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Complex interplay between T helper (Th) cells and macrophages contributes to the formation and progression of atherosclerotic plaques. While Th1 cytokines promote inflammatory activation of lesion macrophages, Th2 cytokines attenuate macrophage-mediated inflammation and enhance their repair functions. In spite of its biologic importance, the biochemical and molecular basis of how Th2 cytokines promote maturation of anti-inflammatory macrophages is not understood. We show here that in response to interleukin-4 (IL-4), signal transducer and activator of transcription 6 (STAT6) and PPARgamma-coactivator-1beta (PGC-1beta) induce macrophage programs for fatty acid oxidation and mitochondrial biogenesis. Transgenic expression of PGC-1beta primes macrophages for alternative activation and strongly inhibits proinflammatory cytokine production, whereas inhibition of oxidative metabolism or RNAi-mediated knockdown of PGC-1beta attenuates this immune response. These data elucidate a molecular pathway that directly links mitochondrial oxidative metabolism to the anti-inflammatory program of macrophage activation, suggesting a potential role for metabolic therapies in treating atherogenic inflammation.

Original publication

DOI

10.1016/j.cmet.2006.05.011

Type

Journal article

Journal

Cell Metab

Publication Date

07/2006

Volume

4

Pages

13 - 24

Keywords

Animals, Cells, Cultured, Energy Metabolism, Fatty Acids, Feedback, Physiological, Glucose, Inflammation, Interferon-gamma, Interleukin-4, Lipopolysaccharides, Macrophage Activation, Macrophages, Mice, Mice, Transgenic, Mitochondria, Models, Biological, Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha, STAT6 Transcription Factor, Trans-Activators, Transcription Factors