title: Potentiation of tumor necrosis factor alpha-induced secreted phospholipase A2 (sPLA2)-IIA expression in mesangial cells by an autocrine loop involving sPLA2 and peroxisome proliferator-activated receptor alpha activation.
abstract: In rat mesangial cells, exogenously added secreted phospholipases A2 (sPLA2s) potentiate the expression of pro-inflammatory sPLA2-IIA first induced by cytokines like tumor necrosis factor-alpha (TNFalpha) and interleukin-1 beta. The transcriptional pathway mediating this effect is, however, unknown. Because products of PLA2 activity are endogenous activators of peroxisome proliferator-activated receptor alpha (PPAR alpha, we postulated that sPLA2s mediate their effects on sPLA2-IIA expression via sPLA2 activity and subsequent PPAR alpha activation. This study shows that various sPLA2s, including venom enzymes, human sPLA2-IIA, and wild-type and catalytically inactive H48Q mutant of porcine pancreatic sPLA2-IB, enhance the TNF alpha-induced sPLA2-IIA expression at the mRNA and protein levels. In cells transfected with luciferase sPLA2-IIA promoter constructs, sPLA2s are active only when the promoter contains a functional PPRE-1 site. The effect of exogenous sPLA2s is also blocked by the PPAR alpha inhibitor MK886. Interestingly, the expression of sPLA2-IIA induced by TNF alpha alone is also attenuated by MK886, by the sPLA2-IIA inhibitor LY311727, by heparinase, which prevents the binding of sPLA2-IIA to heparan sulfate proteoglycans, and by the specific cPLA2-alpha inhibitor pyrrolidine-1. Together, these data indicate that sPLA2-IIA released from mesangial cells by TNF alpha stimulates its own expression via an autocrine loop involving cPLA2 and PPAR alpha. This signaling pathway is also used by exogenously added sPLA2s including pancreatic sPLA2-IB and is distinct from that used by TNF alpha.
authors.affiliation: Center of Pharmacology, University Hospital Frankfurt, 60590 Frankfurt, Germany.
authors.forename: Sabine
authors.initials: S
authors.lastname: Beck
authors.forename: Gérard
authors.initials: G
authors.lastname: Lambeau
authors.forename: Kristen
authors.initials: K
authors.lastname: Scholz-Pedretti
authors.forename: Michael H
authors.initials: MH
authors.lastname: Gelb
authors.forename: Marcel J W
authors.initials: MJ
authors.lastname: Janssen
authors.forename: Suzanne H
authors.initials: SH
authors.lastname: Edwards
authors.forename: David C
authors.initials: DC
authors.lastname: Wilton
authors.forename: Josef
authors.initials: J
authors.lastname: Pfeilschifter
authors.forename: Marietta
authors.initials: M
authors.lastname: Kaszkin
mesh_terms: D000818:Animals; D001094:Arachidonate 5-Lipoxygenase / Q000378:metabolism; D001665:Binding Sites; D015153:Blotting, Western; D002478:Cells, Cultured; D004247:DNA / Q000378:metabolism; D004281:Docosahexaenoic Acids / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D017930:Genes, Reporter; D005920:Glomerular Mesangium / Q000166:cytology*; D054501:Group II Phospholipases A2; D006801:Humans; D007211:Indoles / Q000494:pharmacology; D019787:Linoleic Acid / Q000494:pharmacology; D008156:Luciferases / Q000378:metabolism; D008954:Models, Biological; D009154:Mutation; D010741:Phospholipases A / Q000378:metabolism*; D054467:Phospholipases A2; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D011759:Pyrrolidines / Q000494:pharmacology; D012313:RNA / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D013552:Swine; D013997:Time Factors; D014157:Transcription Factors / Q000378:metabolism*; D014162:Transfection; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*; D014688:Venoms / Q000378:metabolism; D002722:Chlorobenzenes
chemical_list: D001094:Arachidonate 5-Lipoxygenase; D004247:DNA; D004281:Docosahexaenoic Acids; D004791:Enzyme Inhibitors; D054501:Group II Phospholipases A2; D007211:Indoles; D019787:Linoleic Acid; D008156:Luciferases; D010741:Phospholipases A; D054467:Phospholipases A2; D011759:Pyrrolidines; D012313:RNA; D012333:RNA, Messenger; D018160:Receptors, Cytoplasmic and Nuclear; D014157:Transcription Factors; D014409:Tumor Necrosis Factor-alpha; D014688:Venoms; C095553:LY 311727; C060893:MK-886; D002722:Chlorobenzenes; C032519:pyrrolidine