Abstract
Lipopolysaccharide (LPS) was found to induce inflammatory responses in the airways and exerted as a potent stimulus for PG synthesis. This study was to determine the mechanisms of LPS-enhanced cyclooxygenase (COX)-2 expression associated with PGE 2 synthesis in tracheal smooth muscle cells (TSMCs). LPS markedly increased the expression of COX-2 and release of PGE 2 in a time- and concentration-dependent manner, whereas COX-1 remained unaltered. Both the expression of COX-2 and the generation of PGE 2 in response to LPS were attenuated by a tyrosine kinase inhibitor genistein, a phosphatidylcholine-phospholipase C inhibitor D609, a phosphatidylinositol-phospholipase C inhibitor U73122, protein kinase C inhibitors, GF109203X and staurosporine, removal of Ca 2+ by addition of BAPTA/AM plus EGTA, and phosphatidylinositol 3-kinase (PI3-K) inhibitors, LY294002 and wortmannin. Furthermore, LPS-induced NF-κB activation correlated with the degradation of IκB-α, COX-2 expression, and PGE 2 synthesis, was inhibited by transfection with dominant negative mutants of NIK and IKK-α, but not by IKK-β. LPS-induced COX-2 expression and PGE 2 synthesis were completely inhibited by PD98059 (an inhibitor of MEK1/2) and SB203580 (an inhibitor of p38 MAPK inhibitor), but these two inhibitors had no effect on LPS-induced NF-κB activation, indicating that NF-κB is activated by LPS independently of activation of p42/p44 MAPK and p38 MAPK pathways in TSMCs. Taken together, these findings suggest that the increased expression of COX-2 correlates with the release of PGE 2 from LPS-challenged TSMCs, at least in part, independently mediated through MAPKs and NF-κB signalling pathways. LPS-mediated responses were modulated by PLC, Ca 2+, PKC, tyrosine kinase, and PI3-K in these cells.
Published Version
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