Feedback control of the arachidonate cascade in rheumatoid synoviocytes by 15-deoxy-Delta(12,14)-prostaglandin J2.
Rheumatoid arthritis (RA) is a chronic polyarticular joint disease associated with massive synovial proliferation, inflammation, and angiogenesis. PPAR-gamma ligands, both 15-deoxy-Delta(12,14)-prostaglandin J2 (15d- PGJ2) and troglitazone (TRO), can inhibit the growth of RA synoviocytes in vitro, and suppress the chronic inflammation of adjuvant-induced arthritis in rats, but the potency of 15d-PGJ2 is higher than TRO. Prostaglandin (PG) E2 plays important roles in joint erosion and synovial inflammation. In the present study, 15d-PGJ2, but not TRO and other prostanoids, suppressed interleukin (IL)-1beta-induced PGE2 synthesis in rheumatoid synovial fibroblasts (RSFs) through the inhibition of cyclooxygenase (COX-2) and cytosolic phospholipase A2 (cPLA2) expression. Furthermore, the inhibition was not affected by pretreatment with anti-PPAR-gamma antibody. It means that this anti-inflammatory effect of 15d-PGJ2 for PG synthesis may be independent of PPAR-gamma and 15d-PGJ2 is a key regulator of negative feedback of the arachidonate cascade on the COX pathway. These findings provide new insight into the feedback mechanism of the arachidonate cascade.
Tsubouchi
Y
Y
First Department of Internal Medicine, Kyoto Prefectural University of Medicine, 465 Kajii-cho, Kawaramachi-hirokoji, Kamigyo-ku, Kyoto, 602-8566, Japan.
Kawahito
Y
Y
Kohno
M
M
Inoue
K
K
Hla
T
T
Sano
H
H
D016718:Arachidonic Acid / Q000378:metabolism*; D001172:Arthritis, Rheumatoid / Q000378:metabolism* / Q000473:pathology; D002839:Chromans / Q000494:pharmacology; D051546:Cyclooxygenase 2; D003545:Cysteine / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D015232:Dinoprostone / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D005246:Feedback; D006801:Humans; D007527:Isoenzymes / Q000276:immunology / Q000378:metabolism; D020024:Leukotriene Antagonists; D007975:Leukotriene B4 / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D015289:Leukotrienes / Q000096:biosynthesis; D008565:Membrane Proteins; D015230:Prostaglandin D2 / Q000031:analogs & derivatives / Q000378:metabolism*; D011451:Prostaglandin-Endoperoxide Synthases / Q000276:immunology / Q000378:metabolism; D018160:Receptors, Cytoplasmic and Nuclear / Q000276:immunology; D013583:Synovial Membrane / Q000378:metabolism*; D013844:Thiazoles / Q000494:pharmacology; D045162:Thiazolidinediones; D014157:Transcription Factors / Q000276:immunology; D000077288:Troglitazone
C097240:15-deoxy-delta(12,14)-prostaglandin J2; D002839:Chromans; D007527:Isoenzymes; D020024:Leukotriene Antagonists; D015289:Leukotrienes; D008565:Membrane Proteins; D018160:Receptors, Cytoplasmic and Nuclear; D013844:Thiazoles; D045162:Thiazolidinediones; D014157:Transcription Factors; C112381:cysteinyl-leukotriene; D007975:Leukotriene B4; D016718:Arachidonic Acid; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D011451:Prostaglandin-Endoperoxide Synthases; D000077288:Troglitazone; D015232:Dinoprostone; D003545:Cysteine; D015230:Prostaglandin D2