Proteinase-activated receptors induce interleukin-8 expression by intestinal epithelial cells through ERK/RSK90 activation and histone acetylation.
Proteinase-activated receptors (PARs) are involved in both inflammation and tumorigenesis in epithelial cells. Interleukin (IL)-8 is a potent chemoattractant and is also involved in angiogenesis. The molecular mechanism whereby PARs induce epithelial IL-8 expression is not known. In HT-29 colonic epithelial cells, PAR(1) or PAR(2) agonists stimulated the expression of ... IL-8 through a NF-kappaB-dependent pathway without inducing IkappaB degradation and disassociation of IkappaB from NF-kappaB. Further studies revealed that PAR activation induced the phosphorylation of p65 at Ser-276 in the nucleus, which increased the recruitment of histone acetyltransferase (HAT) p300 to p50. Inhibition of ERK activation completely blocked PAR-induced IL-8 expression, phosphorylation of p65 and HAT activity. We also demonstrated that RSK p90 was the downstream kinase that mediated ERK-induced nuclear p65 phosphorylation. In conclusion, activation of either PAR(1) or PAR(2) stimulated the transcriptional up-regulation of IL-8 in HT-29 colonic epithelial cells through a pathway that involved ERK/RSK p90, NF-kappaB phosphorylation, and HAT activity. These studies provide evidence of a new role for serine proteinases and PARs in the regulation of gene expression in colonic inflammation and tumorigenesis.
Mesh Terms:
Acetylation, Blotting, Western, Cells, Cultured, Colon, Enzyme-Linked Immunosorbent Assay, Epithelial Cells, Gene Expression Regulation, Histone Acetyltransferases, Histones, Humans, I-kappa B Proteins, Immunoprecipitation, Interleukin-8, Luciferases, Mitogen-Activated Protein Kinase 1, Mitogen-Activated Protein Kinase 3, NF-kappa B, Phosphorylation, Protein Processing, Post-Translational, RNA, Messenger, Receptor, PAR-1, Receptor, PAR-2, Reverse Transcriptase Polymerase Chain Reaction, Ribosomal Protein S6 Kinases, 90-kDa, Transfection, p300-CBP Transcription Factors
Acetylation, Blotting, Western, Cells, Cultured, Colon, Enzyme-Linked Immunosorbent Assay, Epithelial Cells, Gene Expression Regulation, Histone Acetyltransferases, Histones, Humans, I-kappa B Proteins, Immunoprecipitation, Interleukin-8, Luciferases, Mitogen-Activated Protein Kinase 1, Mitogen-Activated Protein Kinase 3, NF-kappa B, Phosphorylation, Protein Processing, Post-Translational, RNA, Messenger, Receptor, PAR-1, Receptor, PAR-2, Reverse Transcriptase Polymerase Chain Reaction, Ribosomal Protein S6 Kinases, 90-kDa, Transfection, p300-CBP Transcription Factors
FASEB J.
Date: Jun. 01, 2010
PubMed ID: 20065107
View in: Pubmed Google Scholar
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