Cytokine-hormone interactions:: Tumor necrosis factor α impairs biologic activity and downstream activation signals of the insulin-like growth factor I receptor in myoblasts
Cytokine-hormone interactions:: Tumor necrosis factor α impairs biologic activity and downstream activation signals of the insulin-like growth factor I receptor in myoblasts
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DOI：
10.1210/en.2003-0087
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发表时间：
2003-07-01
期刊：
影响因子：
4.8
通讯作者：
Kelley, KW
中科院分区：
文献类型：
--
作者：
Broussard, SR;McCusker, RH;Kelley, KW
骨骼肌损伤后，肿瘤坏死因子α升高。在这里，我们提供的证据表明，肿瘤坏死因子α作用于肌肉细胞，诱导IGF-I受体抵抗状态。我们发现，在原代猪成肌细胞中，肿瘤坏死因子α抑制了IGF-I刺激的蛋白质合成。在C2C12小鼠成肌细胞中也观察到了类似的结果，仅0.01 ng/mlTNFpha就能显著抑制IGF-I诱导的蛋白质合成。肿瘤坏死因子α也削弱了IGF-I诱导关键的生肌转录因子--肌生成素表达的能力。肿瘤坏死因子α对IGF-I诱导的蛋白合成和肌生成素表达的抑制不是由于肿瘤坏死因子α直接杀伤成肌细胞所致。虽然IGF-I诱导其受体的β链酪氨酸磷酸化约19倍，但肿瘤坏死因子α并不抑制这种自磷酸化。相反，肿瘤坏死因子α显著降低了IGF-I刺激的两个主要下游受体对接分子-胰岛素受体底物(IRS)-1和IRS-2的酪氨酸磷酸化水平约50%。这些结果表明，低皮克浓度的肿瘤坏死因子α作用于猪和小鼠成肌细胞，损害IRS-1和IRS-2的酪氨酸磷酸化，但不影响受体本身。这些数据与以下观点是一致的，即非常低的生理浓度的TNFpha通过诱导IGF-I受体抵抗来干扰蛋白质合成和肌肉细胞发育。
TNFalpha is elevated following damage to skeletal muscle. Here we provide evidence that TNFalpha acts on muscle cells to induce a state of IGF-I receptor resistance. We establish that TNFalpha inhibits IGF-I-stimulated protein synthesis in primary porcine myoblasts. Similar results were observed in C2C12 murine myoblasts, where as little as 0.01 ng/ml TNFalpha significantly inhibits protein synthesis induced by IGF-I. TNFalpha also impairs the ability of IGF-I to induce expression of a key myogenic transcription factor, myogenin. The inhibition by TNFalpha of IGF-I-induced protein synthesis and expression of myogenin is not due to direct killing of myoblasts by TNFalpha. Although IGF-I induces an approximately 19-fold induction in tyrosine phosphorylation of the beta-chains of its receptor, TNFalpha does not inhibit this autophosphorylation. Instead, TNFalpha significantly reduces by approximately 50% IGF-I-stimulated tyrosine phosphorylation of two of the major downstream receptor docking molecules, insulin receptor substrate (IRS)-1 and IRS-2. These results establish that low picogram concentrations of TNFalpha acts on both porcine and murine myoblasts to impair tyrosine phosphorylation of both IRS-1 and IRS-2, but not the receptor itself. These data are consistent with the notion that very low physiological concentrations of TNFalpha interfere with both protein synthesis and muscle cell development by inducing a state of IGF-I receptor resistance.