Hepatitis C virus (HCV)-induced suppressor of cytokine signaling (SOCS) 3 regulates proinflammatory TNF-α responses

Abstract

TNF-α is a proinflammatory cytokine, dramatically elevated during pathogenic infection and often responsible for inflammation-induced disease pathology. SOCS proteins are inhibitors of cytokine signaling and regulators of inflammation. In this study, we found that both SOCS1 and SOCS3 were transiently induced by TNF-α and negatively regulate its NF-κB-mediated signal transduction. We discovered that PBMCs from HCV-infected patients have elevated endogenous SOCS3 expression but less TNF-α-mediated IκB degradation and proinflammatory cytokine production than healthy controls. HCV protein expression in Huh7 hepatocytes also induced SOCS3 and directly inhibited TNF-α-mediated IL-8 production. Furthermore, we found that SOCS3 associates with TRAF2 and inhibits TRAF2-mediated NF-κB promoter activity, suggesting a mechanism by which SOCS3 inhibits TNF-α-mediated signaling. These results demonstrate a role for SOCS3 in regulating proinflammatory TNF-α signal transduction and reveal a novel immune-modulatory mechanism by which HCV suppresses inflammatory responses in primary immune cells and hepatocytes, perhaps explaining mild pathology often associated with acute HCV infection.

Effect of Hepatitis C virus proteins on the production of proinflammatory and profibrotic cytokines in Huh7.5 human hepatoma cells

“…Published data are discrepant; i.e., HCV proteins have been reported both to induce [10,11] and to suppress [12] the production of proinflammatory cytokines in different studies. The discrepancies are attributable to a great extent to differences in experimental design, including models (peripheral blood or liver biopsy material), experimental systems (cultured cells, virus constructs, replicons, and mutant viruses and animals), and methods to examine cells, viruses, and biologically active molecules (ELISA, nucleic acid hybridization, and PCR).…”

Identification and analysis of long non-coding RNAs that are involved in inflammatory process in response to transmissible gastroenteritis virus infection

“…Virus can activate the inflammatory response by multiple means, including Nuclear factor-kappa B (NF-κB), Jak-STAT, TLRs, T cell receptors (TCRs), NLRs, TNF, RLRs signaling pathway [1][2][3][4][5][6][7]. Previous studies have described that TGEV can impair IPECs and trigger inflammatory response [8].…”

Suppressor of cytokine signaling 3 plays an important role in porcine circovirus type 2 subclinical infection by downregulating proinflammatory responses

“…SOCS3 plays a role in regulating proinflammatory TNF-α signal transduction, leading to the silent progression of acute hepatitis C virus infection to chronicity27. TNF-α and IL-6 induce SOCS3 expression, and SOCS3 plays an important role in the negative feedback of some proinflammatory signal transducers such as TNF-α and IL-628.…”