Differential regulation of interleukin-1 beta-induced cyclooxygenase-2 gene expression by nimesulide in human synovial fibroblasts

Osteoarthritic (OA) human synovial fibroblasts (HSF) in culture were treate d with the preferential COX-2 inhibitors nimesulide or NS-398, the non-spec ific COX-1/COX-2 inhibitor naproxen, or dexamethasone, in the presence or a bsence of IL-1 beta or LPS, Nimesulide or NS-398 inhibited IL-1 beta -induc ed PGE(2) production at all concentrations tested, and in addition they sup pressed IL-1 beta -induced COX-2 mRNA expression and protein synthesis. The se suppressive effects were most evident at therapeutic levels of the drugs . Mechanistic studies revealed that the drug-induced inhibition of COX-2 ex pression and synthesis was not promoter-based, but may be associated with t he blockade of IL-1 beta -dependent calcium flux and increased cellular cal cium levels.