An extensive literature links the immune responses to neuroendocrine regulation. We have examined the effects of the neuropeptide hormone angiotensin II on the production of the immunomodulatory lymphokine interferon-gamma (IFN-gamma). Angiotensin II (10(-6)-10(-8) M) stimulated (three- to fivefold) the IFN-gamma production in human blood lymphocytes obtained from normal individuals. At 10(-9) M angiotensin II stimulation disappeared and was reestablished at physiological concentrations of the neuropeptide (10(-10)-10(-11) M). Stimulation by angiotensin II was compared with the classical effect of the lectin phytohemagglutinin, and it was seen that both actions are mediated by external calcium (as they are blocked by EGTA 2.5 mM) and that the stimuli follow different kinetics, reaching the steady state at 6 h with angiotensin II and later (18 h) when the lectin was used. The effect of angiotensin II over the IFN-gamma production was blocked by its analog sarcosine 1-isoleucine 8-angiotensin II, showing the specificity of angiotensin II action. These findings demonstrate a selective biological regulation of IFN-gamma production by angiotensin II and suggest another regulation pathway of immune responses.