title: n-3 polyunsaturated fatty acids suppress phosphatidylinositol 4,5-bisphosphate-dependent actin remodelling during CD4+ T-cell activation.
abstract: n-3 PUFA (polyunsaturated fatty acids), i.e. DHA (docosahexaenoic acid), found in fish oil, exhibit anti-inflammatory properties; however, the molecular mechanisms remain unclear. Since PtdIns(4,5)P2 resides in raft domains and DHA can alter the size of rafts, we hypothesized that PtdIns(4,5)P2 and downstream actin remodelling are perturbed by the incorporation of n-3 PUFA into membranes, resulting in suppressed T-cell activation. CD4+ T-cells isolated from Fat-1 transgenic mice (membranes enriched in n-3 PUFA) exhibited a 50% decrease in PtdIns(4,5)P2. Upon activation by plate-bound anti-CD3/anti-CD28 or PMA/ionomycin, Fat-1 CD4+ T-cells failed to metabolize PtdIns(4,5)P2. Furthermore, actin remodelling failed to initiate in Fat-1 CD4+ T-cells upon stimulation; however, the defect was reversed by incubation with exogenous PtdIns(4,5)P2. When Fat-1 CD4+ T-cells were stimulated with anti-CD3/anti-CD28-coated beads, WASP (Wiskott-Aldrich syndrome protein) failed to translocate to the immunological synapse. The suppressive phenotype, consisting of defects in PtdIns(4,5)P2 metabolism and actin remodelling, were recapitulated in CD4+ T-cells isolated from mice fed on a 4% DHA triacylglycerol-enriched diet. Collectively, these data demonstrate that n-3 PUFA, such as DHA, alter PtdIns(4,5)P2 in CD4+ T-cells, thereby suppressing the recruitment of WASP to the immunological synapse, and impairing actin remodelling in CD4+ T-cells.
authors.affiliation: Department of Biochemistry and Biophysics, Texas A&M University, College Station, Texas, USA.
authors.forename: Tim Y
authors.initials: TY
authors.lastname: Hou
authors.forename: Jennifer M
authors.initials: JM
authors.lastname: Monk
authors.forename: Yang-Yi
authors.initials: YY
authors.lastname: Fan
authors.forename: Rola
authors.initials: R
authors.lastname: Barhoumi
authors.forename: Yong Q
authors.initials: YQ
authors.lastname: Chen
authors.forename: Gonzalo M
authors.initials: GM
authors.lastname: Rivera
authors.forename: David N
authors.initials: DN
authors.lastname: McMurray
authors.forename: Robert S
authors.initials: RS
authors.lastname: Chapkin
mesh_terms: D008841:Actin Cytoskeleton / Q000378:metabolism*; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D015820:Cadherins / Q000235:genetics; D002478:Cells, Cultured; D015525:Fatty Acids, Omega-3 / Q000494:pharmacology*; D054992:Immunological Synapses / Q000378:metabolism; D008213:Lymphocyte Activation; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D019269:Phosphatidylinositol 4,5-Diphosphate / Q000378:metabolism / Q000494:pharmacology / Q000502:physiology*; D021381:Protein Transport; D013154:Spleen / Q000166:cytology; D051316:Wiskott-Aldrich Syndrome Protein / Q000378:metabolism
chemical_list: D000893:Anti-Inflammatory Agents; D015820:Cadherins; D015525:Fatty Acids, Omega-3; D019269:Phosphatidylinositol 4,5-Diphosphate; C495768:Was protein, mouse; D051316:Wiskott-Aldrich Syndrome Protein; C502406:fat1 protein, mouse