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

FUNCTIONAL SWITCH BY ITS LIGAND^*

Xiaoyan Wen, Yingjian Li, , and Youhua Liu¹

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

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

Key Words: Chemokines • Gene Regulation • Inflammation • Kidney • NF-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}upmc.edu.

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