Sci. Signal., 28 September 2010
Pharmacology NF-B Needs PPAR
Nancy R. Gough
Science Signaling, AAAS, Washington, DC 20005, USA
Peroxisome proliferator–activated receptor- (PPAR) 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 agonists reduced the production of inflammatory mediators in response to proinflammatory signals such as those mediated by tumor necrosis factor– (TNF-), which activates the transcription factor nuclear factor B (NF-B). Wen et al. report opposite ligand-independent and ligand-dependent functions for PPAR in regulating the expression of NF-B target genes. Incubation of rat glomerular mesangial cells with natural or synthetic PPAR agonists reduced TNF-–stimulated production of the proinflammatory mediators RANTES and MCP-1. A cell-permeable inhibitor of NF-B also blocked RANTES production in response to TNF-; however, the PPAR agonists failed to reduce early events in NF-B activation and did not prevent nuclear translocation of NF-B subunits. Instead, PPAR agonists blocked the association of PPAR with the NF-B subunit p65, which was detected by coimmunoprecipitation, following TNF- stimulation. Chromatin immunoprecipitation experiments with a portion of the RANTES promoter revealed that p65 from TNF-–stimulated cells bound to the promoter and that this interaction was reduced if the cells were also exposed to PPAR agonists. Consistent with this model that unliganded PPAR promotes NF-B binding to this promoter, knockdown of PPAR blocked the induction of RANTES and association of p65 at the RANTES promoter by TNF- in the mesangial cells. Thus, PPAR appears to have a dual function in inflammatory signaling: Unliganded PPAR promotes NF-B binding to target gene promoters (proinflammatory), and agonist-bound PPAR inhibits this NF-B binding (anti-inflammatory).
X. Wen, Y. Li, Y. Liu, Opposite action of peroxisome proliferator-activated receptor- in regulating renal inflammation: Functional switch by its ligand. J. Biol. Chem. 285, 29981–29988 (2010). [Abstract] [Full Text]
Citation: N. R. Gough, NF-B Needs PPAR. Sci. Signal. 3, ec296 (2010).
Science Signaling. ISSN 1937-9145 (online), 1945-0877 (print). Pre-2008: Science's STKE. ISSN 1525-8882