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The aim of the present study was to investigate the mechanisms involved in the modulation of human lymphocyte proliferation by different fatty acids. We evaluated the effects of palmitic (PA), stearic (SA), oleic (OA), linoleic (LA), docosahexaenoic (DHA), and eicosapentaenoic (EPA) acids on IL-2 signaling pathways in addition to the involvement of the de novo ceramide synthesis and PI3K pathway. PA, SA, DHA, and EPA decreased the JAK1/JAK3/STAT5 pathway and IL-2-induced Akt phosphorylation. OA and LA had no effect. The inhibitory effect of DHA and EPA on lymphocyte proliferation was abolished by fumonisin B1 (FB1, an inhibitor of the de novo ceramide synthesis), whereas the effect of the other fatty acids remained unchanged. ERK1/2 phosphorylation was increased by OA and LA but markedly decreased by the other fatty acids. PKC-ζ phosphorylation was increased by OA and LA only. These effects were abolished in the presence of wortmannin, a PI3K inhibitor. In conclusion, the findings reported herein contribute for understanding the mechanisms by which different fatty acids modulate lymphocyte proliferation. The inhibitory effect of PA, SA, DHA and EPA on lymphocyte proliferation was associated with a reduction in the IL-2- mediated activation of the JAK/STAT, ERK, and Akt pathways. Decreased lymphocyte proliferation promoted by DHA and EPA also involved de novo ceramide synthesis. The stimulatory effect of OA and LA on lymphocyte proliferation was associated with improved activity of the MAP kinase and PI3K pathways, as demonstrated by increased ERK1/2 and PKC-ζ phosphorylation.