Effects of dexamethasone and transforming growth factor-beta 2 on group II phospholipase A(2) mRNA and activity levels in interleukin 1 beta- 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 elevating agent. Previously we have shown that dexamethasone and transforming growth factor-beta 2 (TGF-beta 2) suppress sPLA(2) protein synthesis and enzyme activity induced by cytokines and forskolin. The regulation of sPLA(2) by pro-inflammatory cytokines suggests that the enzyme may play a role in glomerular inflammatory reactions. In order to understand the regulation of sPLA(2) in more detail, we investigated whether dexamethasone and TGF-beta 2 also suppress sPLA, mRNA after its induction by either interleukin-1 beta (IL-1 beta) or forskolin. We found that IL-1 beta-induced sPLA(2) mRNA in rat mesangial cells is not down-regulated by pretreatment of the cells with dexamethasone, even at a concentration of 10 mu M, which dramatically decreases sPLA(2) protein 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 is inhibited by dexamethasone in a concentration-dependent manner. Likewise, TGF-beta 2 inhibits the elevation of sPLA(2) mRNAs induced by either IL-1 beta or forskolin. The decrease in sPLA(2) mRNA caused by TGF-beta 2 corresponds with the decrease in sPLA(2) enzyme levels and activity. These data suggest that cytokine- and forskolin-induced sPLA(2) expression is tightly controlled via both transcriptional and post-transcriptional mechanisms. Furthermore, we show that pretreatment of mesangial 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.