title: n-3 PUFAs reduce T-helper 17 cell differentiation by decreasing responsiveness to interleukin-6 in isolated mouse splenic CD4⁺ T cells.
abstract: Cluster of differentiation 4(+) (CD4(+)) effector T-cell subsets [e.g., T-helper (Th) 1 and Th17] are implicated in autoimmune and inflammatory disorders such as multiple sclerosis, psoriasis, and rheumatoid arthritis. Interleukin (IL)-6 is a pleiotropic cytokine that induces Th17 polarization via signaling through the membrane-bound transducer glycoprotein 130 (GP130). Previously, we demonstrated that n-3 (ω-3) polyunsaturated fatty acids (PUFAs) reduce CD4(+) T-cell activation and differentiation into pathogenic Th17 cells by 25-30%. Here we report that n-3 PUFAs alter the response of CD4(+) T cells to IL-6 in a lipid raft membrane-dependent manner. Naive splenic CD4(+) T cells from fat-1 transgenic mice exhibited 30% lower surface expression of the IL-6 receptor. This membrane-bound receptor is known to be shed during cellular activation, but the release of soluble IL-6 receptor after treatment with anti-CD3 and anti-CD28 was not changed in the CD4(+) T cells from fat-1 mice, suggesting that the decrease in surface expression was not due to ectodomain release. We observed a significant 20% decrease in the association of GP130 with lipid rafts in activated fat-1 CD4(+) T cells and a 35% reduction in GP130 homodimerization, an obligate requirement for downstream signaling. The phosphorylation of signal transducer and activator of transcription 3 (STAT3), a downstream target of IL-6-dependent signaling, was also decreased by 30% in response to exogenous IL-6 in fat-1 CD4(+) T cells. Our results suggest that n-3 PUFAs suppress Th17 cell differentiation in part by reducing membrane raft-dependent responsiveness to IL-6, an essential polarizing cytokine.
authors.affiliation: Program in Integrative Nutrition and Complex Diseases, Nutrition and Food Science.
authors.forename: M Jeannie
authors.initials: MJ
authors.lastname: Allen
authors.affiliation: Program in Integrative Nutrition and Complex Diseases, Nutrition and Food Science.
authors.forename: Yang-Yi
authors.initials: YY
authors.lastname: Fan
authors.affiliation: Program in Integrative Nutrition and Complex Diseases, Nutrition and Food Science.
authors.forename: Jennifer M
authors.initials: JM
authors.lastname: Monk
authors.affiliation: Program in Integrative Nutrition and Complex Diseases, Biochemistry and Biophysics.
authors.forename: Tim Y
authors.initials: TY
authors.lastname: Hou
authors.affiliation: College of Veterinary Medicine and Biomedical Sciences Image Analysis Laboratory, and.
authors.forename: Rola
authors.initials: R
authors.lastname: Barhoumi
authors.affiliation: Program in Integrative Nutrition and Complex Diseases, Microbial Pathogenesis and Immunology, School of Medicine, Texas A&M University Health Science Center, College Station, TX.
authors.forename: David N
authors.initials: DN
authors.lastname: McMurray
authors.affiliation: Program in Integrative Nutrition and Complex Diseases, Nutrition and Food Science, Center for Translational Environmental Health Research, Texas A&M University, College Station, TX; and Microbial Pathogenesis and Immunology, School of Medicine, Texas A&M University Health Science Center, College Station, TX r-chapkin@tamu.edu.
authors.forename: Robert S
authors.initials: RS
authors.lastname: Chapkin
mesh_terms: D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000378:metabolism*; D002452:Cell Count; D002454:Cell Differentiation / Q000187:drug effects; D050822:Cytokine Receptor gp130 / Q000235:genetics / Q000378:metabolism; D015525:Fatty Acids, Omega-3 / Q000494:pharmacology*; D005260:Female; D015850:Interleukin-6 / Q000378:metabolism*; D008213:Lymphocyte Activation / Q000187:drug effects; D008297:Male; D051379:Mice; D010766:Phosphorylation; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D019947:Receptors, Interleukin-6 / Q000235:genetics / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D013154:Spleen / Q000187:drug effects / Q000378:metabolism; D058504:Th17 Cells / Q000187:drug effects*
chemical_list: D015525:Fatty Acids, Omega-3; C494200:Il6st protein, mouse; D015850:Interleukin-6; D012333:RNA, Messenger; D019947:Receptors, Interleukin-6; D050796:STAT3 Transcription Factor; C494087:Stat3 protein, mouse; D050822:Cytokine Receptor gp130