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J. Biol. Chem. 285 (39): 29981-29988

© 2010 by The American Society for Biochemistry and Molecular Biology, Inc.

Opposite Action of Peroxisome Proliferator-activated Receptor-{gamma} in Regulating Renal Inflammation


Xiaoyan Wen, Yingjian Li, , and Youhua Liu1

From the Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15261

ABSTRACT Back to Top

Abstract: Peroxisome proliferator-activated receptor-{gamma} (PPAR{gamma}) agonists, a new class of antidiabetic agents, have been shown to possess antiinflammatory activity. In this study, we investigated the molecular mechanism by which PPAR{gamma} agonists inhibit proinflammatory cytokine expression in rat glomerular mesangial cells. Both natural and synthetic PPAR{gamma} agonists potently inhibited RANTES (regulated upon activation, normal T cell expressed and secreted) and monocyte chemoattractant protein-1 expression induced by TNF-{alpha} in mesangial cells, which was dependent on NF-{kappa}B signaling. However, PPAR{gamma} agonists had little effect on TNF-{alpha}-triggered I{kappa}B{alpha} phosphorylation and its subsequent degradation, p65 phosphorylation, and nuclear translocation. In the absence of PPAR{gamma} ligand, TNF-{alpha} induced a physical interaction between nuclear p65 and PPAR{gamma}, as demonstrated by co-immunoprecipitation. Such an interaction was mediated by the C-terminal region of p65. Activation of PPAR{gamma} by its agonist prevented PPAR{gamma}·p65 complex formation. Chromatin immunoprecipitation assay revealed that TNF-{alpha} induced p65 binding to the cis-acting {kappa}B elements in rat RANTES promoter, whereas disruption of PPAR{gamma}·p65 by its agonist blocked p65 interaction with its cognate {kappa}B sites. Knockdown of PPAR{gamma} via siRNA strategy completely abolished TNF-{alpha}-mediated p65 binding to {kappa}B sites and negated RANTES induction, suggesting that unliganded PPAR{gamma} is obligatory for NF-{kappa}B signaling. Consistently, overexpression of PPAR{gamma} in the absence of its ligand sensitized mesangial cells to TNF-{alpha} stimulation. These results uncover a paradoxical action of the unliganded and ligand-activated PPAR{gamma} in regulating NF-{kappa}B signaling and demonstrate PPAR{gamma} ligand as a molecular switch that controls its ability to modulate inflammatory responses in opposite directions.

Key Words: Chemokines • Gene Regulation • Inflammation • Kidney • NF-{kappa}B • PPAR • Tumor Necrosis Factor

Received for publication February 4, 2010. Revision received June 21, 2010.

1 To whom correspondence should be addressed: Dept. of Pathology, University of Pittsburgh School of Medicine, S-405 Biomedical Science Tower, 200 Lothrop St., Pittsburgh, PA 15261. Tel.: 412-648-8253; Fax: 412-648-1916; E-mail: liuy{at}

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