期刊
FASEB JOURNAL
卷 15, 期 2, 页码 535-544出版社
WILEY
DOI: 10.1096/fj.00-0187com
关键词
anti-inflammatory; sepsis; desensitization; respiratory burst
Desensitization of macrophages is important during the development of sepsis. It was our intention to identify mechanisms that promote macrophage deactivation upon contact with endotoxin (LPS) and interferon-gamma (IFN-gamma) in vitro. Macrophage activation was achieved with 12-O-tetradecanoylphorbol 13-acetate (TPA), and the oxidative burst (i.e., oxygen radical formation) was followed by oxidation of the redox-sensitive dyes hydroethidine and dichlorodihy-drofluorescein diacetate, Prestimulation of macrophages for 15 h with a combination of LPS/IFN-gamma attenuated oxygen radical formation in response to TPA, Taking the anti-inflammatory properties of the peroxisome proliferator-activating receptory (PPAR gamma) into consideration, we established activation of PPAR gamma in response to LPS/IFN-gamma by an electrophoretic mobility shift, supershift, and a reporter gene assay. The reporter contains a triple PPAR-responsive element (PPRE) in front of a thymidine kinase minimal promoter driving the luciferase gene, We demonstrated that PPRE decoy oligonucleotides, supplied in front of LPS/IFN-gamma, allowed a full oxidative burst to recover upon TPA addition, Furthermore, we suppressed the oxidative burst by using the PPAR gamma agonists 15-deoxy-Delta (12,14)-prostaglandin J(2), BRL. 49653, or ciglitazone. No effect was observed with WY 14643, a PPAR alpha agonist, We conclude that activation of PPARs, most likely PPAR gamma, promotes macrophage desensitization, thus attenuating the oxidative burst, This process appears important during development of sepsis.
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