Lipopolysaccharide regulates proinflammatory cytokine expression in mouse myoblasts and skeletal muscle
Lipopolysaccharide regulates proinflammatory cytokine expression in mouse myoblasts and skeletal muscle
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DOI：
10.1152/ajpregu.00039.2002
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发表时间：
2002-09-01
影响因子：
2.8
通讯作者：
Lang, CH
中科院分区：
文献类型：
--
作者：
Frost, RA;Nystrom, GJ;Lang, CH
本研究旨在探讨脂多糖(LPS)对C2C12成肌细胞和小鼠骨骼肌中肿瘤坏死因子(TNF)-α和白介素6(IL-6)的调节作用。脂多糖可使C2C12成肌细胞中的肿瘤坏死因子-α和白介素6的mRNA含量呈剂量和时间依赖性增加。金黄色葡萄球菌细胞壁的肽聚糖可以模拟内毒素诱导的细胞因子反应，而酿酒酵母的细胞壁成分酵母多糖A不能模拟内毒素诱导的细胞因子反应。正在进行的蛋白质合成不是这两种细胞因子mRNAs增加所必需的。转录抑制剂5，6-dichloro-beta-D-ribofuranosylbenzimidazole可阻断脂多糖刺激的IL-6mRNA表达，但不改变其半衰期。抗炎糖皮质激素地塞米松选择性地阻断了内毒素刺激的IL-6mRNA积聚，但不能阻断肿瘤坏死因子-α。相反，蛋白酶体抑制剂MG-132可抑制肿瘤坏死因子-α的mRNA表达，但不能抑制IL-6的表达。成肌细胞暴露于内毒素后，核因子-kappaB抑制物(I kappaB、α和epsilon)迅速下降，这种反应也可被MG-132阻断。用IL-1或TNF-α处理心肌细胞也能增加IL-6mRNA的含量，但IL-1或TNF的拮抗剂均不能阻止内毒素引起的IL-6mRNA的增加。在体内条件下，内毒素可增加野生型小鼠血浆中肿瘤坏死因子-α和白介素6的浓度，并刺激其在包括骨骼肌在内的多个组织中的mRNAs积聚。相反，在Toll样受体4突变的小鼠中，内毒素刺激相同细胞因子的能力显著降低。我们的数据表明，内毒素不仅能刺激经典免疫组织中细胞因子的表达，还能刺激骨骼肌中细胞因子的表达。
The purpose of the present study was to examine the regulation of tumor necrosis factor (TNF)-alpha and interleukin (IL)-6 by lipopolysaccharide (LPS) in C2C12 myoblasts and mouse skeletal muscle. LPS produced dose- and time-dependent increases in TNF-alpha and IL-6 mRNA content in C2C12 myoblasts. The LPS-induced cytokine response could be mimicked by peptidoglycan from the cell wall of Staphylococcus aureus but not by zymosan A, a cell wall component from Saccharomyces cerevisiae. Ongoing protein synthesis was not necessary for the increase in the two cytokine mRNAs. The transcriptional inhibitor 5,6-dichloro-beta-D-ribofuranosylbenzimidazole blocked LPS-stimulated IL-6 mRNA expression without changing its mRNA half-life. The anti-inflammatory glucocorticoid dexamethasone selectively blocked LPS-stimulated IL-6 mRNA accumulation but not TNF-alpha. In contrast, the proteasomal inhibitor MG-132 blocked TNF-alpha mRNA expression but not IL-6. Exposure of myoblasts to LPS was associated with a rapid decrease in the inhibitor of nuclear factor-kappaB (I kappaB, alpha, and epsilon), and this response was also blocked by MG-132. Treatment of myocytes with IL-1 or TNF-alpha also increased IL-6 mRNA content, but the increase in IL-6 mRNA due to LPS could not be prevented by pretreatment with antagonists to either IL-1 or TNF. Under in vivo conditions, LPS increased the plasma concentration of TNF-alpha and IL-6 and stimulated the accumulation of their mRNAs in multiple tissues including skeletal muscle from wild-type mice. In contrast, the ability of LPS to stimulate the same cytokines was markedly decreased in mice that harbor a mutation in the Toll-like receptor 4. Our data suggest that LPS stimulates cytokine expression not only in classical immune tissues but also in skeletal muscle.