4510], 'J.': [16, 20, 24, 47, 68, 89, 120, 155, 157, 161, 185, 200, 237, 402, 406, 410, 433, 454, 475, 506, 541, 543, 547, 571, 586, 623, 918, 927, 941, 999, 1015, 1126, 1177, 1209, 1222, 1305, 1309, 1313, 1336, 1357, 1378, 1409, 1464, 1467, 1502, 1559, 1575, 1576, 1593, 1623, 1654, 1703, 1724, 1874, 1878, 1882, 1905, 1926, 1947, 1978, 2958, 2976, 2980, 2988, 2996, 3016, 3018, 3026, 3202, 3213, 3255, 3312, 3342, 3350, 3552, 3561, 3575, 3633, 3649, 3760, 3811, 3843, 3856, 3939, 3943, 3947, 3970, 3991, 4012, 4043, 4099, 4102, 4137, 4194, 4210, 4211, 4228, 4258, 4289, 4338, 4359, 4511, 4515, 4519, 4542, 4563, 4584, 4615], 'Huang': [17, 403, 1306, 1875, 3940, 4512], 'A.': [18, 37, 234, 404, 423, 620, 863, 1116, 1307, 1326, 1567, 1876, 1895, 2974, 3004, 3012, 3032, 3038, 3054, 3060, 3070, 3108, 3138, 3231, 3241, 3346, 3497, 3750, 3941, 3960, 4202, 4513, 4532], 'Stinson': [19, 405, 1308, 1877, 3942, 4514], 'Heldens': [21, 407, 1310, 1879, 3944, 4516], 'S.': [22, 36, 153, 408, 422, 539, 865, 950, 1114, 1148, 1172, 1211, 1246, 1311, 1325, 1880, 1894, 3022, 3048, 3052, 3064, 3066, 3078, 3130, 3140, 3209, 3243, 3245, 3247, 3336, 3499, 3584, 3748, 3782, 3806, 3845, 3880, 3945, 3959, 4517, 4531], 'Foster': [23, 56, 409, 442, 1312, 1345, 1712, 1881, 1914, 3946, 3979, 4347, 4518, 4551], 'Dowd': [25, 411, 1314, 1883, 3948, 4520], 'P.': [26, 197, 220, 412, 583, 606, 948, 998, 1055, 1093, 1123, 1238, 1315, 1884, 2984, 3036, 3126, 3128, 3180, 3278, 3294, 3582, 3632, 3689, 3727, 3757, 3872, 3949, 4521], 'Gurney': [27, 66, 413, 452, 1316, 1355, 1722, 1885, 1924, 3950, 3989, 4357, 4522, 4561], 'A.L.': [28, 67, 414, 453, 1317, 1356, 1723, 1886, 1925, 3951, 3990, 4358, 4523, 4562], 'Wood': [29, 64, 415, 450, 1318, 1353, 1720, 1887, 1922, 3952, 3987, 4355, 4524, 4559], 'W.I.': [30, 65, 416, 451, 1319, 1354, 1721, 1888, 1923, 3953, 3988, 4356, 4525, 4560], 'Proc.': [31, 417, 1154, 1191, 1320, 1889, 3788, 3825, 3954, 4526], 'Natl.': [32, 418, 1321, 1890, 3955, 4527], 'Acad.': [33, 419, 1322, 1891, 3956, 4528], 'Sci.': [34, 420, 1323, 1892, 3957, 4529], 'U.': [35, 421, 1324, 1893, 3958, 4530], '2000;': [38, 123, 424, 509, 1084, 1097, 1128, 1192, 1327, 1412, 1657, 1896, 1981, 3718, 3731, 3762, 3826, 3961, 4046, 4292, 4533, 4618], '97:': [39, 425, 1328, 1897, 3962, 4534], '773-778Crossref': [40, 426, 1329, 1898, 3963, 4535], 'PubMed': [41, 79, 131, 226, 427, 465, 517, 612, 852, 876, 933, 957, 984, 1022, 1061, 1087, 1100, 1131, 1158, 1194, 1229, 1254, 1330, 1368, 1420, 1478, 1496, 1517, 1586, 1599, 1665, 1735, 1899, 1937, 1989, 3152, 3364, 3486, 3510, 3567, 3591, 3618, 3656, 3695, 3721, 3734, 3765, 3792, 3828, 3863, 3888, 3964, 4002, 4054, 4113, 4131, 4152, 4221, 4234, 4300, 4370, 4536, 4574, 4626], 'Scopus': [42, 80, 132, 227, 428, 466, 518, 613, 853, 877, 934, 958, 985, 1023, 1062, 1088, 1101, 1132, 1159, 1195, 1255, 1331, 1369, 1421, 1479, 1497, 1518, 1587, 1600, 1666, 1736, 1900, 1938, 1990, 3153, 3365, 3487, 3511, 3568, 3592, 3619, 3657, 3696, 3722, 3735, 3766, 3793, 3829, 3889, 3965, 4003, 4055, 4114, 4132, 4153, 4222, 4235, 4301, 4371, 4537, 4575, 4627], '(275)': [43, 429, 1332, 1901, 3966, 4538], 'Google': [44, 82, 134, 169, 190, 205, 229, 242, 430, 468, 520, 555, 576, 591, 615, 628, 855, 879, 923, 936, 960, 987, 1004, 1025, 1064, 1090, 1103, 1134, 1161, 1182, 1197, 1230, 1257, 1333, 1371, 1423, 1481, 1499, 1520, 1564, 1589, 1602, 1668, 1738, 1902, 1940, 1992, 3155, 3367, 3489, 3513, 3557, 3570, 3594, 3621, 3638, 3659, 3698, 3724, 3737, 3768, 3795, 3816, 3831, 3864, 3891, 3967, 4005, 4057, 4116, 4134, 4155, 4199, 4224, 4237, 4303, 4373, 4539, 4577, 4629], 'Scholar,': [45, 83, 170, 191, 206, 230, 431, 469, 556, 577, 592, 616, 924, 937, 961, 988, 1005, 1065, 1091, 1162, 1183, 1198, 1334, 1372, 1482, 1500, 1565, 1590, 1903, 1941, 3156, 3558, 3571, 3595, 3622, 3639, 3699, 3725, 3796, 3817, 3832, 3968, 4006, 4117, 4135, 4200, 4225, 4540, 4578], '2Lee': [46, 432, 1335, 1904, 3969, 4541], 'Ho': [48, 434, 1337, 1704, 1906, 3971, 4339, 4543], 'W.H.': [49, 435, 1338, 1705, 1907, 3972, 4340, 4544], 'Maruoka': [50, 436, 1339, 1706, 1908, 3973, 4341, 4545], 'M.': [51, 195, 208, 437, 581, 594, 1045, 1119, 1340, 1466, 1552, 1707, 1909, 2964, 3000, 3056, 3074, 3146, 3172, 3196, 3223, 3227, 3237, 3265, 3352, 3679, 3753, 3974, 4101, 4187, 4342, 4546], 'Corpuz': [52, 438, 1341, 1708, 1910, 3975, 4343, 4547], 'R.T.': [53, 439, 1342, 1709, 1911, 3976, 4344, 4548], 'Baldwin': [54, 440, 1343, 1710, 1912, 2957, 3977, 4345, 4549], 'D.T.': [55, 441, 1344, 1711, 1913, 3978, 4346, 4550], 'J.S.': [57, 443, 1346, 1713, 1915, 3980, 4348, 4552], 'Goddard': [58, 444, 1347, 1714, 1916, 3981, 4349, 4553], 'A.D.': [59, 445, 1348, 1715, 1917, 3982, 4350, 4554], 'Yansura': [60, 446, 1349, 1716, 1918, 3983, 4351, 4555], 'D.G.': [61, 447, 1350, 1717, 1919, 3984, 4352, 4556], 'Vandlen': [62, 448, 1351, 1718, 1920, 3985, 4353, 4557], 'R.L.': [63, 449, 1008, 1352, 1719, 1921, 3642, 3986, 4354, 4558], 'Biol.': [69, 121, 164, 455, 507, 550, 1358, 1410, 1468, 1655, 1725, 1927, 1979, 3992, 4044, 4103, 4290, 4360, 4564, 4616], 'Chem.': [70, 122, 456, 508, 1359, 1411, 1469, 1656, 1726, 1928, 1980, 3993, 4045, 4104, 4291, 4361, 4565, 4617], '2001;': [71, 457, 1058, 1360, 1727, 1929, 3149, 3361, 3692, 3994, 4362, 4566], '276:': [72, 458, 1361, 1728, 1930, 3995, 4363, 4567], '1660-1664Abstract': [73, 459, 1362, 1729, 1931, 3996, 4364, 4568], 'Full': [74, 76, 126, 128, 460, 462, 512, 514, 849, 1363, 1365, 1415, 1417, 1473, 1475, 1581, 1583, 1660, 1662, 1730, 1732, 1932, 1934, 1984, 1986, 3483, 3997, 3999, 4049, 4051, 4108, 4110, 4216, 4218, 4295, 4297, 4365, 4367, 4569, 4571, 4621, 4623], 'Text': [75, 77, 127, 129, 461, 463, 513, 515, 850, 1364, 1366, 1416, 1418, 1474, 1476, 1582, 1584, 1661, 1663, 1731, 1733, 1933, 1935, 1985, 1987, 3484, 3998, 4000, 4050, 4052, 4109, 4111, 4217, 4219, 4296, 4298, 4366, 4368, 4570, 4572, 4622, 4624], 'PDF': [78, 130, 464, 516, 851, 1367, 1419, 1477, 1585, 1664, 1734, 1936, 1988, 3485, 4001, 4053, 4112, 4220, 4299, 4369, 4573, 4625], '(319)': [81, 467, 1370, 1737, 1939, 4004, 4372, 4576], '3Shi': [84, 470, 1373, 1942, 4007, 4579], 'Y.': [85, 471, 1374, 1619, 1943, 3308, 3314, 4008, 4254, 4580], 'Ullrich': [86, 472, 1375, 1620, 1944, 4009, 4255, 4581], 'S.J.': [87, 473, 1376, 1621, 1945, 4010, 4256, 4582], 'Zhang': [88, 474, 1377, 1622, 1946, 3187, 3201, 4011, 4257, 4583], 'Connolly': [90, 476, 1379, 1624, 1948, 4013, 4259, 4585], 'K.': [91, 99, 477, 485, 1380, 1388, 1569, 1625, 1633, 1949, 1957, 2960, 2962, 2972, 2986, 3251, 3253, 3259, 3271, 3280, 4014, 4022, 4204, 4260, 4268, 4586, 4594], 'Grzegorzewski': [92, 478, 1381, 1626, 1950, 4015, 4261, 4587], 'K.J.': [93, 479, 1382, 1627, 1951, 4016, 4262, 4588], 'Barber': [94, 480, 1383, 1628, 1952, 4017, 4263, 4589], 'M.C.': [95, 481, 1384, 1629, 1953, 2956, 3102, 4018, 4264, 4590], 'Wang': [96, 158, 160, 482, 544, 546, 1385, 1630, 1954, 3343, 3345, 3347, 3349, 4019, 4265, 4591], 'W.': [97, 483, 1053, 1146, 1170, 1386, 1631, 1955, 2966, 2994, 3286, 3288, 3338, 3687, 3780, 3804, 4020, 4266, 4592], 'Wathen': [98, 484, 1387, 1632, 1956, 4021, 4267, 4593], 'Hodge': [100, 486, 1389, 1634, 1958, 4023, 4269, 4595], 'V.': [101, 113, 487, 499, 1244, 1390, 1402, 1635, 1647, 1959, 1971, 3261, 3276, 3878, 4024, 4036, 4270, 4282, 4596, 4608], 'Fisher': [102, 488, 1391, 1636, 1960, 4025, 4271, 4597], 'C.L.': [103, 489, 1392, 1637, 1961, 4026, 4272, 4598], 'Olsen': [104, 490, 1393, 1638, 1962, 3137, 4027, 4273, 4599], 'Ruben': [106, 492, 1395, 1640, 1964, 4029, 4275, 4601], 'S.M.': [107, 493, 1396, 1641, 1965, 4030, 4276, 4602], 'Knyazev': [108, 494, 1397, 1642, 1966, 4031, 4277, 4603], 'I.': [109, 495, 1398, 1643, 1967, 3040, 3233, 3267, 4032, 4278, 4604], 'Cho': [110, 496, 1399, 1644, 1968, 4033, 4279, 4605], 'Y.H.': [111, 497, 1400, 1645, 1969, 4034, 4280, 4606], 'Kao': [112, 498, 1401, 1646, 1970, 4035, 4281, 4607], 'Wilkinson': [114, 500, 1403, 1648, 1972, 4037, 4283, 4609], 'K.A.': [115, 501, 1404, 1649, 1973, 3304, 4038, 4284, 4610], 'Carrell': [116, 502, 1405, 1650, 1974, 4039, 4285, 4611], 'J.A.': [117, 503, 1214, 1406, 1509, 1651, 1975, 3848, 4040, 4144, 4286, 4612], 'Ebner': [118, 504, 1407, 1652, 1976, 4041, 4287, 4613], 'R.': [119, 505, 943, 1408, 1653, 1977, 2968, 2982, 3002, 3020, 3034, 3042, 3072, 3076, 3229, 3263, 3269, 3354, 3577, 4042, 4288, 4614], '275:': [124, 510, 1413, 1658, 1982, 4047, 4293, 4619], '19167-19176Abstract': [125, 511, 1414, 1659, 1983, 4048, 4294, 4620], '(181)': [133, 519, 1422, 1667, 1991, 4056, 4302, 4628], 'Scholar),': [135, 521, 1104, 1135, 1231, 3738, 3769, 3865], 'although': [136, 522], 'founding': [138, 524], 'member,': [139, 525], 'interleukin-17,': [140, 526], 'is': [141, 261, 527, 647, 882, 1028, 1428, 1434, 1856, 2102, 2169, 2319, 2386, 2393, 2397, 2481, 2512, 2582, 2602, 2633, 2683, 2767, 2878, 2886, 2901, 3516, 3662, 4063, 4069, 4492], 'expressed': [142, 372, 528, 758, 797, 815, 1857, 3449, 4493], 'exclusively': [143, 529], 'T': [145, 531], 'cells': [146, 149, 532, 535, 796, 818, 3452], 'and': [147, 246, 274, 283, 327, 336, 357, 367, 382, 533, 632, 660, 669, 713, 722, 743, 753, 768, 857, 1232, 1278, 1285, 1290, 1456, 1544, 1546, 1615, 1684, 1745, 1788, 1801, 1814, 1843, 1846, 1861, 1869, 2011, 2019, 2070, 2132, 2144, 2183, 2220, 2228, 2236, 2336, 2361, 2430, 2445, 2595, 2621, 2748, 2773, 2781, 2849, 2869, 2892, 3381, 3389, 3407, 3423, 3429, 3433, 3491, 3866, 3912, 3919, 3924, 4091, 4179, 4181, 4250, 4319, 4380, 4424, 4437, 4450, 4479, 4482, 4497, 4506, 4648, 4656], 'B': [148, 534, 795], '(4Zhou': [150, 536], 'L.': [151, 159, 218, 537, 545, 604, 969, 1049, 2978, 3044, 3062, 3194, 3239, 3603, 3683], 'Peng': [152, 538], 'Duan': [154, 540], 'Zhou': [156, 542], 'Biochem.': [162, 548, 872, 1489, 3506, 4124], 'Mol.': [163, 549], 'Int.': [165, 551, 951, 3585], '1998;': [166, 552, 954, 1226, 1470, 3588, 3860, 4105], '45:': [167, 553], '1113-1119PubMed': [168, 554], '5Yao': [171, 557], 'Z.': [172, 558, 905, 963, 3274, 3292, 3302, 3306, 3310, 3344, 3539, 3597], 'Painter': [173, 559, 906, 976, 3540, 3610], 'S.L.': [174, 560, 907, 977, 3100, 3541, 3611], 'Fanslow': [175, 561, 908, 1141, 1165, 3542, 3775, 3799], 'W.C.': [176, 562, 909, 1142, 1166, 3543, 3776, 3800], 'Ulrich': [177, 563, 910, 3544], 'D.': [178, 564, 911, 1236, 1507, 1571, 2970, 3014, 3024, 3046, 3235, 3332, 3545, 3870, 4142, 4206], 'Macduff': [179, 565, 912, 3546], 'B.M.': [180, 566, 913, 3547], 'Spriggs': [181, 567, 914, 964, 3548, 3598], 'M.K.': [182, 568, 915, 926, 965, 3549, 3560, 3599], 'Armitage': [183, 569, 916, 978, 3550, 3612], 'R.J.': [184, 570, 917, 979, 3166, 3221, 3551, 3613], 'Immunol.': [186, 201, 238, 572, 587, 624, 919, 929, 953, 1000, 1127, 1178, 1560, 3553, 3563, 3587, 3634, 3761, 3812, 4195], '1995;': [187, 573, 920, 3554], '155:': [188, 574, 921, 3555], '5483-5486PubMed': [189, 575, 922, 3556], '6Aarvak': [192, 578], 'T.': [193, 579, 869, 973, 1462, 3050, 3122, 3132, 3503, 3607, 4097], 'Chabaud': [194, 580], 'Miossec': [196, 219, 582, 605, 1054, 3688], 'Natvig': [198, 584], 'J.B.': [199, 585, 3110], '1999;': [202, 223, 239, 588, 609, 625, 1019, 1155, 1179, 1251, 1493, 1514, 1561, 1578, 3653, 3789, 3813, 3885, 4128, 4149, 4196, 4213], '162:': [203, 240, 589, 626, 1180, 1562, 3814, 4197], '1246-1251PubMed': [204, 590], '7Chabaud': [207, 593], 'Durand': [209, 595], 'J.M.': [210, 596, 967, 3601], 'Buchs': [211, 597], 'N.': [212, 598, 867, 1242, 1573, 3008, 3010, 3030, 3134, 3217, 3322, 3501, 3876, 4208], 'Fossiez': [213, 599, 1206, 3840], 'F.': [214, 600, 861, 939, 996, 1144, 1168, 1207, 1504, 3290, 3318, 3495, 3573, 3630, 3778, 3802, 3841, 4139], 'Page': [215, 601], 'G.': [216, 236, 602, 622, 1125, 3198, 3759], 'Frappart': [217, 603], 'Arthritis': [221, 607, 1056, 1082, 1512, 3690, 3716, 4147], 'Rheum.': [222, 608, 1083, 1513, 3717, 4148], '42:': [224, 610, 1515, 4150], '963-970Crossref': [225, 611], '(806)': [228, 614], '8Albanesi': [231, 617], 'C.': [232, 618, 946, 1110, 1112, 1201, 2954, 2992, 2998, 3006, 3028, 3058, 3142, 3207, 3225, 3249, 3282, 3356, 3358, 3580, 3744, 3746, 3835], 'Cavani': [233, 619, 1115, 3749], 'Girolomoni': [235, 621, 1124, 3758], '494-502PubMed': [241, 627], 'Scholar).': [243, 629, 880, 1026, 1258, 1521, 1603, 1669, 1739, 3368, 3514, 3660, 3892, 4058, 4156, 4238, 4304, 4374], 'The': [244, 630, 2022, 2040, 2314, 2579, 2630, 2831, 2875, 3369, 3415, 4059, 4391, 4659, 4677], 'cloning': [245, 631, 1795, 4431], 'characterization': [247, 633], 'novel': [250, 636, 1854, 2077, 2806, 3420, 4490], 'single-pass': [251, 637, 1831, 2104, 2488, 4467], 'transmembrane': [252, 326, 638, 712, 1832, 1842, 2105, 2189, 2199, 2489, 2549, 2594, 2652, 2891, 4468, 4478], 'protein': [253, 639, 775, 778, 784, 787, 2078, 2085, 2106, 2137], 'with': [254, 640, 832, 1283, 1538, 2107, 2260, 2342, 2444, 2593, 2705, 2855, 3466, 3917, 4173], 'limited': [255, 641, 2153, 2271], 'homology': [256, 642, 1282, 2053, 2091, 3916], 'to': [257, 318, 342, 643, 704, 728, 829, 896, 1446, 1531, 1675, 1693, 1763, 2033, 2047, 2054, 2080, 2092, 2269, 2462, 2483, 2604, 2741, 2758, 2795, 2823, 2914, 3463, 3530, 4081, 4166, 4310, 4328, 4399, 4670], 'receptor': [260, 646, 903, 1441, 1606, 1612, 1671, 1690, 1752, 1773, 1855, 2688, 2783, 2791, 2911, 3421, 3537, 4076, 4241, 4247, 4306, 4325, 4387, 4409, 4491], 'reported.': [262, 648], 'High': [263, 649], 'mRNA': [264, 650, 1800, 2124, 2296, 2378, 2443, 4436], 'levels': [265, 651], 'were': [266, 278, 291, 652, 664, 677, 808, 2222, 3442], 'detected': [267, 280, 653, 666, 2710], 'prostate,': [269, 655, 2841], 'cartilage,': [270, 656], 'kidney,': [271, 657], 'liver,': [272, 658], 'heart,': [273, 659], 'muscle,': [275, 661], 'whereas': [276, 662, 2752], 'transcripts': [277, 663, 2357], 'barely': [279, 665], 'thymus': [282, 668], 'leukocytes.': [284, 670, 823, 3457], 'At': [285, 671], 'least': [286, 672, 2500, 3385], '11': [287, 673], 'RNA': [288, 674, 2164, 2402, 2425, 3413], 'splice': [289, 334, 675, 720, 1826, 2179, 2205, 2240, 2258, 2288, 3425, 4462], 'variants': [290, 676, 1827, 2180, 2206, 2259, 4463], 'found,': [292, 678], 'transcribed': [293, 679], 'from': [294, 316, 332, 680, 702, 718, 1866, 2276, 2323, 2358, 2404, 2408, 2442, 2718, 2912, 4503], '19': [295, 681, 2237, 3379], 'exons': [296, 682, 2229, 2254, 2264, 2331, 2511, 2519, 2529, 3380], 'on': [297, 683, 891, 2052, 2089, 2129, 3525], 'human': [298, 378, 684, 764, 1781, 1859, 2120, 2930, 2938, 4417, 4495], 'chromosome': [299, 685], '3p25.3–3p24.1.': [300, 686], 'Differential': [301, 687], 'exon': [302, 688, 1817, 2382, 2390, 2447, 2543, 4453], 'usage': [303, 689, 1818, 2392, 4454], 'was': [304, 371, 690, 757, 1607, 1672, 1685, 1691, 2046, 2799, 2820, 2843, 2860, 4242, 4307, 4320, 4326], 'found': [305, 368, 691, 754, 2145, 2202], 'different': [307, 693, 893, 1820, 2204, 2706, 3387, 3527, 4456], 'by': [309, 345, 695, 731, 2371, 2515, 2699, 2810, 3404, 3412], 'quantitative': [310, 696, 2372], 'reverse': [311, 697, 805], 'transcriptase-PCR.': [312, 698], 'Predicted': [313, 699], 'proteins': [314, 324, 700, 710, 1760, 1833, 1838, 2440, 2613, 2666, 2704, 2733, 4396, 4469, 4474], 'range': [315, 701], '186': [317, 703], '720': [319, 705], 'amino': [320, 706], 'acids.': [321, 707], 'Soluble': [322, 708], 'secreted': [323, 709, 813, 1837, 2196, 2557, 2662, 3447, 4473], 'lacking': [325, 711], 'intracellular': [328, 714], 'domains': [329, 359, 715, 745, 1845, 4481], 'predicted': [331, 717, 2482, 2603, 2946], 'several': [333, 719, 1758, 2226, 2606, 3395, 4394], 'isoforms': [335, 721, 2689, 2730, 2896, 3426], 'may': [337, 723, 1847, 2297, 2417, 2434, 2458, 2690, 2792, 4483], 'function': [338, 724, 1848, 2692, 3403, 3417, 3432, 4484], 'as': [339, 347, 725, 733, 811, 1541, 1610, 1834, 1836, 1849, 2126, 2128, 2693, 3445, 4176, 4245, 4470, 4472, 4485], 'extracellular': [340, 358, 726, 744, 776, 800, 2109, 2577, 2590, 2639, 2747, 2763, 2816, 2883], 'antagonists': [341, 727, 2695], 'signaling': [344, 730, 1426, 2468, 2694, 2923, 4061], 'functioning': [346, 732], 'soluble': [348, 734, 812, 1850, 2661, 2687, 2780, 2790, 2894, 3446, 4486], 'decoy': [349, 735, 1851, 2697, 2895, 4487], 'receptors.': [350, 736, 1852, 2039, 4488, 4676], 'Using': [351, 737], 'antibodies': [352, 738, 2742, 2759], 'directed': [353, 739, 2743, 2760, 2813, 2879], 'at': [354, 740, 2122, 2135, 2499, 3384], 'cytoplasmic': [356, 742, 803, 1844, 2596, 2600, 2750, 4480], 'this': [361, 747, 825, 1751, 1776, 1790, 2060, 2084, 2167, 2428, 2609, 3459, 4386, 4412, 4426], 'protein,': [362, 748], 'we': [363, 749, 1779, 1792, 2062, 2279, 2350, 3374, 4415, 4428], 'investigated': [364, 750], 'its': [365, 751, 889, 902, 1448, 1804, 1809, 2090, 2114, 2141, 3424, 3431, 3523, 3536, 4083, 4440, 4445], 'localization': [366, 752, 2769, 2778, 2803, 2827], 'that': [369, 755, 819, 887, 1032, 1828, 1839, 2374, 2389, 2415, 2422, 2432, 2454, 2480, 2533, 2685, 2702, 2728, 2785, 2903, 2936, 3453, 3521, 3666, 4464, 4475], 'it': [370, 756, 1433, 2101, 2396, 2819, 2900, 4068], 'normal': [377, 763, 2018, 2840, 4655], 'including': [380, 766, 1041, 3675], 'prostate': [381, 384, 767, 770, 1860, 1863, 2772, 2774, 2809, 2829, 2853, 2905, 4496, 4499], 'cancer.': [385, 771, 4500], 'interleukin': [772], 'receptor-like': [774], 'signal-regulated': [777], 'kinase': [779, 785, 788, 1437, 1459, 4072, 4094], 'c-jun': [780], 'N-terminal': [781, 1295, 2882, 3929], 'kinases': [782], 'stress-activated': [783], 'mitogen-activated': [786], 'nuclear': [789], 'factor': [790, 2467], 'κ': [791], 'chain': [792], 'transcription': [793, 3406], 'sequence': [798, 2096, 2274], 'tag': [799], 'domain,': [801, 2190, 2550, 2751, 2884], 'CYTO,': [802], 'domain': [804, 2591, 2601, 2640, 2817], 'transcriptase': [806], 'Interleukins': [807, 3441], 'historically': [809, 3443], 'defined': [810, 3444], 'factors': [814, 2421, 3448], 'immune': [817, 1107, 3451, 3741], 'mediate': [820, 3454], 'interactions': [821, 3455], 'between': [822, 2439, 3456], 'However,': [824, 1740, 2349, 3458, 4375], 'definition': [826, 3460], 'has': [827, 1033, 1261, 1443, 2001, 2473, 2614, 3378, 3461, 3667, 3895, 4078, 4638], 'evolved': [828, 3462], 'include': [830, 3464], 'cytokines': [831, 2010, 2029, 3465, 4647, 4666], 'spectrum': [834, 3468], 'pleiotropic': [836, 3470], 'actions': [837, 3471], '(reviewed': [838, 3472], 'Refs.': [840, 3474], '9Paul': [841, 3475], 'W.E.': [842, 3476], 'Seder': [843, 3477], 'R.A.': [844, 3176, 3478], 'Cell.': [845, 3479], '1994;': [846, 3480], '76:': [847, 3481], '241-251Abstract': [848, 3482], '(1687)': [854, 3488], 'Scholar': [856, 3490], '10Arai': [858, 3492], 'K.I.': [859, 3493], 'Lee': [860, 3494], 'Miyajima': [862, 3496], 'Miyatake': [864, 3498], 'Arai': [866, 3500], 'Yokota': [868, 3502], 'Annu.': [870, 3504], 'Rev.': [871, 952, 3505, 3586], '1990;': [873, 3507], '59:': [874, 3508], '783-836Crossref': [875, 3509], '(1168)': [878, 3512], 'Interleukin-17': [881, 3515], 'recently': [884, 3518], 'discovered': [885, 3519], 'exerts': [888, 3522], 'effect': [890, 3524], 'many': [892, 2328, 3526], 'due': [895, 2268, 3529], 'nearly': [898, 3532], 'ubiquitous': [899, 3533], 'distribution': [900, 3534], '(5Yao': [904, 3538], '11Spriggs': [925, 3559], 'Clin.': [928, 3562], '1997;': [930, 981, 3564, 3615], '17:': [931, 3565], '366-369Crossref': [932, 3566], '(78)': [935, 3569], '12Fossiez': [938, 3572], 'Banchereau': [940, 1208, 3574, 3842], 'Murray': [942, 3576], 'Van': [944, 1217, 3578, 3851], 'Kooten': [945, 1200, 3579, 3834], 'Garrone': [947, 3581], 'Lebecque': [949, 1210, 3583, 3844], '16:': [955, 3589], '541-551Crossref': [956, 3590], '(213)': [959, 3593], '13Yao': [962, 3596], 'Derry': [966, 3600], 'Strockbine': [968, 3602], 'Park': [970, 3604], 'L.S.': [971, 3605], 'VandenBos': [972, 3606], 'Zappone': [974, 3608], 'J.D.': [975, 3086, 3178, 3609], 'Cytokine.': [980, 3614], '9:': [982, 1227, 3616, 3861], '794-800Crossref': [983, 3617], '(243)': [986, 3620], '14Rouvier': [989, 3623], 'E.': [990, 1047, 1067, 3124, 3144, 3257, 3624, 3681, 3701], 'Luciani': [991, 3625], 'M.F.': [992, 3626], 'Mattei': [993, 3627], 'M.G.': [994, 3628], 'Denizot': [995, 3629], 'Golstein': [997, 3631], '1993;': [1001, 3635], '150:': [1002, 3636], '5445-5456PubMed': [1003, 3637], '15Van': [1006, 3640], 'Bezooijen': [1007, 3641], 'Farih-Sips': [1009, 3643], 'H.C.': [1010, 1558, 3644, 4193], 'Papapoulos': [1011, 3645], 'S.E.': [1012, 1488, 3646, 4123], 'Lowik': [1013, 3647], 'C.W.': [1014, 3648], 'Bone': [1016, 3650], 'Miner.': [1017, 3651], 'Res.': [1018, 1057, 1491, 3652, 3691, 4126], '14:': [1020, 3654], '1513-1521Crossref': [1021, 3655], '(139)': [1024, 3658], 'IL-171': [1027, 3661], 'proinflammatory': [1030, 3664], 'been': [1034, 1444, 2299, 3668, 4079], 'implicated': [1035, 2012, 3669, 4649], 'number': [1038, 2023, 2154, 2175, 3672, 4660], 'diseases': [1040, 3674], 'rheumatoid': [1042, 3676], 'arthritis': [1043, 3677], '(16Chabaud': [1044, 3678], 'Lubberts': [1046, 3680], 'Joosten': [1048, 1068, 3682, 3702], 'van': [1050, 1070, 1074, 1078, 3684, 3704, 3708, 3712], 'Den': [1051, 3685], 'Berg': [1052, 1080, 3686, 3714], '3:': [1059, 3693], '168-177Crossref': [1060, 3694], '(265)': [1063, 3697], '17Lubberts': [1066, 3700], 'L.A.': [1069, 1077, 1219, 3092, 3703, 3711, 3853], 'de': [1071, 3705], 'Loo': [1072, 3706], 'F.A.': [1073, 3707], 'den': [1075, 1079, 3709, 3713], 'Gersselaar': [1076, 3710], 'W.B.': [1081, 3715], '43:': [1085, 3719], '1300-1306Crossref': [1086, 3720], '(90)': [1089, 3723], '18Miossec': [1092, 3726], 'Curr.': [1094, 3728], 'Opin.': [1095, 3729], 'Rheumatol.': [1096, 3730], '12:': [1098, 3732], '181-185Crossref': [1099, 3733], '(33)': [1102, 3736], 'allergic': [1105, 3739], 'skin': [1106, 3740], 'response': [1108, 2461, 3742], '(19Albanesi': [1109, 3743], 'Scarponi': [1111, 3745], 'Sebastiani': [1113, 3747], 'De': [1117, 1212, 3751, 3846], 'Federici': [1118, 3752], 'Pita': [1120, 3754], 'O.': [1121, 3755], 'Puddu': [1122, 3756], '165:': [1129, 3763], '1395-1402Crossref': [1130, 3764], '(99)': [1133, 3767], 'organ': [1136, 3770], 'transplant': [1137, 3771], 'rejection': [1138, 3772], '(20Antonysamy': [1139, 3773], 'M.A.': [1140, 1164, 3088, 3774, 3798], 'Fu': [1143, 1167, 3777, 3801], 'Li': [1145, 1169, 1555, 3163, 3309, 3311, 3779, 3803, 4190], 'Qian': [1147, 1171, 3781, 3805], 'Troutt': [1149, 1173, 3783, 3807], 'A.B.': [1150, 1174, 3784, 3808], 'Thomson': [1151, 1175, 3785, 3809], 'A.W.': [1152, 1176, 3786, 3810], 'Transplant.': [1153, 1190, 3787, 3824], '31:': [1156, 3790], '93Crossref': [1157, 3791], '(50)': [1160, 3794], '21Antonysamy': [1163, 3797], '577-584PubMed': [1181, 3815], '22Loong': [1184, 3818], 'C.C.': [1185, 3819], 'Lin': [1186, 3315, 3820], 'C.Y.': [1187, 3821], 'Lui': [1188, 3822], 'W.Y.': [1189, 3823], '321773Crossref': [1193, 3827], '(22)': [1196, 3830], '23Van': [1199, 3833], 'Boonstra': [1202, 3836], 'J.G.': [1203, 3837], 'Paape': [1204, 3838], 'M.E.': [1205, 3298, 3839], 'Bruijn': [1213, 3847], 'Fijter': [1215, 3849], 'J.W.': [1216, 3850], 'Es': [1218, 3852], 'Daha': [1220, 3854], 'M.R.': [1221, 3855], 'Am.': [1223, 3857], 'Soc.': [1224, 3858], 'Nephrol.': [1225, 3859], '1526-1534Crossref': [1228, 3862], 'multiple': [1233, 2356, 2703, 2729, 3410, 3867], 'sclerosis': [1234, 3868], '(24Matusevicius': [1235, 3869], 'Kivisakk': [1237, 3871], 'He': [1239, 3873], 'B.': [1240, 2952, 3330, 3340, 3874], 'Kostulas': [1241, 3875], 'Ozenci': [1243, 3877], 'Fredrikson': [1245, 3879], 'Link': [1247, 3881], 'Mult.': [1249, 3883], 'Scler.': [1250, 3884], '5:': [1252, 3886], '101-104Crossref': [1253, 3887], '(619)': [1256, 3890], 'Recent': [1259, 3893], 'work': [1260, 1865, 3894, 4502], 'identified': [1262, 1609, 2002, 2026, 2071, 3896, 4244, 4639, 4663], 'three': [1263, 3897], 'related': [1264, 2079, 3898], 'proteins,': [1265, 2584, 2635, 3899], 'establishing': [1266, 3900], 'an': [1267, 1697, 2031, 2108, 3901, 4332, 4668], 'IL-17': [1268, 1284, 1425, 1440, 1526, 1772, 2007, 2027, 2057, 3902, 3918, 4060, 4075, 4161, 4408, 4644, 4664], 'cytokines.': [1271, 3905], 'These': [1272, 3906], 'new': [1273, 1798, 2003, 2049, 3907, 4434, 4640], 'members,': [1275, 3909], 'IL-17B,': [1276, 3910], 'IL-17C,': [1277, 3911], 'IL-17E,': [1279, 3913], 'share': [1280, 3914], '20–30%': [1281, 3915], 'have': [1286, 1676, 2063, 2238, 2247, 2280, 2298, 2351, 2369, 2586, 3375, 3920, 4311], 'four': [1287, 3921], 'conserved': [1288, 3922], 'cysteines,': [1289, 3923], 'all': [1291, 3925], 'contain': [1292, 2381, 2572, 2605, 2637, 3926], 'putative': [1294, 3928], 'signal': [1296, 1449, 1742, 2627, 2679, 3930, 4084, 4377], 'peptide': [1297, 3931], 'typically': [1298, 1536, 3932, 4171], 'required': [1299, 3933], 'for': [1300, 1613, 1679, 1682, 1830, 2075, 2284, 2547, 2618, 2622, 2676, 3383, 3934, 4248, 4314, 4317, 4466], 'secretion': [1301, 3935], 'Scholar).The': [1424], 'pathway': [1427, 1744, 4062, 4379], 'currently': [1429, 2211, 4064], 'being': [1430, 4065], 'studied.': [1431, 4066], 'Although': [1432, 2504, 4067], 'not': [1435, 1754, 2320, 2367, 2380, 2513, 2793, 4070, 4389], 'itself,': [1438, 4073], '(IL-17R)': [1442, 4077], 'shown': [1445, 1674, 1692, 4080, 4309, 4327], 'transduce': [1447, 4082], 'through': [1450, 4085], 'activation': [1452, 1548, 2464, 2624, 2677, 4087, 4183], 'ERK,': [1454, 4089], 'JNK/SAPK,': [1455, 4090], 'p38': [1457, 4092], 'MAP': [1458, 4093], 'pathways': [1460, 1529, 4095, 4164], '(25Shalom-Barak': [1461, 4096], 'Quach': [1463, 4098], 'Lotz': [1465, 4100], '273:': [1471, 4106], '27467-27473Abstract': [1472, 4107], '(345)': [1480, 4115], '26Subramaniam': [1483, 4118], 'S.V.': [1484, 4119], 'Cooper': [1485, 4120], 'R.S.': [1486, 3114, 4121], 'Adunyah': [1487, 4122], 'Biophys.': [1490, 4125], 'Commun.': [1492, 4127], '262:': [1494, 4129], '14-19Crossref': [1495, 4130], '(97)': [1498, 4133], '27Martel-Pelletier': [1501, 4136], 'Mineau': [1503, 4138], 'Di': [1505, 3272, 4140], 'Jovanovic': [1506, 4141], 'Battista': [1508, 4143], 'Pelletier': [1510, 4145], 'J.P.': [1511, 2990, 4146], '2399-2409Crossref': [1516, 4151], '(145)': [1519, 4154], 'In': [1522, 2838, 2852, 4157], 'presence': [1524, 2354, 4159], 'ligand,': [1527, 4162], 'these': [1528, 2665, 4163], 'lead': [1530, 4165], 'up-regulation': [1533, 4168], 'genes': [1535, 2943, 4170], 'associated': [1537, 4172], 'inflammation,': [1539, 4174], 'such': [1540, 4175], 'stromelysin,': [1542, 4177], 'IL-6,': [1543, 4178], 'IL-1β,': [1545, 4180], 'NFkB': [1550, 1695, 4185, 4330], '(28Awane': [1551, 4186], 'Andres': [1553, 4188], 'P.G.': [1554, 4189], 'D.J.': [1556, 4191], 'Reinecker': [1557, 4192], '5337-5344PubMed': [1563, 4198], '29Kehlen': [1566, 4201], 'Thiele': [1568, 4203], 'Riemann': [1570, 4205], 'Rainov': [1572, 4207], 'Langner': [1574, 4209], 'Neuroimmunol.': [1577, 4212], '101:': [1579, 4214], '1-6Abstract': [1580, 4215], '(57)': [1588, 4223], '30Broxmeyer': [1591, 4226], 'H.E.': [1592, 4227], 'Exp.': [1594, 4229], 'Med.': [1595, 4230], '1996;': [1596, 4231], '183:': [1597, 4232], '2411-2415Crossref': [1598, 4233], '(64)': [1601, 4236], 'One': [1604, 4239], 'additional': [1605, 1768, 2038, 2452, 2502, 4240, 4404, 4675], 'first': [1608, 2580, 2610, 4243], 'IL-17B': [1614, 1683, 4249, 4318], 'named': [1616, 1687, 2083, 4251, 4322], 'IL-17BR': [1617, 4252], '(3Shi': [1618, 4253], 'This': [1670, 1689, 1853, 2413, 2449, 2654, 2776, 4305, 4324, 4489], 'subsequently': [1673, 4308], 'greater': [1677, 4312], 'affinity': [1678, 4313], 'IL-17E': [1680, 4315], 'than': [1681, 2198, 2407, 2944, 4316], 'also': [1686, 2431, 2726, 2824, 4321], 'IL-17Rh1.': [1688, 4323], 'activate': [1694, 4329], 'vitro': [1699, 4334], 'luciferase': [1700, 4335], 'assay': [1701, 4336], '(2Lee': [1702, 4337], 'transduction': [1743, 2628, 2680, 4378], 'vivo': [1748, 4383], 'functions': [1749, 4384], 'known.The': [1755], 'existence': [1756, 1766, 2036, 4392, 4402, 4673], 'IL-17-related': [1759, 4395], 'led': [1761, 4397], 'us': [1762, 4398], 'explore': [1764, 2034, 4400, 4671], 'members': [1769, 2004, 4405, 4641], 'family.': [1774, 4410], 'With': [1775, 4411], 'mind,': [1778, 4414], 'searched': [1780, 2064, 4416], 'sequences': [1782, 2157, 4418], 'GenBankTM': [1785, 4421], 'data': [1786, 2068, 2162, 2214, 2312, 4422], 'base,': [1787, 4423], 'report,': [1791, 4427], 'describe': [1793, 4429], 'IL-17R-related': [1799, 4435], 'elucidation': [1802, 4438], 'genomic': [1805, 2142, 4441], 'structure.': [1806, 4442], 'We': [1807, 1822, 2082, 2112, 2139, 2201, 4443, 4458], 'characterize': [1808, 4444], 'expression': [1810, 2115, 2921, 4446], 'various': [1812, 4448], 'demonstrate': [1815, 4451], 'differential': [1816, 2777, 4452], 'tissues.': [1821, 4457], 'evidence': [1824, 2146, 2283, 2388, 4460], 'code': [1829, 4465], 'well': [1835, 2127, 4471], 'lack': [1840, 4476], 'cancer.DISCUSSIONPrevious': [1864], 'our': [1867, 3439, 4504], 'laboratory': [1868, 4505], 'others': [1870, 4507], 'Scholar)': [1993, 4630], '2L.': [1994, 4631], 'Rose,': [1995, 4632], 'personal': [1996, 4633], 'communication,': [1997, 4634], 'manuscript': [1998, 4635], 'preparation.': [2000, 4637], 'them': [2013, 4650], 'disease-related': [2020, 4657], 'conditions.': [2021, 4658], 'newly': [2025, 4662], 'provided': [2030, 4667], 'impetus': [2032, 4669], 'aim': [2041, 4678], 'study': [2045], 'identify': [2048], 'receptors': [2050], 'based': [2051, 2088], 'published': [2056], 'receptor.': [2058], 'To': [2059], 'end,': [2061], 'public': [2066, 2161], 'EST': [2067, 2156, 2311], 'base': [2069], 'cDNA': [2073, 2472], 'coding': [2074], 'IL-17R.': [2081, 2093], 'IL17-RL': [2086, 2807, 2842, 3422], '(receptor-like)': [2087], 'Its': [2094], 'primary': [2095], 'suggests': [2097], 'that,': [2098], 'like': [2099], 'IL-17R,': [2100], 'N': [2110], 'terminus.': [2111], 'characterized': [2113], 'level,': [2125], 'tissue': [2130], 'extracts': [2131], 'histological': [2133], 'sections': [2134], 'level.': [2138], 'determined': [2140], 'structure': [2143], 'alternative': [2148, 2317], 'splicing': [2149, 2165, 2318, 2426, 2457], 'even': [2150], 'available': [2158, 2275], 'bases.The': [2163], 'gene': [2168, 2429, 3373], 'particular': [2171], 'interest': [2172, 2822], 'because': [2173, 2301, 2327, 2395, 2736], 'observed': [2178], 'introduce': [2181], 'frameshifts': [2182], 'stop': [2184, 2536, 2540, 2645], 'codons': [2185], 'before': [2186, 2542, 2650], 'C-terminal': [2188], 'resulting': [2191], 'translation': [2194, 2554, 2561, 3408], 'rather': [2197], 'protein.': [2200, 2490, 2558], '12': [2203, 3386], '108': [2209], 'ESTs': [2210, 2246], 'base.': [2215, 2313], 'Exons': [2216], '7,': [2217, 2520], '12,': [2218, 2521], '14,': [2219, 2234], '15': [2221], 'spliced': [2223, 2255, 2495, 2722], 'out': [2224], 'ESTs,': [2227], '6,': [2230], '8,': [2231], '9,': [2232], '11,': [2233], '18,': [2235], 'alternate': [2239], 'donor': [2241], 'or': [2242, 2251, 2411, 2522, 2649, 2660, 2696, 2922], 'acceptor': [2243], 'sites.': [2244], 'Some': [2245], 'combinations': [2248, 2261], 'two': [2250, 2567], 'more': [2252], 'nearby': [2253], 'out.': [2256], 'Additional': [2257], 'distant': [2263], 'possible,': [2266], 'but': [2267, 2641, 2672], 'length': [2272, 2345], 'each': [2277], 'EST,': [2278], 'no': [2281], 'direct': [2282], 'this.': [2285], 'Also,': [2286], 'further': [2287], 'variations': [2289], '5′': [2292], 'end': [2293], 'missed': [2300], 'inherent': [2304], 'bias': [2305], 'toward': [2306], '3′': [2307], 'ends': [2308], 'extent': [2315], 'immediately': [2321], 'evident': [2322], 'Northern': [2324], 'blot': [2325], 'analysis': [2326, 2725], 'similar': [2334], 'size': [2335], 'relatively': [2338], 'small': [2339], 'when': [2340], 'compared': [2341], 'overall': [2344], 'mRNA.': [2348, 2723], 'confirmed': [2352], 'single': [2359, 2475, 2715], 'cell': [2362], 'lines': [2363], 'using': [2364], 'RT-PCR': [2365, 2373], '(data': [2366], 'shown).We': [2368], 'demonstrated': [2370], 'most': [2375, 2527], 'does': [2379], '7.': [2383, 2448, 2837], 'Moreover,': [2384], 'there': [2385, 2416, 2433, 2798, 2859], 'some': [2387, 2737], '7': [2391], 'tissue-specific': [2394, 2419], 'less': [2399], 'frequently': [2400], 'isolated': [2403], 'brain': [2406], 'liver': [2410], 'heart.': [2412], 'implies': [2414, 2784], 'be': [2418, 2435, 2564, 3392], 'regulatory': [2420], 'control': [2423], 'functional': [2437, 3396], 'difference': [2438], 'made': [2441], 'without': [2446, 2673], 'raises': [2450], 'possibility': [2453], 'regulation': [2455, 3401, 3434], 'occur': [2459], 'growth': [2466], 'pathways.The': [2469], 'assembled': [2470], 'full-length': [2471, 2583], 'large': [2476], 'open': [2477, 2506], 'reading': [2478, 2507], 'frame': [2479, 2508], 'encode': [2484], '720-amino': [2486], 'acid': [2487], 'Translation': [2491], 'alternatively': [2494, 2721], 'mRNAs': [2496, 3388], 'results': [2497, 2832], 'eleven': [2501], 'proteins.': [2503, 2663], 'downstream': [2510], 'affected': [2514], 'removal': [2517, 2525], '15,': [2523], 'other': [2528, 2753], 'causes': [2530], 'frameshift': [2532], 'introduces': [2534], 'in-frame': [2535, 2539], 'codons.': [2537], 'An': [2538], 'codon': [2541, 2646], '17,': [2544], 'which': [2545, 2585, 2636, 2643, 2885, 3377], 'codes': [2546, 3382], 'will': [2551], 'result': [2552], 'Therefore,': [2559], 'products': [2562], 'can': [2563, 2734, 3391], 'classified': [2565], 'into': [2566, 3394], 'general': [2568], 'categories.': [2569], 'Both': [2570], 'categories': [2571], 'presumed': [2574], 'ligand': [2575, 2588, 2619, 2669], 'binding': [2576, 2589, 2620, 2670], 'domain.': [2578, 2653, 2764], 'category': [2581, 2611, 2632, 2655], 'along': [2592], 'domains.': [2597], 'Since': [2598], 'phosphorylation': [2607], 'sites,': [2608], 'potential': [2616], 'both': [2617, 2745, 2846, 2889], 'subsequent': [2623], 'cytosolic': [2626], 'pathways.': [2629, 2681], 'second': [2631], 'truncated': [2634], 'occurs': [2647], 'consists': [2656], 'either': [2658], 'membrane-associated': [2659], 'Presumably': [2664], 'retain': [2667], 'activity': [2671], 'capacity': [2675], 'It': [2682], 'likely': [2684], 'thus': [2691], 'receptors.Analysis': [2698], 'immunoblotting': [2700], 'confirms': [2701], 'molecular': [2707], 'weights': [2708], 'homogenates': [2712], 'tissue,': [2716], 'presumably': [2717], 'translations': [2719], 'Immunohistochemical': [2724], 'indicates': [2727], 'exist': [2735], 'bind': [2739, 2756], 'strongly': [2740, 2757], 'against': [2744, 2761, 2814, 2880], 'only': [2755], 'Especially': [2765], 'noteworthy': [2766], 'cancers.': [2775, 2830], 'membrane-bound': [2782], 'certain': [2786], 'expressing': [2788], 'primarily': [2789], 'respond': [2794], 'ligand.As': [2797], 'strong': [2801], 'immunohistochemical': [2802], 'antibody': [2812, 2876], '(anti-ECD),': [2818], 'compare': [2825], 'depicted': [2834], 'Fig.': [2836], 'localized': [2844], 'epithelial': [2848, 2913], 'stromal': [2850, 2915], 'compartments.': [2851], 'cancers': [2854], 'increasing': [2856], 'Gleason': [2857], 'grade,': [2858], 'progressive': [2862], 'loss': [2863], 'staining': [2865, 2871], 'epithelium': [2868], 'increased': [2870], 'stroma.': [2874], 'used': [2877], 'IL17-RL.': [2898], 'Thus,': [2899], 'possible': [2902], 'cancer,': [2906], 'redistribution': [2908], 'compartments': [2916], 'signifies': [2917], 'dysregulation': [2919], 'IL17-RL.With': [2925], 'completion': [2927], 'genome': [2931, 2939], 'project': [2932], 'came': [2933], 'realization': [2935], 'contains': [2940], 'far': [2941], 'fewer': [2942], 'originally': [2945], '(31Lander': [2947], 'E.S.': [2948], 'Linton': [2949], 'L.M.': [2950], 'Birren': [2951], 'Nusbaum': [2953], 'Zody': [2955], 'Devon': [2959], 'Dewar': [2961], 'Doyle': [2963], 'FitzHugh': [2965], 'Funke': [2967], 'Gage': [2969], 'Harris': [2971], 'Heaford': [2973], 'Howland': [2975], 'Kann': [2977], 'Lehoczky': [2979], 'LeVine': [2981], 'McEwan': [2983], 'McKernan': [2985], 'Meldrim': [2987], 'Mesirov': [2989], 'Miranda': [2991], 'Morris': [2993], 'Naylor': [2995], 'Raymond': [2997], 'Rosetti': [2999], 'Santos': [3001], 'Sheridan': [3003], 'Sougnez': [3005], 'Stange-Thomann': [3007], 'Stojanovic': [3009], 'Subramanian': [3011, 3197], 'Wyman': [3013], 'Rogers': [3015], 'Sulston': [3017], 'Ainscough': [3019], 'Beck': [3021], 'Bentley': [3023], 'Burton': [3025], 'Clee': [3027], 'Carter': [3029], 'Coulson': [3031], 'Deadman': [3033], 'Deloukas': [3035], 'Dunham': [3037, 3039], 'Durbin': [3041], 'French': [3043], 'Grafham': [3045], 'Gregory': [3047], 'Hubbard': [3049], 'Humphray': [3051], 'Hunt': [3053], 'Jones': [3055], 'Lloyd': [3057], 'McMurray': [3059], 'Matthews': [3061], 'Mercer': [3063], 'Milne': [3065], 'Mullikin': [3067], 'J.C.': [3068, 3158], 'Mungall': [3069], 'Plumb': [3071], 'Ross': [3073], 'Shownkeen': [3075], 'Sims': [3077], 'Waterston': [3079], 'R.H.': [3080], 'Wilson': [3081], 'R.K.': [3082], 'Hillier': [3083], 'L.W.': [3084], 'McPherson': [3085], 'Marra': [3087], 'Mardis': [3089], 'E.R.': [3090], 'Fulton': [3091, 3113], 'Chinwalla': [3093], 'A.T.': [3094], 'Pepin': [3095], 'K.H.': [3096], 'Gish': [3097], 'W.R.': [3098], 'Chissoe': [3099], 'Wendl': [3101], 'Delehaunty': [3103, 3107], 'K.D.': [3104], 'Miner': [3105], 'T.L.': [3106], 'Kramer': [3109], 'Cook': [3111], 'L.L.': [3112], 'Johnson': [3115], 'D.L.': [3116], 'Minx': [3117], 'P.J.': [3118], 'Clifton': [3119], 'S.W.': [3120], 'Hawkins': [3121], 'Branscomb': [3123], 'Predki': [3125], 'Richardson': [3127], 'Wenning': [3129], 'Slezak': [3131], 'Doggett': [3133], 'Cheng': [3135], 'J.F.': [3136], 'Lucas': [3139], 'Elkin': [3141], 'Uberbacher': [3143], 'Frazier': [3145], 'et': [3147, 3359], 'al.Nature.': [3148], '409:': [3150], '860-921Crossref': [3151], '(17490)': [3154], '32Venter': [3157], 'Adams': [3159], 'M.D.': [3160], 'Myers': [3161], 'E.W.': [3162], 'P.W.': [3164], 'Mural': [3165], 'Sutton': [3167], 'G.G.': [3168], 'Smith': [3169], 'H.O.': [3170], 'Yandell': [3171], 'Evans': [3173], 'C.A.': [3174], 'Holt': [3175], 'Gocayne': [3177], 'Amanatides': [3179], 'Ballew': [3181], 'R.M.': [3182], 'Huson': [3183], 'D.H.': [3184], 'Wortman': [3185], 'J.R.': [3186], 'Q.': [3188], 'Kodira': [3189], 'C.D.': [3190], 'Zheng': [3191], 'X.H.': [3192], 'Skupski': [3195], 'Thomas': [3199], 'P.D.': [3200], 'Gabor': [3203], 'Miklos': [3204], 'G.L.': [3205], 'Nelson': [3206], 'Broder': [3208], 'Clark': [3210], 'A.G.': [3211], 'Nadeau': [3212], 'McKusick': [3214], 'V.A.': [3215, 3328], 'Zinder': [3216], 'Levine': [3218], 'A.J.': [3219], 'Roberts': [3220], 'Simon': [3222], 'Slayman': [3224], 'Hunkapiller': [3226], 'Bolanos': [3228], 'Delcher': [3230], 'Dew': [3232], 'Fasulo': [3234], 'Flanigan': [3236], 'Florea': [3238], 'Halpern': [3240], 'Hannenhalli': [3242], 'Kravitz': [3244], 'Levy': [3246], 'Mobarry': [3248], 'Reinert': [3250], 'Remington': [3252], 'Abu-Threideh': [3254], 'Beasley': [3256], 'Biddick': [3258], 'Bonazzi': [3260], 'Brandon': [3262], 'Cargill': [3264], 'Chandramouliswaran': [3266], 'Charlab': [3268], 'Chaturvedi': [3270], 'Deng': [3273], 'Francesco': [3275], 'Dunn': [3277], 'Eilbeck': [3279], 'Evangelista': [3281], 'Gabrielian': [3283], 'A.E.': [3284], 'Gan': [3285], 'Ge': [3287], 'Gong': [3289], 'Gu': [3291], 'Guan': [3293], 'Heiman': [3295], 'T.J.': [3296], 'Higgins': [3297], 'Ji': [3299], 'R.R.': [3300], 'Ke': [3301], 'Ketchum': [3303], 'Lai': [3305], 'Lei': [3307], 'Liang': [3313], 'X.': [3316, 3348], 'Lu': [3317], 'Merkulov': [3319], 'G.V.': [3320], 'Milshina': [3321], 'Moore': [3323], 'H.M.': [3324], 'Naik': [3325], 'A.K.': [3326], 'Narayan': [3327], 'Neelam': [3329], 'Nusskern': [3331], 'Rusch': [3333], 'D.B.': [3334], 'Salzberg': [3335], 'Shao': [3337], 'Shue': [3339], 'Sun': [3341], 'Wei': [3351], 'Wides': [3353], 'Xiao': [3355], 'Yan': [3357], 'al.Science.': [3360], '291:': [3362], '1304-1351Crossref': [3363], '(10466)': [3366], 'complexity': [3370], 'identified,': [3376], 'therefore': [3390], 'translated': [3393], 'isoforms,': [3397], 'demonstrates': [3398], 'intricate': [3400], 'RNAs': [3411], 'splicing.': [3414], 'precise': [3416], 'remains': [3427], 'unknown,': [3428], 'understanding': [3430], 'focus': [3437], 'laboratory.': [3440], 'known.': [4390], 'DISCUSSIONPrevious': [4501], 'prese': [4681]}, 'cited_by_api_url': 'https://api.openalex.org/works?filter=cites:W2040831260', 'counts_by_year': 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