Department of Clinical Pharmacology, University of Toyama, Sugitani, Toyama, Japan.
Am J Physiol Endocrinol Metab. 2011 Jun;300(6):E1112-23. doi: 10.1152/ajpendo.00370.2010. Epub 2011 Mar 8.
Although elevation of the blood glucose level is a causal adverse effect of treatment with interferon (IFN), the precise underlying molecular mechanism is largely unknown. We examined the effects of type I and type II IFN (IFN-β and IFN-γ) on insulin-induced metabolic signaling leading to glucose uptake in 3T3-L1 adipocytes. IFN-β suppressed insulin-induced tyrosine phosphorylation of IRS-1 without affecting its expression, whereas IFN-γ reduced both the protein level and tyrosine phosphorylation. Although both IFNs stimulated phosphorylation of STAT1 (at Tyr(701)) and STAT3 (at Tyr(705)) after treatment for 30 min, subsequent properties of induction of the SOCS isoform were different. IFN-β preferentially induced SOCS1 rather than SOCS3, whereas IFN-γ strongly induced SOCS3 expression alone. In addition, adenovirus-mediated overexpression of either SOCS1 or SOCS3 inhibited insulin-induced tyrosine phosphorylation of IRS-1, whereas the reduction of IRS-1 protein was observed only in SOCS3-expressed cells. Notably, IFN-β-induced SOCS1 expression and suppression of insulin-induced tyrosine phosphorylation of IRS-1 were attenuated by siRNA-mediated knockdown of STAT1. In contrast, adenovirus-mediated expression of a dominant-negative STAT3 (F-STAT3) attenuated IFN-γ-induced SOCS3 expression, reduction of IRS-1 protein, and suppression of insulin-induced glucose uptake but did not have any effect on the IFN-β-mediated SOCS1 expression and inhibition of insulin-induced glucose uptake. Interestingly, pretreatment of IFN-γ with IL-6 synergistically suppressed insulin signaling, even when IL-6 alone had no significant effect. These results indicate that type I and type II IFN induce insulin resistance by inducing distinct SOCS isoforms, and IL-6 synergistically augments IFN-γ-induced insulin resistance by potentiating STAT3-mediated SOCS3 induction in 3T3-L1 adipocytes.
虽然升高血糖水平是干扰素（IFN）治疗的一个因果性不良作用，但确切的潜在分子机制在很大程度上仍是未知的。我们检测了 I 型和 II 型 IFN（IFN-β 和 IFN-γ）对胰岛素诱导的代谢信号转导导致 3T3-L1 脂肪细胞葡萄糖摄取的影响。IFN-β 抑制胰岛素诱导的 IRS-1 酪氨酸磷酸化，而不影响其表达，而 IFN-γ 则降低了 IRS-1 的蛋白水平和酪氨酸磷酸化。尽管两种 IFN 在处理 30 分钟后均能刺激 STAT1（在 Tyr(701)）和 STAT3（在 Tyr(705)）的磷酸化，但诱导 SOCS 同工型的后续特性是不同的。IFN-β 优先诱导 SOCS1 而不是 SOCS3，而 IFN-γ 则强烈地单独诱导 SOCS3 表达。此外，腺病毒介导的 SOCS1 或 SOCS3 的过表达均抑制胰岛素诱导的 IRS-1 酪氨酸磷酸化，而 IRS-1 蛋白的减少仅在 SOCS3 表达的细胞中观察到。值得注意的是，siRNA 介导的 STAT1 敲低可减弱 IFN-β 诱导的 SOCS1 表达和对 IRS-1 酪氨酸磷酸化的抑制。相反，腺病毒介导的显性失活 STAT3（F-STAT3）的表达可减弱 IFN-γ 诱导的 SOCS3 表达、IRS-1 蛋白减少和胰岛素诱导的葡萄糖摄取的抑制，但对 IFN-β 介导的 SOCS1 表达和对胰岛素诱导的葡萄糖摄取的抑制没有任何影响。有趣的是，用 IL-6 预处理 IFN-γ 可协同抑制胰岛素信号，即使 IL-6 单独作用时没有显著影响。这些结果表明，I 型和 II 型 IFN 通过诱导不同的 SOCS 同工型诱导胰岛素抵抗，而 IL-6 通过增强 STAT3 介导的 SOCS3 诱导协同增强 IFN-γ 诱导的胰岛素抵抗。
