title: Interferon alpha antagonizes STAT3 and SOCS3 signaling triggered by hepatitis C virus.
abstract: We aimed to investigate regulation of signal transducer and activator of transcription 3 (STAT3) and suppressor of cytokine signaling 3 (SOCS3) by interferon alpha (IFN-α) and to analyze the relationship between STAT3 and SOCS3 during hepatitis C virus (HCV) infection. Changes in STAT3 and SOCS3 were analyzed at both mRNA and protein levels in human hepatoma cells infected with HCV (J6/JFH1). At 72h of HCV infection, STAT3 expression was decreased with sustained phosphorylation, and IFN-α increased such decrease and phosphorylation. HCV increased SOCS3 expression, while IFN-α impaired such increase, indicating different regulation of STAT3 and SOCS3 by IFN-α. IFN-α-induced expression and phosphorylation of upstream kinases of the JAK/STAT pathway, Tyk2 and Jak1, were suppressed by HCV. Moreover, knockdown of STAT3 by RNA interference led to decreases in HCV RNA replication and viral protein expression, without affecting either the expression of Tyk2 and Jak1 or the SOCS3 induction in response to IFN-α. These results show that IFN-α antagonizes STAT3 and SOCS3 signaling triggered by HCV and that STAT3 regulation correlates inversely with SOCS3 induction by IFN-α, which may be important in better understanding the complex interplay between IFN-α and signal molecules during HCV infection.
authors.affiliation: Department of Microbiology, Shanghai Key Laboratory of Medical Biodefence, Second Military Medical University, Shanghai 200433, China.
authors.forename: Lan-Juan
authors.initials: LJ
authors.lastname: Zhao
authors.affiliation: Department of Microbiology, Shanghai Key Laboratory of Medical Biodefence, Second Military Medical University, Shanghai 200433, China.
authors.forename: Sheng-Fei
authors.initials: SF
authors.lastname: He
authors.affiliation: Department of Microbiology, Shanghai Key Laboratory of Medical Biodefence, Second Military Medical University, Shanghai 200433, China.
authors.forename: Wen
authors.initials: W
authors.lastname: Wang
authors.affiliation: Department of Microbiology, Shanghai Key Laboratory of Medical Biodefence, Second Military Medical University, Shanghai 200433, China.
authors.forename: Hao
authors.initials: H
authors.lastname: Ren
authors.affiliation: Department of Microbiology, Shanghai Key Laboratory of Medical Biodefence, Second Military Medical University, Shanghai 200433, China. Electronic address: qizt@smmu.edu.cn.
authors.forename: Zhong-Tian
authors.initials: ZT
authors.lastname: Qi
mesh_terms: D006528:Carcinoma, Hepatocellular; D045744:Cell Line, Tumor; D005786:Gene Expression Regulation; D016174:Hepacivirus / Q000502:physiology*; D006801:Humans; D000077190:Interferon alpha-2; D016898:Interferon-alpha / Q000494:pharmacology / Q000502:physiology*; D008113:Liver Neoplasms; D011994:Recombinant Proteins / Q000494:pharmacology; D050796:STAT3 Transcription Factor / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D050826:Suppressor of Cytokine Signaling Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D014779:Virus Replication
chemical_list: D000077190:Interferon alpha-2; D016898:Interferon-alpha; D011994:Recombinant Proteins; D050796:STAT3 Transcription Factor; D050826:Suppressor of Cytokine Signaling Proteins
keywords: Hepatitis C virus; Interferon alpha; Signal transducer and activator of transcription 3; Suppressor of cytokine signaling 3