title: IL-17A enhances the expression of profibrotic genes through upregulation of the TGF-β receptor on hepatic stellate cells in a JNK-dependent manner.
abstract: Activation of hepatic stellate cells (HSCs) is a key event in the initiation of liver fibrosis, characterized by enhanced extracellular matrix production and altered degradation. Activation of HSCs can be modulated by cytokines produced by immune cells. Recent reports have implicated the proinflammatory cytokine IL-17A in liver fibrosis progression. We hypothesized that IL-17A may enhance activation of HSCs and induction of the fibrogenic signals in these cells. The human HSC line LX2 and primary human HSCs were stimulated with increasing doses of IL-17A and compared with TGF-β- and PBS-treated cells as positive and negative controls, respectively. IL-17A alone did not induce activation of HSCs. However, IL-17A sensitized HSCs to the action of suboptimal doses of TGF-β as confirmed by strong induction of α-smooth muscle actin, collagen type I (COL1A1), and tissue inhibitor of matrix metalloproteinase I gene expression and protein production. IL-17A specifically upregulated the cell surface expression of TGF-βRII following stimulation. Pretreatment of HSCs with IL-17A enhanced signaling through TGF-βRII as observed by increased phosphorylation of SMAD2/3 in response to stimulation with suboptimal doses of TGF-β. This enhanced TGF-β response of HSCs induced by IL-17A was JNK-dependent. Our results suggest a novel profibrotic function for IL-17A by enhancing the response of HSCs to TGF-β through activation of the JNK pathway. IL-17A acts through upregulation and stabilization of TGF-βRII, leading to increased SMAD2/3 signaling. These findings represent a novel example of cooperative signaling between an immune cytokine and a fibrogenic receptor.
authors.affiliation: Centre de Recherche du Centre Hospitalier de l'Université de Montréal, Montreal, Quebec H2X 0A9, Canada; Département de Microbiologie, Infectiologie et Immunologie, Université de Montréal, Montreal, Quebec H3C 3J7, Canada;
authors.forename: Thomas
authors.initials: T
authors.lastname: Fabre
authors.affiliation: Centre de Recherche du Centre Hospitalier de l'Université de Montréal, Montreal, Quebec H2X 0A9, Canada;
authors.forename: Hassen
authors.initials: H
authors.lastname: Kared
authors.affiliation: Division of Liver Diseases, Icahn School of Medicine at Mount Sinai, New York, NY 10029; and.
authors.forename: Scott L
authors.initials: SL
authors.lastname: Friedman
authors.affiliation: Centre de Recherche du Centre Hospitalier de l'Université de Montréal, Montreal, Quebec H2X 0A9, Canada; Département de Médecine, Faculté de Médecine, Université de Montréal, Montreal, Quebec H3C 3J7, Canada Naglaa.shoukry@umontreal.ca.
authors.forename: Naglaa H
authors.initials: NH
authors.lastname: Shoukry
mesh_terms: D000199:Actins / Q000096:biosynthesis; D002460:Cell Line; D024042:Collagen Type I / Q000096:biosynthesis; D000090602:Collagen Type I, alpha 1 Chain; D005786:Gene Expression Regulation; D055166:Hepatic Stellate Cells / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D020381:Interleukin-17 / Q000494:pharmacology / Q000502:physiology*; D048031:JNK Mitogen-Activated Protein Kinases / Q000276:immunology*; D008099:Liver / Q000166:cytology / Q000473:pathology; D008103:Liver Cirrhosis / Q000235:genetics* / Q000276:immunology; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000096:biosynthesis; D000077294:Receptor, Transforming Growth Factor-beta Type II; D018125:Receptors, Transforming Growth Factor beta / Q000096:biosynthesis / Q000235:genetics*; D015398:Signal Transduction / Q000276:immunology; D051899:Smad2 Protein / Q000378:metabolism; D051900:Smad3 Protein / Q000378:metabolism; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000096:biosynthesis; D016212:Transforming Growth Factor beta / Q000494:pharmacology*; D015854:Up-Regulation
chemical_list: C541116:ACTA2 protein, human; D000199:Actins; D024042:Collagen Type I; D000090602:Collagen Type I, alpha 1 Chain; C508717:IL17A protein, human; D020381:Interleukin-17; D018125:Receptors, Transforming Growth Factor beta; C497782:SMAD2 protein, human; C497790:SMAD3 protein, human; D051899:Smad2 Protein; D051900:Smad3 Protein; C560822:TIMP1 protein, human; D019715:Tissue Inhibitor of Metalloproteinase-1; D016212:Transforming Growth Factor beta; D017346:Protein Serine-Threonine Kinases; D048031:JNK Mitogen-Activated Protein Kinases; D000077294:Receptor, Transforming Growth Factor-beta Type II