Existence of a reciprocal neuroendocrine-immune relationship led us to study an immunomodulatory role for the corticotropin-releasing factor (CRF) which is a low molecular weight peptide neurohormone of the neuroendocrine system. In the present study, the CRF-induced modulation of natural killer (NK) cell-mediated lysis (CML) was investigated. The pretreatment for 16-18 h of human peripheral blood mononuclear cells (MNC) with CRF in nanomolar concentrations caused a statistically significant increase in the CML function of NK cells as measured against K562 target cells in the 4-h 51Cr-release assay. The maximum stimulation occurred at a final concentration of 1 nM CRF despite some variability from one blood donor to another. The depletion of monocytes from MNC abolished the stimulatory effect of CRF but the effect was reconstituted by the supplementation of monocyte-derived interleukin-1 (IL-1), suggesting the involvement of IL-1 in the stimulation of NK cell-mediated lysis. Additionally, the CRF-induced stimulatory effect was inhibited by specific antibodies to IL-1 (anti-IL-1) or beta-endorphin (anti-beta E), indirectly suggesting that IL-1 and beta E may act as the mediators of stimulation by CRF of NK cell function. Based on these in vitro studies, we hypothesize that the CRF modulates NK cell-mediated lysis via initial stimulation of monocytes to produce IL-1 triggering the release by B cells of beta E for the stimulation of NK cell function.