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Abstract
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.