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

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.

Kandhi R ，Bobbala D ，Yeganeh M ，Mayhue M ，Menendez A ，Ilangumaran S ... -  《-》

Essential role of suppressor of cytokine signaling 1 (SOCS1) in hepatocytes and macrophages in the regulation of liver fibrosis.

The hepatic fibrogenic response is a protective mechanism activated by hepatocyte damage and is resolved upon elimination of the cause. However, persistent injuries cause liver fibrosis (LF) to evolve into cirrhosis, which promotes the development of hepatocellular carcinoma (HCC). Development of efficient treatments for LF requires better understanding the underlying molecular pathogenic mechanisms. The loss of suppressor of cytokine signaling 1 (SOCS1) expression promotes LF and HCC in human and mice, but the underlying mechanisms remain unclear. SOCS1 is a key regulator of immune cell activation. To investigate the anti-fibrogenic functions of SOCS1 in hepatocytes and macrophages, we generated mice lacking SOCS1 in hepatocytes (Socs1fl/flAlbCre) or macrophages (Socs1fl/flLysMCre) and evaluated hepatic fibrogenic response to carbon tetrachloride (CCl4). Socs1fl/flAlbCre and Socs1fl/flLysMCre mice showed severe LF characterized by increased collagen deposition, hydroxyproline content, myofibroblast accumulation along with elevated expression of Acta2 and Col1a1 genes. CCl4 treatment triggered significant damage to hepatocytes in Socs1fl/flAlbCre mice but not in Socs1fl/flLysMCre mice. In both mice CCl4 treatment reduced the expression of Mmp2 and increased the expression of Timp1. SOCS1 deficiency in hepatocytes or macrophages did not affect Il6, Tnfa or Tgfb, but diminished Infg and augmented Pdgfb expression. Both Socs1fl/flAlbCre and Socs1fl/flLysMCre livers showed increased mononuclear cell infiltration accompanied by elevated Ccl2 expression. Our findings show that SOCS1 exerts non-redundant functions in hepatocytes and macrophages to regulate the hepatic fibrogenic response possibly through limiting hepatocyte damage and the inflammatory response of macrophages, and support the idea of exploiting SOCS1 in LF treatment.

Mafanda EK ，Kandhi R ，Bobbala D ，Khan MGM ，Nandi M ，Menendez A ，Ramanathan S ，Ilangumaran S ... -  《-》

Hepatic stellate cell-intrinsic role of SOCS1 in controlling hepatic fibrogenic response and the pro-inflammatory macrophage compartment during liver fibrosis.

Kandhi R ，Yeganeh M ，Yoshimura A ，Menendez A ，Ramanathan S ，Ilangumaran S ... -  《Frontiers in Immunology》

SOCS1 controls liver regeneration by regulating HGF signaling in hepatocytes.

Frequent repression of the Socs1 (suppressor of cytokine signaling 1) gene in hepatocellular carcinoma (HCC) and increased susceptibility of SOCS1-deficient mice to hepatocarcinogens suggest a tumor suppressor role for SOCS1 in the liver, but the underlying mechanisms remain unclear. Here we investigated the role of SOCS1 in regulating hepatocyte proliferation following partial hepatectomy and HGF stimulation. Because Socs1(-/-) mice die prematurely due to deregulated IFNγ signaling, we used Socs1(-/-)Ifng(-/-) mice to study the role of SOCS1 in liver regeneration following partial hepatectomy. We examined the activation of signaling molecules downstream of IL-6 and hepatocyte growth factor (HGF) receptors in the regenerating liver, primary hepatocytes, and in human hepatoma cells. We examined the interaction between SOCS1 and the HGF receptor c-Met by reciprocal immunoprecipitation. Socs1(-/-)Ifng(-/-) mice displayed accelerated liver regeneration with increased DNA synthesis compared to Ifng(-/-) and wild type mice. The regenerating liver of Socs1(-/-)Ifng(-/-) mice did not show increased IL-6 signaling, but displayed earlier phosphorylation of Gab1, a signaling adaptor downstream of c-Met. Following HGF stimulation, hepatocytes from Socs1(-/-)Ifng(-/-) mice displayed increased phosphorylation of c-Met and Gab1, cell migration and proliferation. Accordingly, SOCS1 overexpression attenuated HGF-induced phosphorylation of c-Met, Gab1, and ERK1/2 in hepatoma cells, and decreased their proliferation and migration. SOCS1 interacted with the Tpr-Met, an oncogenic form of the Met receptor. SOCS1 attenuates c-Met signaling and thus negative regulation of HGF signaling could be an important mechanism underlying the anti-tumor role of SOCS1 in the liver.

Gui Y ，Yeganeh M ，Ramanathan S ，Leblanc C ，Pomerleau V ，Ferbeyre G ，Saucier C ，Ilangumaran S ... -  《-》

Regulation of High-fat Diet-induced Liver Fibrosis by SOCS1 Expression in Hepatic Stellate Cells.

Kandhi R ，Menendez A ，Ramanathan S ，Ilangumaran S ... -  《-》