MAP kinases contribute to IL-8 secretion by intestinal epithelial cells via a posttranscriptional mechanism

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Abstract
The intracellular pathways that regulate intestinal epithelial gene expression are poorly understood. In this study we examined the roles of extracellular signal-regulated kinase (ERK) and p38 in the expression of interleukin-8 (IL-8) and intercellular adhesion molecule-1 (ICAM-1) using the human intestinal cell line HT-29. HT-29 cells were treated with tumor necrosis factor-α (TNF-α) in the presence or absence of ERK and p38 pathway inhibitors. TNF-α treatment resulted in increased IL-8 and ICAM-1 protein and mRNA synthesis, increased ERK and p38 activity, and activation of the transcription factors activator protein-1 (AP-1) and nuclear factor-κB (NF-κB). Inhibition of the ERK and p38 pathways attenuated IL-8 secretion but did not alter ICAM-1 expression. Furthermore, AP-1 and NF-κB DNA binding was not affected by ERK and p38 inhibition. In contrast, ERK and p38 inhibition resulted in the accelerated degradation of the IL-8 mRNA, suggesting that in HT-29 cells, p38 and ERK contribute to TNF-α-stimulated IL-8 secretion by intestinal epithelial cells via a posttranscriptional mechanism that involves stabilization of the IL-8 transcript.

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