Negative regulation of the hepatic fibrogenic response by suppressor of cytokine signaling 1

Suppressor of cytokine signaling 1 (SOCS1) is an indispensable regulator of IFN gamma 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 IFN gamma, 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 IFN gamma-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 Socs(-/-)Ifng(-/-) mice with dimethylnitrosamine or carbon tetrachloride. Ifng(-/-) and C57BL/6 mice served as controls. Following fibrogenic treatments, Socs(-/-)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 IFN gamma and that part of this regulation may occur via regulating HSC proliferation and limiting growth factor availability. (C) 2016 Elsevier Ltd. All rights reserved.