Feedback control of cyclooxygenase-2 expression through PPARgamma.
Cyclooxygenase-2 (COX-2), a rate-limiting enzyme for prostaglandins (PG), plays a key role in inflammation, tumorigenesis, development, and circulatory homeostasis. The PGD(2) metabolite 15-deoxy-Delta(12, 14) PGJ(2) (15d-PGJ(2)) was identified as a potent natural ligand for the peroxisome proliferator-activated receptor-gamma (PPARgamma). PPARgamma expressed in macrophages has been postulated as a negative regulator of inflammation and a positive regulator of differentiation into foam cell associated with atherogenesis. Here, we show that 15d-PGJ(2) suppresses the lipopolysaccharide (LPS)-induced expression of COX-2 in the macrophage-like differentiated U937 cells but not in vascular endothelial cells. PPARgamma mRNA abundantly expressed in the U937 cells, not in the endothelial cells, is down-regulated by LPS. In contrast, LPS up-regulates mRNA for the glucocorticoid receptor which ligand anti-inflammatory steroid dexamethasone (DEX) strongly suppresses the LPS-induced expression of COX-2, although both 15d-PGJ(2) and DEX suppressed COX-2 promoter activity by interfering with the NF-kappaB signaling pathway. Transfection of a PPARgamma expression vector into the endothelial cells acquires this suppressive regulation of COX-2 gene by 15d-PGJ(2) but not by DEX. A selective COX-2 inhibitor, NS-398, inhibits production of PGD(2) in the U937 cells. Taking these findings together, we propose that expression of COX-2 is regulated by a negative feedback loop mediated through PPARgamma, which makes possible a dynamic production of PG, especially in macrophages, and may be attributed to various expression patterns and physiological functions of COX-2.
Inoue
H
H
Department of Pharmacology, National Cardiovascular Center Research Institute, 5-7-1 Fujishiro-dai, Suita, Osaka 565-8565, Japan. inoue@ri.ncvc.go.jp
Tanabe
T
T
Umesono
K
K
D000818:Animals; D001011:Aorta; D002417:Cattle; D002454:Cell Differentiation; D002478:Cells, Cultured; D051546:Cyclooxygenase 2; D015232:Dinoprostone / Q000378:metabolism; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects / Q000502:physiology*; D005246:Feedback; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D017930:Genes, Reporter; D006801:Humans; D007527:Isoenzymes / Q000235:genetics*; D007700:Kinetics; D008070:Lipopolysaccharides / Q000494:pharmacology*; D008156:Luciferases / Q000235:genetics; D008264:Macrophages / Q000187:drug effects / Q000502:physiology*; D008565:Membrane Proteins; D015230:Prostaglandin D2 / Q000031:analogs & derivatives* / Q000494:pharmacology; D011451:Prostaglandin-Endoperoxide Synthases / Q000235:genetics*; D018160:Receptors, Cytoplasmic and Nuclear / Q000502:physiology*; D011993:Recombinant Fusion Proteins / Q000096:biosynthesis; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D014157:Transcription Factors / Q000502:physiology*; D014158:Transcription, Genetic; D014162:Transfection; D020298:U937 Cells
C097240:15-deoxy-delta(12,14)-prostaglandin J2; D007527:Isoenzymes; D008070:Lipopolysaccharides; D008565:Membrane Proteins; D018160:Receptors, Cytoplasmic and Nuclear; D011993:Recombinant Fusion Proteins; D014157:Transcription Factors; D008156:Luciferases; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D011451:Prostaglandin-Endoperoxide Synthases; D015232:Dinoprostone; D013755:Tetradecanoylphorbol Acetate; D015230:Prostaglandin D2