Control of pro-atherogenic TNFα production through nuclear receptor co-factor RIP140

Accelerated atherosclerosis represents a hallmark of the metabolic syndrome as observed in insulin-restistant patients. Defects in lipid and cytokine metabolism in macrophages are critically linked to the initiation and progression of atherosclerosis. Given the importance for atherosclerotic lesion development during insulin resistance, this study aimed to explore the transcriptional regulation of pro-inflammatory cytokine production in macrophages. We were able to show that nuclear receptor co-factor RIP140 enhances cytokine tumor necrosis factor (TNF)α gene activity upon lipopolysaccharide (LPS)-mediated macrophage activation. This effect was shown to be conferred via the LPS responsive TNFα promoter region. Indeed, RIP140 was recruited to the endogenous TNFα promoter in a LPS-dependent manner. Co-immunoprecipitation studies revealed that RIP140 interacted with the LPS-inducible transcription factor c-Jun in macrophages in vivo. To this end, mutation of the c-Jun binding site reduced the induction of TNFα through RIP140 in transcriptional activation studies. As RIP140-mediated TNFα gene expression was also translated into strongly potentiated TNFα release from macrophages, these results support the idea that RIP140 controls parts of the inflammatory response of macrophages. Therefore, interference with RIP140 activity might be a potential new strategy for the development of anti-atherogenic drugs in the treatment of the metabolic syndrome.