title: SOCS3 transactivation by PPARγ prevents IL-17-driven cancer growth.
abstract: Activation of the transcription factor PPARγ by the n-3 fatty acid docosahexaenoic acid (DHA) is implicated in controlling 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 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 PPARγ by DHA. Furthermore, 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.
authors.affiliation: Institut National de la Santé et de la Recherche Medicale (INSERM), U866, France.
authors.forename: Hélène
authors.initials: H
authors.lastname: Berger
authors.forename: Frédérique
authors.initials: F
authors.lastname: Végran
authors.forename: Madijd
authors.initials: M
authors.lastname: Chikh
authors.forename: Federica
authors.initials: F
authors.lastname: Gilardi
authors.forename: Sylvain
authors.initials: S
authors.lastname: Ladoire
authors.forename: Hélène
authors.initials: H
authors.lastname: Bugaut
authors.forename: Grégoire
authors.initials: G
authors.lastname: Mignot
authors.forename: Fanny
authors.initials: F
authors.lastname: Chalmin
authors.forename: Mélanie
authors.initials: M
authors.lastname: Bruchard
authors.forename: Valentin
authors.initials: V
authors.lastname: Derangère
authors.forename: Angélique
authors.initials: A
authors.lastname: Chevriaux
authors.forename: Cédric
authors.initials: C
authors.lastname: Rébé
authors.forename: Bernhard
authors.initials: B
authors.lastname: Ryffel
authors.forename: Caroline
authors.initials: C
authors.lastname: Pot
authors.forename: Aziz
authors.initials: A
authors.lastname: Hichami
authors.forename: Béatrice
authors.initials: B
authors.lastname: Desvergne
authors.forename: François
authors.initials: F
authors.lastname: Ghiringhelli
authors.forename: Lionel
authors.initials: L
authors.lastname: Apetoh
mesh_terms: D000818:Animals; D015153:Blotting, Western; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects; D045744:Cell Line, Tumor; D004032:Diet; D004281:Docosahexaenoic Acids / Q000008:administration & dosage / Q000494:pharmacology; D005260:Female; D020381:Interleukin-17 / Q000378:metabolism; D008325:Mammary Neoplasms, Experimental / Q000235:genetics* / Q000473:pathology / Q000517:prevention & control; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008819:Mice, Nude; D047495:PPAR gamma / Q000819:agonists / Q000235:genetics* / Q000378:metabolism; D011401:Promoter Regions, Genetic / Q000235:genetics; D034622:RNA Interference; D020133:Reverse Transcriptase Polymerase Chain Reaction; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins / Q000235:genetics* / Q000378:metabolism; D058504:Th17 Cells / Q000187:drug effects / Q000378:metabolism; D015533:Transcriptional Activation; D047368:Tumor Burden / Q000187:drug effects / Q000235:genetics
chemical_list: D020381:Interleukin-17; D047495:PPAR gamma; C491411:Socs3 protein, mouse; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D004281:Docosahexaenoic Acids