Microenvironment and Immunology SOCS 3 Transactivation by PPAR g Prevents IL-17 – Driven Cancer Growth

Activation of the transcription factor PPARg by the n-3 fatty acid docosahexaenoic acid (DHA) is implicated in controlling proinflammatory cytokine secretion, but the intracellular signaling pathways engaged by PPARg are incompletely characterized. Here, we identify the adapter-encoding gene SOCS3 as a critical transcriptional target of PPARg . SOCS3 promoter binding and gene transactivation by PPARg was associated with a repression in differentiation of proinflammatory T-helper (TH)17 cells. Accordingly, TH17 cells induced in vitro displayed increased SOCS3 expression and diminished capacity to produce interleukin (IL)-17 following activation of PPARg by DHA. Furthermore, na€ ve 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 bywhich PPARg-induced SOCS3 expression prevents IL-17–mediated cancer growth. Cancer Res; 73(12); 3578–90. 2013 AACR.