Cell-specific regulation of type II phospholipase A2 expression in rat mesangial cells.
IL-1 stimulates mesangial cells to synthesize specific proteins, including a non-pancreatic (Type II) phospholipase A2 (PLA2). We have studied the regulation of PLA2 by proinflammatory mediators, implicated in the pathogenesis of glomerulonephritis, and have assessed whether the activation of second messenger systems modulates or mimics PLA2 gene expression by cytokines. IL-1 alpha and beta, TNF alpha, and LPS, but not serum, IL-2, or PDGF, potently induce PLA2 mRNA, and enzyme expression. IL-1-stimulated mesangial cells express a 1.0 kB PLA2 mRNA transcript that is induced in a dose- and time-dependent manner. IL-1-stimulated increases in steady-state PLA2 mRNA abundance result from a moderate increase in PLA2 transcription rate that is amplified by the prolonged persistence of the transcript. Forskolin and dibutyryl cAMP potentiate 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 induce PLA2 expression or to alter the effect of IL-1 when coincubated with the cytokine. In contrast, serum deprivation for 24 h specifically enhances IL-1-stimulated PLA2. Genistein potentiates PLA2 mRNA expression in cells exposed to both IL-1 and serum. The inhibitory effect of serum on IL-1-induced PLA2 mRNA abundance is reproduced by PDGF but not dexamethasone. These data demonstrate that the signaling pathways directly engaged by IL-1 to induce PLA2 expression in mesangial cells interact with several second messenger systems in a cell-specific manner. We speculate that IL-1 induces specialized changes in mesangial cell structure and function through direct activation of a transcription factor(s), that result in induction of a specific gene set.
Konieczkowski
M
M
Department of Medicine, School of Medicine, Case Western Reserve University, Cleveland, Ohio.
Sedor
J R
JR
D000818:Animals; D003994:Bucladesine / Q000494:pharmacology; D002467:Cell Nucleus / Q000378:metabolism; D005576:Colforsin / Q000494:pharmacology; D004075:Diglycerides / Q000494:pharmacology; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D005920:Glomerular Mesangium / Q000187:drug effects / Q000201:enzymology*; D007375:Interleukin-1 / Q000494:pharmacology; D007376:Interleukin-2 / Q000494:pharmacology; D008070:Lipopolysaccharides / Q000494:pharmacology; D010703:Phorbol Esters / Q000494:pharmacology; D010712:Phosphatidic Acids / Q000494:pharmacology; D010741:Phospholipases A / Q000096:biosynthesis* / Q000145:classification / Q000235:genetics / Q000378:metabolism; D054467:Phospholipases A2; D010982:Platelet-Derived Growth Factor / Q000494:pharmacology; D012333:RNA, Messenger / Q000096:biosynthesis*; D051381:Rats; D015398:Signal Transduction; D014018:Tissue Distribution; D014158:Transcription, Genetic
D004075:Diglycerides; D007375:Interleukin-1; D007376:Interleukin-2; D008070:Lipopolysaccharides; D010703:Phorbol Esters; D010712:Phosphatidic Acids; D010982:Platelet-Derived Growth Factor; D012333:RNA, Messenger; D005576:Colforsin; D003994:Bucladesine; D010741:Phospholipases A; D054467:Phospholipases A2