MAP kinases contribute to IL-8 secretion by intestinal epithelial cells via a posttranscriptional mechanism.
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-alpha (TNF-alpha) in the presence or absence of ERK and p38 pathway inhibitors. TNF-alpha 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-kappaB (NF-kappaB). Inhibition of the ERK and p38 pathways attenuated IL-8 secretion but did not alter ICAM-1 expression. Furthermore, AP-1 and NF-kappaB 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-alpha-stimulated IL-8 secretion by intestinal epithelial cells via a posttranscriptional mechanism that involves stabilization of the IL-8 transcript.
Jijon
Humberto B
HB
Gastrointestinal Research Group, University of Calgary, Calgary T2N 4N1, Canada T6G 2C2. hjijon@ualberta.ca
Panenka
William J
WJ
Madsen
Karen L
KL
Parsons
Howard G
HG
D002460:Cell Line; D002462:Cell Membrane / Q000378:metabolism; D006801:Humans; D018799:Intercellular Adhesion Molecule-1 / Q000235:genetics / Q000378:metabolism; D016209:Interleukin-8 / Q000235:genetics / Q000378:metabolism*; D007413:Intestinal Mucosa / Q000166:cytology / Q000378:metabolism*; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases / Q000502:physiology*; D016328:NF-kappa B / Q000502:physiology; D011499:Protein Processing, Post-Translational; D020871:RNA Stability / Q000502:physiology; D012333:RNA, Messenger / Q000378:metabolism; D018808:Transcription Factor AP-1 / Q000502:physiology; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D048051:p38 Mitogen-Activated Protein Kinases
D016209:Interleukin-8; D016328:NF-kappa B; D012333:RNA, Messenger; D018808:Transcription Factor AP-1; D014409:Tumor Necrosis Factor-alpha; D018799:Intercellular Adhesion Molecule-1; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases