PPAR-gamma agonists inhibit production of monocyte inflammatory cytokines.
The peroxisome proliferator-activated receptor-gamma (PPAR-gamma) is a member of the nuclear receptor family of transcription factors, a large and diverse group of proteins that mediate ligand-dependent transcriptional activation and repression. Expression of PPAR-gamma is an early and pivotal event in the differentiation of adipocytes. Several agents that promote differentiation of fibroblast lines into adipocytes have been shown to be PPAR-gamma agonists, including several prostanoids, of which 15-deoxy-delta-prostaglandin J2 is the most potent, as well as members of a new class of oral antidiabetic agents, the thiazolidinediones, and a variety of non-steroidal anti-inflammatory drugs (NSAIDs). Here we show that PPAR-gamma agonists suppress monocyte elaboration of inflammatory cytokines at agonist concentrations similar to those found to be effective for the promotion of adipogenesis. Inhibition of cytokine production may help to explain the incremental therapeutic benefit of NSAIDs observed in the treatment of rheumatoid arthritis at plasma drug concentrations substantially higher than are required to inhibit prostaglandin G/H synthase (cyclooxygenase).
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Department of Molecular Biology, Massachusetts General Hospital, Boston 02114, USA.
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D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology; D002460:Cell Line; D002839:Chromans / Q000494:pharmacology; D016207:Cytokines / Q000096:biosynthesis* / Q000235:genetics; D006801:Humans; D018836:Inflammation Mediators; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D015230:Prostaglandin D2 / Q000031:analogs & derivatives / Q000494:pharmacology; D018160:Receptors, Cytoplasmic and Nuclear / Q000819:agonists* / Q000502:physiology; D013844:Thiazoles / Q000494:pharmacology; D045162:Thiazolidinediones; D014157:Transcription Factors / Q000819:agonists* / Q000502:physiology; D000077288:Troglitazone; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis / Q000502:physiology
C097240:15-deoxy-delta(12,14)-prostaglandin J2; D000894:Anti-Inflammatory Agents, Non-Steroidal; D002839:Chromans; D016207:Cytokines; D018836:Inflammation Mediators; D018160:Receptors, Cytoplasmic and Nuclear; D013844:Thiazoles; D045162:Thiazolidinediones; D014157:Transcription Factors; D014409:Tumor Necrosis Factor-alpha; D000077288:Troglitazone; D015230:Prostaglandin D2