Inhibition of the production of platelet activating factor and of leukotriene B4 in activated neutrophils by nimesulide due to an elevation of intracellular cyclic adenosine monophosphate

Abstract

Nimesulide (CAS 51803-78-2) has been shown to exert a marked anti-inflammatory effect in several in vivo models of inflammation. Recent studies indicate that nimesulide not only inhibits prostaglandin synthesis in certain cell types, but also has pleiotropic effects on neutrophil functions, including the respiratory burst, integrin-mediated adherence and synthesis of platelet-activating factor (PAF). In the present study, the effect of nimesulide on PAF synthesis was compared with its effect on the production of leukotriene B4 (LTB4). Nimesulide dose-dependently inhibited both processes in neutrophils stimulated by serum-treated zymosan (STZ) with a comparable efficacy (IC50 values between 10 and 20 mumol/l). In formyl-methionyl-leucyl-phenylalanine-stimulated neutrophils (treated with cytochalasin B), these IC50 values were 30 and 50 mumol/l for PAF and LTB4 synthesis, respectively. These results indicate an inhibition by nimesulide of a common step in the release of these lipid mediators, i.e. the activation of phospholipase A2, possibly by elevating intracellular cAMP. In support of this latter hypothesis, it was observed that nimesulide increased the level of cAMP almost 3-fold after STZ stimulation, whereas in fMLP-stimulated neutrophils these changes in cAMP levels were more dramatic. Furthermore, the inhibitory effects of nimesulide on PAF and LTB4 production could largely be prevented by addition of H89, an inhibitor of cAMP-dependent protein kinase (PK-A). It is concluded that an increase in intracellular cAMP is instrumental in the observed effects of nimesulide on the release of PAF and LTB4 by activated neutrophils and that limited availability of arachidonic acid, also the substrate for the cyclooxygenase pathway, may very well contribute to the effects of nimesulide on prostaglandin synthesis observed in other cell types.