Basic fibroblast growth factor upregulates cyclooxygenase-2 in I407 cells through p38 MAP kinase

The intestinal cell line I407 responds to basic fibroblast growth factor (bFGF) by upregulating cyclooxygenase-2 (COX-2) mRNA and protein expression and increasing PGE2 production. bFGF treatment of I407 cells results in phosphorylation of p38, and the p38 inhibitor SB-203580 abrogates bFGF-induced PGE₂ synthesis. Wild-type p38α (p38αWT) and dominant-negative p38α (p38αDN) stable transfectant clones of I407 cells were used to examine the role of the p38 MAP kinase pathway in the events controlling PGE₂ synthesis after treatment with bFGF. Treatment of p38αWT clones with bFGF resulted in increased COX-2 protein levels and PGE2 synthesis similar to those seen in bFGF-treated control-transfected cells. In contrast, the p38αDN clones failed to upregulate COX-2 protein or increase PGE₂ synthesis when treated with bFGF. Exogenous arachidonate did not restore PGE2 synthesis by p38αDN cells. bFGF treatment increased COX-2 mRNA stability, and the p38 inhibitor SB-203580 attenuated COX-2 mRNA stability in bFGF-treated I407 cells. These data demonstrate a crucial role for p38a in growth factor-induced PGE2 synthesis by intestinal cells. Furthermore, they indicate that p38 activity is required at a step distal to arachidonate release, most likely COX-2 upregulation, because exogenous arachidonate did not restore PGE₂ synthesis.