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Am J Physiol Cell Physiol (December 27, 2002). doi:10.1152/ajpcell.00126.2002
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Submitted on March 19, 2002
Accepted on December 17, 2002

PAR1-Dependent and Independent Increases in COX-2 and PGE2 in Human Colonic Myofibroblasts Stimulated by Thrombin

Michelle L Seymour1, Nosheen F Zaidi1, Morley D Hollenberg1, and Wallace K MacNaughton1*

1 Mucosal Inflammation Research Group, University of Calgary, Calgary, AB, Canada

* To whom correspondence should be addressed. E-mail: wmacnaug{at}ucalgary.ca.

Subepithelial myofibroblast-derived prostaglandin (PG)E2 regulates epithelial chloride secretion in the intestine. Thrombin is elevated in inflammatory conditions of the bowel. Therefore, we sought to determine a role for thrombin in regulating PGE2 synthesis by colonic myofibroblasts. Incubation of cultured CCD-18Co colonic myofibroblasts with thrombin, the proteinase activated receptor 1 (PAR1)-activating peptide (Cit-NH2), and peptides corresponding to 2 non-catalytic regions of thrombin (TP367 and TP508) for 18 hours increased both cyclooxygenase (COX)-2 expression (immunocytochemistry) and PGE2 synthesis (enzyme immunoassay). Inhibition of thrombin by D-Phe-Pro-Arg-chloromethylketone (PPACK) did not significantly reduce PGE2 synthesis which remained elevated compared to control. We also investigated the basic fibroblast growth factor (bFGF)-dependence of thrombin-induced PGE2 elevations. Recombinant human bFGF concentration dependently increased PGE2 synthesis and a bFGF neutralizing antibody inhibited PGE2 synthesis induced by TP367 and TP508 (~40%) and by thrombin (~20%) (but not Cit-NH2). Thrombin, therefore, upregulates COX-2-derived PGE2 synthesis by both catalytic cleavage of PAR1 and bFGF-dependent non-catalytic activity. This presents a novel mechanism by which intestinal myofibroblasts might regulate epithelial chloride secretion.




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