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Sci. Signal., 28 September 2010
Vol. 3, Issue 141, p. ec296
[DOI: 10.1126/scisignal.3141ec296]


Pharmacology NF-{kappa}B Needs PPAR{gamma}

Nancy R. Gough

Science Signaling, AAAS, Washington, DC 20005, USA

Peroxisome proliferator–activated receptor-{gamma} (PPAR{gamma}) is a ligand-dependent transcription factor, and agonists of this receptor have been used to treat type 2 diabetes and kidney diseases associated with inflammation. PPAR{gamma} agonists reduced the production of inflammatory mediators in response to proinflammatory signals such as those mediated by tumor necrosis factor–{alpha} (TNF-{alpha}), which activates the transcription factor nuclear factor {kappa}B (NF-{kappa}B). Wen et al. report opposite ligand-independent and ligand-dependent functions for PPAR{gamma} in regulating the expression of NF-{kappa}B target genes. Incubation of rat glomerular mesangial cells with natural or synthetic PPAR{gamma} agonists reduced TNF-{alpha}–stimulated production of the proinflammatory mediators RANTES and MCP-1. A cell-permeable inhibitor of NF-{kappa}B also blocked RANTES production in response to TNF-{alpha}; however, the PPAR{gamma} agonists failed to reduce early events in NF-{kappa}B activation and did not prevent nuclear translocation of NF-{kappa}B subunits. Instead, PPAR{gamma} agonists blocked the association of PPAR{gamma} with the NF-{kappa}B subunit p65, which was detected by coimmunoprecipitation, following TNF-{alpha} stimulation. Chromatin immunoprecipitation experiments with a portion of the RANTES promoter revealed that p65 from TNF-{alpha}–stimulated cells bound to the promoter and that this interaction was reduced if the cells were also exposed to PPAR{gamma} agonists. Consistent with this model that unliganded PPAR{gamma} promotes NF-{kappa}B binding to this promoter, knockdown of PPAR{gamma} blocked the induction of RANTES and association of p65 at the RANTES promoter by TNF-{alpha} in the mesangial cells. Thus, PPAR{gamma} appears to have a dual function in inflammatory signaling: Unliganded PPAR{gamma} promotes NF-{kappa}B binding to target gene promoters (proinflammatory), and agonist-bound PPAR{gamma} inhibits this NF-{kappa}B binding (anti-inflammatory).

X. Wen, Y. Li, Y. Liu, Opposite action of peroxisome proliferator-activated receptor-{gamma} in regulating renal inflammation: Functional switch by its ligand. J. Biol. Chem. 285, 29981–29988 (2010). [Abstract] [Full Text]

Citation: N. R. Gough, NF-{kappa}B Needs PPAR{gamma}. Sci. Signal. 3, ec296 (2010).

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