Editors' ChoicePharmacology

NF-κB Needs PPARγ

Science Signaling  28 Sep 2010:
Vol. 3, Issue 141, pp. ec296
DOI: 10.1126/scisignal.3141ec296

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

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