Generally, females have been found to have a heightened immune response and a concomitantly higher incidence of autoimmune diseases compared to males. We have used male rat peritoneal macrophages (M phi) to study the effect of female sex hormones on tumor necrosis factor (TNF) release. The amount of TNF released by macrophages (M phi) exposed to 10(-2) and 10(-3) ng/ml of 17 beta-estradiol (E2) (35.1 +/- 7.3 and 23.2 +/- 2.5 units/ml, respectively) was significantly (P < 0.05; n = 9) greater than that released by untreated M phi. Progesterone (P) also significantly (P < 0.05; n = 8) stimulated a maximal TNF release (24.4 +/- 2.8 units/ml TNF) at 10(-2) ng/ml. On the other hand, the amount of TNF released by M phi exposed to E2 or P at concentrations greater than 10(-1) or less than 10(-4) ng/ml was significantly (P < 0.05) reduced compared to untreated controls. In contrast, testosterone did not significantly affect TNF release at any concentration. Within the physiological range of E2 and P concentrations, TNF release from M phi is finely regulated and dramatically affected by relatively small changes in hormone concentrations.