Zhao Lan-Juan, He Sheng-Fei, Wang Wen, Ren Hao, Qi Zhong-Tian
Department of Microbiology, Shanghai Key Laboratory of Medical Biodefence, Second Military Medical University, Shanghai 200433, China.
Department of Microbiology, Shanghai Key Laboratory of Medical Biodefence, Second Military Medical University, Shanghai 200433, China.
Cytokine. 2016 Apr;80:48-55. doi: 10.1016/j.cyto.2015.08.264. Epub 2016 Mar 3.
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.
我们旨在研究干扰素α（IFN-α）对信号转导和转录激活因子3（STAT3）及细胞因子信号转导抑制因子3（SOCS3）的调控作用，并分析丙型肝炎病毒（HCV）感染过程中STAT3与SOCS3之间的关系。在感染HCV（J6/JFH1）的人肝癌细胞中，从mRNA和蛋白质水平分析了STAT3和SOCS3的变化。在HCV感染72小时时，STAT3表达下降并伴有持续磷酸化，IFN-α加剧了这种下降和磷酸化。HCV增加SOCS3表达，而IFN-α则抑制这种增加，表明IFN-α对STAT3和SOCS3的调控不同。HCV抑制了IFN-α诱导的JAK/STAT途径上游激酶Tyk2和Jak1的表达及磷酸化。此外，RNA干扰敲低STAT3导致HCV RNA复制和病毒蛋白表达下降，而不影响Tyk2和Jak1的表达或IFN-α诱导的SOCS3表达。这些结果表明，IFN-α拮抗HCV触发的STAT3和SOCS3信号，且STAT3的调控与IFN-α诱导的SOCS3呈负相关，这对于更好地理解HCV感染期间IFN-α与信号分子之间的复杂相互作用可能具有重要意义。
