SOCS3 Transactivation by PPARγ Prevents IL-17-Driven Cancer Growth

Activation of the transcription factor PPAR gamma by the n-3 fatty acid docosahexaenoic acid (DHA) is implicated in controlling proinflammatory cytokine secretion, but the intracellular signaling pathways engaged by PPAR gamma are incompletely characterized. Here, we identify the adapter-encoding gene SOCS3 as a critical transcriptional target of PPAR gamma. SOCS3 promoter binding and gene transactivation by PPAR gamma was associated with a repression in differentiation of proinflammatory T-helper (T-H)17 cells. Accordingly, T(H)17 cells induced in vitro displayed increased SOCS3 expression and diminished capacity to produce interleukin (IL)-17 following activation of PPAR gamma by DHA. Furthermore, naive CD4 T cells derived from mice fed a DHA-enriched diet displayed less capability to differentiate into T(H)17 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 PPAR gamma-induced SOCS3 expression prevents IL-17-mediated cancer growth. (c) 2013 AACR.