Prostaglandin E2 stimulates IL-8 gene expression in human colonic epithelial cells by a posttranscriptional mechanism.
Intestinal mucosal epithelial cells produce IL-8, a neutrophil chemoattractant that contributes to mucosal inflammation in various infectious and inflammatory diseases. However, the mediators involved and the molecular regulation of IL-8 production are poorly understood. As PGE2 is central in gut inflammation and modulates a variety of mucosal epithelial cell functions, we determined whether PGE2 can affect the expression of IL-8. Exogenous PGE2 induced the accumulation of IL-8 mRNA and protein production in a dose- and time-dependent manner in T84 human colonic epithelial cells. Forskolin and dibutyryl cAMP, which increase intracellular cAMP, stimulated IL-8 in a fashion similar to that of PGE2. PGE2 and PGE2 receptor agonists coupling through EP4 receptors elevated intracellular cAMP and up-regulated IL-8 mRNA expression by activating protein kinase A. Unlike PMA, PGE2 and forskolin did not increase IL-8 gene transcription. However, PGE2, forskolin, and PMA enhanced the stability of IL-8 mRNA transcripts, suggesting the involvement of posttranscriptional regulation. Chloramphenicol acetyltransferase reporter gene transfection studies confirmed the presence of a PGE2 responsive cis-element(s) in the IL-8 3' untranslated region. Furthermore, dexamethasone inhibited PGE2-, forskolin-, and dibutyryl cAMP-induced, but not PMA-induced, IL-8 protein production. These results highlight a novel role for PGE2 in up-regulating IL-8 gene expression by colonic epithelial cells, which may contribute to exacerbation of inflammation in the gastrointestinal tract.
Yu
Y
Y
Institute of Parasitology, McGill University, Ste. Anne de Bellevue, Quebec, Canada.
Chadee
K
K
D000230:Adenocarcinoma; D003994:Bucladesine / Q000037:antagonists & inhibitors / Q000494:pharmacology; D005576:Colforsin / Q000037:antagonists & inhibitors / Q000494:pharmacology; D003106:Colon / Q000378:metabolism*; D003110:Colonic Neoplasms; D000242:Cyclic AMP / Q000378:metabolism / Q000502:physiology; D003907:Dexamethasone / Q000494:pharmacology; D015232:Dinoprostone / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000494:pharmacology*; D004306:Dose-Response Relationship, Immunologic; D004847:Epithelial Cells / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D006801:Humans; D016209:Interleukin-8 / Q000096:biosynthesis / Q000235:genetics*; D007424:Intracellular Fluid / Q000378:metabolism; D009363:Neoplasm Proteins / Q000096:biosynthesis; D011499:Protein Processing, Post-Translational / Q000187:drug effects / Q000235:genetics* / Q000276:immunology; D012333:RNA, Messenger / Q000378:metabolism; D018078:Receptors, Prostaglandin E / Q000819:agonists / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D014407:Tumor Cells, Cultured
D016209:Interleukin-8; D009363:Neoplasm Proteins; D012333:RNA, Messenger; D018078:Receptors, Prostaglandin E; D005576:Colforsin; D003994:Bucladesine; D003907:Dexamethasone; D000242:Cyclic AMP; D015232:Dinoprostone; D013755:Tetradecanoylphorbol Acetate