Eicosanoids derived from arachidonic acid (PGE2 and LTB4) have been shown to be involved in the control of mitogen-induced proliferation of lymphocytes but the effects of (n-3) polyunsaturated fatty acids (PUFA)-derived eicosanoids (PGE3 and LTB5) on mitogenic response have not been well described. Supplementation with (n-3) PUFA decreases lymphocyte proliferation in human and animal models. The present study was designed to compare the effect of (n-3)- and (n-6)-derived eicosanoids on mitogenic response. Mouse splenocytes and human peripheral blood mononuclear cells (PBMC) were cultured in the presence or absence of the T cell mitogen Concanavalin A (CON A) with and without the addition of PGE2, LTB4, PGE3 and LTB5 at several concentrations. Lymphocyte proliferation was determined by measuring incorporation of [3H]thymidine into newly synthesized DNA. Both (n-3) and (n-6)-derived eicosanoids inhibited T cell mitogen-induced lymphocyte proliferation in human PBMC and murine splenocytes. The addition of PGE3 and LTB5 decreased Con A-induced mitogenic response in human PBMC more than the same concentration of PGE2 and LTB4 (e.g. -28.7 +/- 4.2% with 10(-9) M PGE3 vs -9.4 +/- 6.3% with 10(-9) M PGE2, P = 0.05 and -95.5 +/- 1.6% with 10(-11) M LTB5 vs -49.2 +/- 3.8% with 10(-11) M LTB4, p < 0.001). A similar trend was observed in murine splenocytes. It is concluded that PGE3 and LTB5 are as potent and at some doses more potent than PGE2 and LTB4 in inhibiting lymphocyte proliferation when added in vitro. These data suggest that eicosanoids derived from (n-3) PUFA may contribute to the (n-3) PUFA-induced suppression of lymphocyte proliferation.