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Proteinase‐activated receptors induce interleukin‐8 expression by intestinal epithelial cells through ERK/RSK90 activation and histone acetylation
Author(s) -
Wang Hongying,
Moreau France,
Hirota Christina L.,
MacNaughton Wallace K.
Publication year - 2010
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fj.09-137646
Subject(s) - phosphorylation , mapk/erk pathway , microbiology and biotechnology , kinase , protease activated receptor , signal transduction , chemistry , inflammation , carcinogenesis , receptor , biology , cancer research , biochemistry , immunology , gene , platelet , thrombin
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‐κB‐dependent pathway without inducing IκB degradation and disassociation of IκB from NF‐κB. 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 PAR1 or PAR2 stimulated the transcriptional up‐regulation of IL‐8 in HT‐29 colonic epithelial cells through a pathway that involved ERK/RSK p90, NF‐κB 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.—Wang, H, Moreau, F., Hirota, C. L., MacNaughton, W. K. Proteinase‐activated receptors induce interleukin‐8 expression by intestinal epithelial cells through ERK/RSK90 activation and histone acetylation. FASEB J. 24, 1971–1980 (2010). www.fasebj.org