Effects of dexamethasone and transforming growth factor-β2 on group II phospholipase A2 mRNA and activity levels in interleukin 1β- and forskolin-stimulated mesangial cells

摘要

pThe expression of 14 kDa group II phospholipase Asub2/sub [also referred to as secretory PLAsub2/sub (sPLAsub2/sub)] 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-β2 (TGF-β2) suppress sPLAsub2/sub protein synthesis and enzyme activity induced by cytokines and forskolin. The regulation of sPLAsub2/sub by pro-inflammatory cytokines suggests that the enzyme may play a role in glomerular inflammatory reactions. In order to understand the regulation of sPLAsub2/sub in more detail, we investigated whether dexamethasone and TGF-β2 also suppress sPLAsub2/sub mRNA after its induction by either interleukin-1β (IL-1β) or forskolin. We found that IL-1β-induced sPLAsub2/sub mRNA in rat mesangial cells is not down-regulated by pretreatment of the cells with dexamethasone, even at a concentration of 10 μM, which dramatically decreases sPLAsub2/sub protein levels and activity. Metabolic labelling experiments indicated that the decreased sPLAsub2/sub levels under these conditions can be explained by inhibition of the rate of sPLAsub2/sub synthesis from the elevated mRNA levels. In contrast, the forskolin-induced elevation of sPLAsub2/sub mRNA is inhibited by dexamethasone in a concentration-dependent manner. Likewise, TGF-β2 inhibits the elevation of sPLAsub2/sub mRNAs induced by either IL-1β or forskolin. The decrease in sPLAsub2/sub mRNA caused by TGF-β2 corresponds with the decrease in sPLAsub2/sub enzyme levels and activity. These data suggest that cytokine- and forskolin-induced sPLAsub2/sub 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-1β or forskolin had no suppressing effect on sPLAsub2/sub levels or enzyme activity, as has been reported previously for osteoblasts./p