title: Gammalinolenic acid and dihomogammalinolenic acid suppress the CD3-mediated signal transduction pathway in human T cells.
abstract: Gammalinolenic acid (GLA; 18:3n6) and dihomogammalinolenic acid (DGLA; 20:3n6) suppress lymphocyte activation, and GLA administration reduces joint swelling and tenderness in rheumatoid arthritis patients with active synovitis. In an effort to dissect the mechanisms whereby GLA, DGLA, and other fatty acids influence lymphocyte function, we examined their effects on anti-CD3 monoclonal antibody (mAb)-mediated early signaling events in human T cells. Peripheral blood mononuclear cells from healthy individuals were incubated overnight at 37 degrees C with or without 10 microg/ml fatty acid and then loaded with the calcium binding fluorescent dye indo-1. Fatty acids did not affect the efficiency of indo-1 loading, and they did not alter cell surface membrane expression of the CD3 molecule. Anti-CD3 mAb (G19-4)-induced intracellular calcium [(Ca2+)i] changes were monitored by flow cytometry in negatively selected human T cells. The ratio of violet to blue fluorescence, which is proportional to (Ca2+)i, was measured over time. Cells enriched with GLA and DGLA but not cells enriched with eicosapentaenoic acid (20:5n3) displayed a significant reduction in anti-CD3 mAb-induced early and late (Ca2+)i responses. T cells loaded with GLA, DGLA, or medium alone displayed similar increases in (Ca2+)i in response to the endoplasmic reticulum Ca2(+)-ATPase inhibitor thapsigargin. Anti-CD3 mAb-mediated inositol phosphate production was also diminished in GLA- and DGLA-treated cells. These experiments suggest that GLA and DGLA suppress T cell activation by interfering with early events in the signal transduction pathway.
authors.affiliation: Department of Clinical Physiology, Walter Reed Army Institute of Research, Washington, DC 20307-5100, USA.
authors.forename: D
authors.initials: D
authors.lastname: Vassilopoulos
authors.forename: R B
authors.initials: RB
authors.lastname: Zurier
authors.forename: R G
authors.initials: RG
authors.lastname: Rossetti
authors.forename: G C
authors.initials: GC
authors.lastname: Tsokos
mesh_terms: D015126:8,11,14-Eicosatrienoic Acid / Q000494:pharmacology*; D000911:Antibodies, Monoclonal / Q000502:physiology; D017252:CD3 Complex / Q000276:immunology / Q000502:physiology*; D002118:Calcium / Q000032:analysis; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D007295:Inositol Phosphates / Q000378:metabolism; D007963:Leukocytes, Mononuclear / Q000737:chemistry / Q000276:immunology; D008213:Lymphocyte Activation / Q000187:drug effects; D015398:Signal Transduction / Q000187:drug effects* / Q000276:immunology*; D013601:T-Lymphocytes / Q000276:immunology*; D019284:Thapsigargin / Q000494:pharmacology; D017965:gamma-Linolenic Acid / Q000494:pharmacology*
chemical_list: D000911:Antibodies, Monoclonal; D017252:CD3 Complex; D004791:Enzyme Inhibitors; D007295:Inositol Phosphates; D019284:Thapsigargin; D017965:gamma-Linolenic Acid; D015126:8,11,14-Eicosatrienoic Acid; D002118:Calcium