SOCS1, a Negative Regulator of Cytokine Signals and TLR Responses, in Human Liver Diseases

Minoru Fujimoto,Tetsuji Naka

doi:10.1155/2010/470468

Abstract

Toll-like receptor (TLR) signaling pathways are strictly coordinated by several mechanisms to regulate adequate innate immune responses. Recent lines of evidence indicate that the suppressor of cytokine signaling (SOCS) family proteins, originally identified as negative-feedback regulators in cytokine signaling, are involved in the regulation of TLR-mediated immune responses. SOCS1, a member of SOCS family, is strongly induced upon TLR stimulation. Cells lacking SOCS1 are hyperresponsive to TLR stimulation. Thus, SOCS1 is an important regulator for both cytokine and TLR-induced responses. As an immune organ, the liver contains various types of immune cells such as T cells, NK cells, NKT cells, and Kupffer cells and is continuously challenged with gut-derived bacterial and dietary antigens. SOCS1 may be implicated in pathophysiology of the liver. The studies using SOCS1-deficient mice revealed that endogenous SOCS1 is critical for the prevention of liver diseases such as hepatitis, cirrhosis, and cancers. Recent studies on humans suggest that SOCS1 is involved in the development of various liver disorders in humans. Thus, SOCS1 and other SOCS proteins are potential targets for the therapy of human liver diseases.

Highlights

Proper and coordinated activation of immune signal pathways is required for immune responses, including eradication of invading pathogens
Since SOCS1 is induced in the liver by multiple factors including cytokines, Toll-like receptor (TLR) ligands, and insulin, SOCS1 should regulate both cytokine and TLR signaling under various physiological and/or pathological conditions
Mice lacking SOCS1 are sensitive to a variety of liver diseases including hepatitis, liver cirrhosis, and hepatocellular carcinoma (HCC)

Summary

Introduction

Proper and coordinated activation of immune signal pathways is required for immune responses, including eradication of invading pathogens. Given the role of JAK kinases in signaling of cytokine receptors, mice lacking SOCS1 exhibit hypersensitivity to a variety of cytokines, including IFN-α, IFN-γ, IL-2, IL-4, IL7, IL-12, and IL-15 (Table 1) [1, 2]. The expression of SOCS1 is induced by various cytokines, including IL-4 and IFN-γ, and by TLR ligands, such as LPS and CpG-DNA (Table 1) [3]. TLR ligands induce SOCS1 expression directly through the activation of early growth response-1 (Egr-1) [6] and/or indirectly through cytokines, including IL-6 and IFN-β induced by initial TLR signaling [3]. This finding raises the possibility that SOCS1 regulates TLR signaling. SOCS1 directly induces the negative regulation of TLR signaling [3, 5]

Mechanisms of Negative Regulation of TLR Signaling by SOCS1

SOCS1 in Liver Pathophysiology

SOCS1 in Human Liver Disease

SOCS3 in TLR Signaling and Human Liver Diseases

Conclusion