title: Negative regulation of the hepatic fibrogenic response by suppressor of cytokine signaling 1.
abstract: Suppressor of cytokine signaling 1 (SOCS1) is an indispensable regulator of IFNγ signaling and has been implicated in the regulation of liver fibrosis. However, it is not known whether SOCS1 mediates its anti-fibrotic functions in the liver directly, or via modulating IFNγ, which has been implicated in attenuating hepatic fibrosis. Additionally, it is possible that SOCS1 controls liver fibrosis by regulating hepatic stellate cells (HSC), a key player in fibrogenic response. While the activation pathways of HSCs have been well characterized, the regulatory mechanisms are not yet clear. The goals of this study were to dissociate IFNγ-dependent and SOCS1-mediated regulation of hepatic fibrogenic response, and to elucidate the regulatory functions of SOCS1 in HSC activation. Liver fibrosis was induced in Socs1(-/-)Ifng(-/-) mice with dimethylnitrosamine or carbon tetrachloride. Ifng(-/-) and C57BL/6 mice served as controls. Following fibrogenic treatments, Socs1(-/-)Ifng(-/-) mice showed elevated serum ALT levels and increased liver fibrosis compared to Ifng(-/-) mice. The latter group showed higher ALT levels and fibrosis than C57BL/6 controls. The livers of SOCS1-deficient mice showed bridging fibrosis, which was associated with increased accumulation of myofibroblasts and abundant collagen deposition. SOCS1-deficient livers showed increased expression of genes coding for smooth muscle actin, collagen, and enzymes involved in remodeling the extracellular matrix, namely matrix metalloproteinases and tissue inhibitor of metalloproteinases. Primary HSCs from SOCS1-deficient mice showed increased proliferation in response to growth factors such as HGF, EGF and PDGF, and the fibrotic livers of SOCS1-deficient mice showed increased expression of the Pdgfb gene. Taken together, these data indicate that SOCS1 controls liver fibrosis independently of IFNγ and that part of this regulation may occur via regulating HSC proliferation and limiting growth factor availability.
authors.affiliation: Immunology Division, Department of Pediatrics, Sherbrooke, Québec J1H 5N4, Canada.
authors.forename: Rajani
authors.initials: R
authors.lastname: Kandhi
authors.affiliation: Immunology Division, Department of Pediatrics, Sherbrooke, Québec J1H 5N4, Canada.
authors.forename: Diwakar
authors.initials: D
authors.lastname: Bobbala
authors.affiliation: Immunology Division, Department of Pediatrics, Sherbrooke, Québec J1H 5N4, Canada.
authors.forename: Mehdi
authors.initials: M
authors.lastname: Yeganeh
authors.affiliation: Immunology Division, Department of Pediatrics, Sherbrooke, Québec J1H 5N4, Canada.
authors.forename: Marian
authors.initials: M
authors.lastname: Mayhue
authors.affiliation: Department of Microbiology and Infectious Diseases, Faculty of Medicine and Health Sciences, Université de Sherbrooke, Sherbrooke, Québec J1H 5N4, Canada; CR-CHUS, Sherbrooke, Québec J1H 5N4, Canada.
authors.forename: Alfredo
authors.initials: A
authors.lastname: Menendez
authors.affiliation: Immunology Division, Department of Pediatrics, Sherbrooke, Québec J1H 5N4, Canada; CR-CHUS, Sherbrooke, Québec J1H 5N4, Canada. Electronic address: Subburaj.Ilangumaran@Usherbrooke.ca.
authors.forename: Subburaj
authors.initials: S
authors.lastname: Ilangumaran
mesh_terms: D000818:Animals; D004815:Epidermal Growth Factor / Q000235:genetics / Q000276:immunology*; D017228:Hepatocyte Growth Factor / Q000235:genetics / Q000276:immunology*; D007371:Interferon-gamma / Q000235:genetics / Q000276:immunology*; D008103:Liver Cirrhosis / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D010982:Platelet-Derived Growth Factor / Q000235:genetics / Q000276:immunology*; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology*; D000071222:Suppressor of Cytokine Signaling 1 Protein / Q000235:genetics / Q000276:immunology*
chemical_list: C553307:HGF protein, mouse; C000611649:IFNG protein, mouse; D010982:Platelet-Derived Growth Factor; C491590:Socs1 protein, mouse; D000071222:Suppressor of Cytokine Signaling 1 Protein; D004815:Epidermal Growth Factor; D017228:Hepatocyte Growth Factor; D007371:Interferon-gamma
keywords: Carbon tetrachloride; Dimethylnitrosamine; Hepatic stellate cells; Liver fibrosis; PDGF; SOCS1