Activation of the transcription factor PPARγ by the n-3 fatty acid docosahexaenoic acid (DHA) is implicated in controling proinflammatory cytokine secretion, but the intracellular signaling pathways engaged by PPARγ are incompletely characterized. Here we identify the adapter encoding gene SOCS3 as a critical transcriptional target of PPARγ. SOCS3 promoter binding and gene transactivation by PPARγ was associated with a repression in differentiation of proinflammatory Th17 cells. Accordingly, Th17 cells induced in vitro displayed increased SOCS3 expression and diminished capacity to produce IL-17 following activation of PPARγ by DHA. Further, naïve CD4 T cells derived from mice fed a DHA-enriched diet displayed less capability to differentiate into Th17 cells. In two different mouse models of cancer, DHA prevented tumor outgrowth and angiogenesis in an IL-17 dependent manner. Altogether, our results uncover a novel molecular pathway by which PPARγ-induced SOCS3 expression prevents IL-17-mediated cancer growth.

PMID:

 

23619236