GAMMA-LINOLENIC ACID AND DIHOMOGAMMALINOLENIC ACID SUPPRESS THE CD3-MEDIATED SIGNAL-TRANSDUCTION PATHWAY IN HUMAN T-CELLS

Gammalinolenic acid (GLA; 18:3n6) and dihomogammalinolenic acid (DGLA; 20:3n6) suppress lymphocyte activation, and GLA administration reduce s 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 si gnaling events in human T cells. Peripheral blood mononuclear cells fr om healthy individuals were incubated overnight at 37 degrees C with o r without 10 mu g/ml fatty acid and then loaded with the calcium bindi ng fluorescent dye indo-1. Fatty acids did not affect the efficiency o f indo-1 loading, and they did not alter cell surface membrane express ion of the CD3 molecule. Anti-CD3 mAb (G19-4)-induced intracellular ca lcium [(Ca2+)(i)] changes were monitored by flow cytometry in negative ly selected human T cells. The ratio of violet to blue fluorescence, w hich is proportional to (Ca2+)(i), was measured over time. Cells enric hed with GLA and DGLA but not cells enriched with eicosapentaenoic aci d(20:5n3) displayed a significant reduction in anti-CDS mAb-induced ea rly and late (Ca2+)(i) responses. T cells loaded with GLA, DGLA, or me dium alone displayed similar increases in (Ca2+)(i) in response to the endoplasmic reticulum Ca2+-ATPase inhibitor thapsigargin. Anti-CD3 mA b-mediated inositol phosphate production was also diminished in GLA- a nd DGLA-treated cells. These experiments suggest that GLA and DGLA sup press T cell activation by interfering with early events in the signal transduction pathway. (C) 1997 Academic Press.