EFFECTS OF DEXAMETHASONE AND TRANSFORMING GROWTH-FACTOR-BETA-2 ON GROUP-II PHOSPHOLIPASE-A(2) MESSENGER-RNA AND ACTIVITY LEVELS IN INTERLEUKIN-1-BETA-STIMULATED AND FORSKOLIN-STIMULATED MESANGIAL CELLS

The expression of 14 kDa group II phospholipase A(2) [also referred to as secretory PLA(2) (sPLA(2))] is induced in rat glomerular mesangial cells by exposure to inflammatory cytokines and forskolin, a cAMP ele vating agent. Previously we have shown that dexamethasone and transfor ming growth factor-beta 2 (TGF-beta 2) suppress sPLA(2) protein synthe sis and enzyme activity induced by cytokines and forskolin. The regula tion of sPLA(2) by pro-inflammatory cytokines suggests that the enzyme may play a role in glomerular inflammatory reactions. In order to und erstand the regulation of sPLA(2) in more detail, we investigated whet her dexamethasone and TGF-beta 2 also suppress sPLA, mRNA after its in duction by either interleukin-1 beta (IL-1 beta) or forskolin. We foun d that IL-1 beta-induced sPLA(2) mRNA in rat mesangial cells is not do wn-regulated by pretreatment of the cells with dexamethasone, even at a concentration of 10 mu M, which dramatically decreases sPLA(2) prote in levels and activity. Metabolic labelling experiments indicated that the decreased sPLA(2) levels under these conditions can be explained by inhibition of the rate of sPLA(2) synthesis from the elevated mRNA levels. In contrast, the forskolin-induced elevation of sPLA(2) mRNA i s inhibited by dexamethasone in a concentration-dependent manner. Like wise, TGF-beta 2 inhibits the elevation of sPLA(2) mRNAs induced by ei ther IL-1 beta or forskolin. The decrease in sPLA(2) mRNA caused by TG F-beta 2 corresponds with the decrease in sPLA(2) enzyme levels and ac tivity. These data suggest that cytokine- and forskolin-induced sPLA(2 ) expression is tightly controlled via both transcriptional and post-t ranscriptional mechanisms. Furthermore, we show that pretreatment of m esangial cells with epidermal growth factor prior to stimulation with IL-1 beta or forskolin had no suppressing effect on sPLA(2) levels or enzyme activity, as has been reported previously for osteoblasts.