Regulation of cyclooxygenase-2 expression in human mesangial cells--transcriptional inhibition by IL-13.
Activated mesangial cells may play an important part in glomerulonephritis. Cytokines can modulate the release of prostanoids by human mesangial cells (HMC). We have investigated the effects of pro-inflammatory stimuli on COX-2 expression in HMC and its potential modulation by interleukin (IL)-13. HMC released increased amounts of prostaglandin E2 (PGE2) after treatment with several combinations of IL-1 beta, tumor necrosis factor (TNF)-alpha and/or lipopolysaccharide. Increases in PGE2 correlated with the induction of COX-2 protein expression. The accumulation of PGE2 elicited by a combination of IL-1 beta/TNF-alpha correlated closely with the temporal pattern of COX-2 protein expression, which reflected the induction of COX-2 mRNA. IL-13 inhibited IL-1 beta/TNF-alpha-elicited PGE2 production, as well as COX-2 protein and mRNA expression in a concentration-dependent fashion. With 50 ng.mL-1 IL-13 these parameters were inhibited by 90, 80 and 84%, respectively. In HMC transfected with the 5' regulatory region of the COX-2 gene, IL-13 suppressed cytokine-induced promoter activation. Our results suggest that COX-2 expression is a major target for IL-13-mediated abrogation of prostaglandin release by HMC and support that this process takes place by transcriptional inhibition of the COX-2 gene.
Díaz-Cazorla
M
M
Departamento de Estructura y Función de Proteínas, Consejo Superior de Investigaciones Científicas (CSIC), Madrid, Spain.
Pérez-Sala
D
D
Ros
J
J
Jiménez
W
W
Fresno
M
M
Lamas
S
S
D002478:Cells, Cultured; D051546:Cyclooxygenase 2; D015232:Dinoprostone / Q000378:metabolism; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects* / Q000235:genetics; D005920:Glomerular Mesangium / Q000201:enzymology*; D006801:Humans; D007375:Interleukin-1 / Q000494:pharmacology; D018793:Interleukin-13 / Q000494:pharmacology*; D007527:Isoenzymes / Q000235:genetics*; D008070:Lipopolysaccharides / Q000494:pharmacology; D008565:Membrane Proteins; D011451:Prostaglandin-Endoperoxide Synthases / Q000235:genetics*; D012333:RNA, Messenger / Q000187:drug effects / Q000378:metabolism; D012045:Regulatory Sequences, Nucleic Acid / Q000235:genetics; D014162:Transfection / Q000235:genetics; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
D007375:Interleukin-1; D018793:Interleukin-13; D007527:Isoenzymes; D008070:Lipopolysaccharides; D008565:Membrane Proteins; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D011451:Prostaglandin-Endoperoxide Synthases; D015232:Dinoprostone