ASPIRIN INHIBITS EXPRESSION OF THE INTERLEUKIN-1-BETA-INDUCIBLE GROUP-II PHOSPHOLIPASE A(2)

Nonsteroidal anti-inflammatory drugs (NSAIDs) clearly inhibit the synt hesis and release of prostaglandins. However, these actions are not su fficient to explain all the anti-inflammatory effects of these drugs. Recently, it has been shown that aspirin and sodium salicylate inhibit the activation of the transcription factor NF-kappa B. Group II phosp holipase A(2) (sPLA(2)) is expressed in rat glomerular mesangial cells upon exposure to the inflammatory cytokine interleukin-1 beta (IL-1 b eta) and this induction is attenuated by the NF-kappa B inhibitor pyrr olidine dithiocarbamate (PDTC). We now report that aspirin inhibits th e IL-1 beta-induced sPLA(2) activity in rat mesangial cells in a dose- dependent manner. The IC50 value of aspirin for sPLA(2) inhibition was 6.5 mM. This decrease in sPLA(2) activity was not due to direct inhib ition of enzymatic activity but rather to the fact that aspirin inhibi ts the expression of IL-1 beta-induced sPLA(2) protein and mRNA. Furth ermore, by electrophoretic mobility shift analysis we demonstrate redu ced DNA binding of the nuclear factor kappa B, an essential component of the IL-1 beta-dependent upregulation of sPLA(2) gene transcription, after treatment of the cells with aspirin. The study described in thi s report indicates that the inhibition of sPLA(2) expression as induce d by pro-inflammatory cytokines potentially represents an additional m echanism of action for aspirin.