Insulin resistance-inducing cytokines differentially regulate SOCS mRNA expression via growth factor- and Jak/Stat-signaling pathways in 3T3-L1 adipocytes
Insulin resistance-inducing cytokines differentially regulate SOCS mRNA expression via growth factor- and Jak/Stat-signaling pathways in 3T3-L1 adipocytes
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DOI：
10.1677/joe.0.1810129
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发表时间：
2004-04-01
影响因子：
4
通讯作者：
Paschke, R
中科院分区：
文献类型：
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作者：
Fasshauer, M;Kralisch, S;Paschke, R
多种细胞因子，包括肿瘤坏死因子 (TNF) α、生长激素 (GH) 和白细胞介素 (IL)-6，可诱导胰岛素抵抗。最近，研究表明TNFα和GH诱导细胞因子信号传导抑制因子(SOCS)-3是这些细胞因子损害胰岛素敏感性的重要机制。目前的研究在 3T3-L1 脂肪细胞中调查了 TNFα 和 GH 是否也上调 SOCS-1 和 SOCS-6（两者均已被证明可以有效抑制胰岛素信号传导），以及 IL-6 是否可能改变 SOCS-1、-3 和 -6 的合成。有趣的是。 10ng/ml TNFα、500ng/ml GH和30ng/ml IL-6时间依赖性地诱导SOCS-1 mRNA，分别在TNFα添加8小时和GH和IL-6添加1小时后可检测到最大刺激。此外。 TNFα和GH导致SOCS-1持续上调长达24小时，而IL-6的刺激只是短暂的，添加效应物后2小时SOCS-1 mRNA恢复到基础水平。 SOCS-1 的诱导是剂量依赖性的，在低至 3 ng/ml TNFα、50 ng/ml GH 和 10 ng/ml IL-6 的浓度下即可检测到显着的刺激。此外，使用药物抑制剂的刺激实验和研究表明，TNFα、GH 和 IL-6 对 SOCS-1 mRNA 的积极作用至少部分是由 Janus 激酶 (Jak) 2 介导的。最后，SOCS-3 的表达是由 IL-6 剂量和时间依赖性诱导的，至少部分是通过 Jak2 诱导的，但没有任何细胞因子影响 SOCS-6 的表达。综上所述，我们的结果显示胰岛素抵抗诱导激素对 SOCS mRNA 的差异调节，并表明 SOCS-1 和 SOCS-3 可能是脂肪细胞中胰岛素抵抗的重要细胞内介质，也是治疗胰岛素敏感性受损的潜在药理学靶点。
Various cytokines, including tumor necrosis factor (TNF) alpha, growth hormone (GH) and interleukin (IL)-6, induce insulin resistance. Recently, it was demonstrated that induction of suppressor of cytokine signaling (SOCS)-3 by TNFalpha and GH is an important mechanism by which these cytokines impair insulin sensitivity. The current study investigated in 3T3-L1 adipocytes whether TNFalpha and GH also upregulate SOCS-1 and SOCS-6, which have both been shown to inhibit insulin signaling potently, and whether IL-6 might alter synthesis of SOCS-1, -3 and -6. Interestingly. 10 ng/ml TNFalpha, 500 ng/ml GH and 30 ng/ml IL-6 induced SOCS-1 mRNA time-dependently with maximal stimulation detectable after 8 h of TNFalpha and I h of GH and IL-6 addition respectively. Furthermore. TNFalpha and GH caused sustained upregulation of SOCS-1 for up to 24 h, whereas stimulation by IL-6 was only transient, with SOCS-1 mRNA returning to basal levels 2 h after effector addition. Induction of SOCS-1 was dose-dependent, and significant stimulation was detectable at concentrations as low as 3 ng/ml TNFalpha, 50 ng/ml GH and 10 ng/ml IL-6. Furthermore, stimulation experiments and studies using pharmacologic inhibitors suggested that the positive effect of TNFalpha, GH and IL-6 on SOCS-1 mRNA is, at least in part, mediated by Janus kinase (Jak) 2. Finally, SOCS-3 expression was dose- and time-dependently induced by IL-6, at least in part via Jak2, but none of the cytokines affected SOCS-6 expression. Taken together, our results show a differential regulation of SOCS mRNA by insulin resistance-inducing hormones, and suggest that SOCS-1, as well as SOCS-3, may be an important intracellular mediator of insulin resistance in fat cells and a potential pharmacologic target for the treatment of impaired insulin sensitivity.