IL-1β impairs insulin-like growth factor I-induced differentiation and downstream activation signals of the insulin-like growth factor I receptor in myoblasts
IL-1β impairs insulin-like growth factor I-induced differentiation and downstream activation signals of the insulin-like growth factor I receptor in myoblasts
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DOI：
10.4049/jimmunol.172.12.7713
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发表时间：
2004-06-15
影响因子：
4.4
通讯作者：
Kelley, KW
中科院分区：
文献类型：
--
作者：
Broussard, SR;McCusker, RH;Kelley, KW
促炎细胞因子在以肌肉萎缩和虚弱为特征的疾病中升高，如炎症性肌病和艾滋病萎缩。我们最近证明，tnf - α损害胰岛素样生长因子(IGF)- 1促进肌肉前体细胞中蛋白质合成的能力。在这项研究中，我们扩展了这些发现，表明低浓度的il -1 β损害了igf - i依赖性成肌细胞的分化，通过肌肉特异性蛋白，肌球蛋白重链的表达来评估。在缺乏外源性igf -1的情况下，il -1 β (1 ng/ml)不会损害肌肉细胞的发育。然而，在igf -1存在的情况下，低100倍浓度的il -1 β (0.01 ng/ml)显著抑制成肌细胞分化、蛋白质合成和肌原素表达。将il -1 β增加至1 ng/ml完全阻断小鼠C2C12成肌细胞中igf -1的合成代谢作用。同样，il -1 β抑制原代猪成肌细胞中igf - i刺激的蛋白质合成。il -1 β在IGF受体远端的一点上破坏了IGF- 1的作用，这不是由于il -1 β诱导的细胞死亡。相反，il -1 β抑制了igf -1磷酸化其下游对接蛋白（胰岛素受体底物1和胰岛素受体底物2）上酪氨酸残基的能力。这些数据表明，生理浓度的il -1 β阻断了igf -1促进蛋白质合成的能力，导致肌原性转录因子、肌原素的表达减少，并导致随后表达肌球蛋白重链的更成熟分化细胞的发育。总的来说，结果与非常低浓度的il -1 β显著损害肌肉形成的观点一致，但在缺乏生长因子igf -1的情况下，它们无法做到这一点。
Proinflammatory cytokines are elevated in disorders characterized by muscle wasting and weakness, such as inflammatory myopathies and AIDS wasting. We recently demonstrated that TNF-alpha impairs the ability of insulin-like growth factor (IGF)-I to promote protein synthesis in muscle precursor cells. In this study we extend these findings by showing that low concentrations of IL-1beta impair IGF-I-dependent differentiation of myoblasts, as assessed by expression of the muscle specific protein, myosin heavy chain. In the absence of exogenous IGF-I, IL-1beta (1 ng/ml) did not impair muscle cell development. However, in the presence of IGF-I, 100-fold lower concentrations of IL-1beta (0.01 ng/ml) significantly suppressed myoblast differentiation, protein synthesis, and myogenin expression. Increasing IL-1beta to I ng/ml completely blocked the anabolic actions of IGF-I in murine C2C12 myoblasts. Similarly, IL-1beta inhibited IGF-I-stimulated protein synthesis in primary porcine myoblasts. IL-1beta impaired the actions of IGF-I at a point distal to the IGF receptor, and this was not due to IL-1beta-induced cell death. Instead, IL-1beta inhibited the ability of IGF-I to phosphorylate tyrosine residues on both of its downstream docking proteins, insulin receptor substrate 1 and insulin receptor substrate 2. These data establish that physiological concentrations of IL-1beta block the ability of IGF-I to promote protein synthesis, leading to reduced expression of the myogenic transcription factor, myogenin, and the subsequent development of more mature differentiated cells that express myosin heavy chain. Collectively, the results are consistent with the notion that very low concentrations of IL-1beta significantly impair myogenesis, but they are unable to do so in the absence of the growth factor IGF-I.