Interleukin-1 beta and tumor necrosis factor-alpha induce MUC5AC overexpression through a mechanism involving ERK/p38 mitogen-activated protein kinases-MSK1-CREB activation in human airway epithelial cells.
Interleukin-1 beta and tumor necrosis factor-alpha induce MUC5AC overexpression through a mechanism involving ERK/p38 mitogen-activated protein kinases-MSK1-CREB activation in human airway epithelial cells.
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发表时间：
2003
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通讯作者：
K. Song;W. Lee;K. Chung;J. Koo;Eun Jin Yang;J. Choi;Joo-Heon Yoon
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作者：
K. Song;W. Lee;K. Chung;J. Koo;Eun Jin Yang;J. Choi;Joo-Heon Yoon
粘液分泌过多常见于许多呼吸道炎症性疾病。MUC 5AC通常被认为是主要的气道粘蛋白，因为MUC 5AC在人气道上皮的杯状细胞中高度表达。此外，它还受到各种炎症细胞因子的调节。然而，白细胞介素（IL）-1 β和肿瘤坏死因子（TNF）-α诱导正常鼻上皮细胞MUC 5AC基因表达的机制，以及参与的信号分子，特别是丝裂原活化蛋白（MAP）激酶的下游信号，仍不清楚。在这里，我们发现，ERK或p38 MAP激酶通路的药理学或遗传抑制废除IL-1 β和TNF-α诱导的MUC 5AC基因在正常人鼻上皮细胞的表达。我们的研究结果还表明，活化的丝裂原和应激活化蛋白激酶1（MSK 1）和cAMP反应元件结合蛋白和cAMP反应元件信号级联通过ERK和p38 MAP激酶是介导MUC 5AC基因表达的细胞内机制的重要方面。总之，这些研究为IL-1 β和TNF-α诱导MUC 5AC基因表达的分子机制提供了新的见解，并增强了我们对炎症过程中粘蛋白高分泌的理解。
Mucin hypersecretion is commonly observed in many inflammatory diseases of the respiratory tract. MUC5AC is generally recognized to be a major airway mucin because MUC5AC is highly expressed in the goblet cells of human airway epithelium. Moreover, it is regulated by various inflammatory cytokines. However, the mechanisms by which the interleukin (IL)-1beta and tumor necrosis factor (TNF)-alpha induce MUC5AC gene expression in normal nasal epithelial cells, and the signal molecules involved, especially in the downstream signaling of mitogen-activated protein (MAP) kinases, remain unclear. Here we show that pharmacologic or genetic inhibition of either ERK or p38 MAP kinase pathway abolished IL-1beta- and TNF-alpha-induced MUC5AC gene expression in normal human nasal epithelial cells. Our results also indicate that the activation of mitogen- and stress-activated protein kinase 1 (MSK1) and cAMP-response element-binding protein and cAMP-response element signaling cascades via ERK and p38 MAP kinases are crucial aspects of the intracellular mechanisms that mediate MUC5AC gene expression. Taken together, these studies give additional insights into the molecular mechanism of IL-1beta- and TNF-alpha-induced MUC5AC gene expression and enhance our understanding on mucin hypersecretion during inflammation.