CELL-SPECIFIC REGULATION OF TYPE-II PHOSPHOLIPASE-A2 EXPRESSION IN RAT MESANGIAL CELLS

IL-1 stimulates mesangial cells to synthesize specific proteins, inclu ding a non-pancreatic (Type II) phospholipase A2 ( PLA2). We have stud ied the regulation of PLA2 by proinflammatory mediators, implicated in the pathogenesis of glomerulo-nephritis, and have assessed whether th e activation of second messenger systems modulates or mimics PLA2 gene expression by cytokines. IL-1alpha and beta, TNFalpha, and LPS, but n ot serum, IL-2, or PDGF, potently induce PLA2 mRNA, and enzyme express ion. IL-1-stimulated mesangial cells express a 1.0 kB PLA2 mRNA transc ript that is induced in a dose- and time-dependent manner. IL-1-stimul ated increases in steady-state PLA2 mRNA abundance result from a moder ate increase in PLA2 transcription rate that is amplified by the prolo nged persistence of the transcript. Forskolin and dibutyryl cAMP poten tiate IL-1-induced PLA2 mRNA and enzyme expression, but have no effect in the absence of cytokine. 12-tetradecanoyl phorbol 13-acetate, sn-1 , 2-dioctanoyl glycerol or 1-oleoyl-2-acetyl-sn-glycerol fail to induc e PLA2 expression or to alter the effect of IL-1 when coincubated with the cytokine. In contrast, serum deprivation for 24 h specifically en hances IL-1-stimulated PLA2. Genistein potentiates PLA2 mRNA expressio n in cells exposed to both IL-1 and serum. The inhibitory effect of se rum on IL-1-induced PLA2 mRNA abundance is reproduced by PDGF but not dexamethasone. These data demonstrate that the signaling pathways dire ctly engaged by IL-1 to induce PLA2 expression in mesangial cells inte ract with several second messenger systems in a cell-specific manner. We speculate that IL-1 induces specialized changes in mesangial cell s tructure and function through direct activation of a transcription fac tor(s), that result in induction of a specific gene set.