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Am J Physiol Cell Physiol 284: C1185-C1192, 2003. First published December 27, 2002; doi:10.1152/ajpcell.00126.2002
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Vol. 284, Issue 5, C1185-C1192, May 2003

PAR1-dependent and independent increases in COX-2 and PGE2 in human colonic myofibroblasts stimulated by thrombin

Michelle L. Seymour, Nosheen F. Zaidi, Morley D. Hollenberg, and Wallace K. MacNaughton

Mucosal Inflammation Research Group, University of Calgary, Calgary, Alberta, Canada T2N 4N1

Subepithelial myofibroblast-derived prostaglandin E2 (PGE2) 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 noncatalytic regions of thrombin (TP367 and TP508) for 18 h 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 with 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 noncatalytic activity. This presents a novel mechanism by which intestinal myofibroblasts might regulate epithelial chloride secretion.

cyclooxygenase; proteinase-activated receptor 1; prostaglandin E2


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