Bombesin and the two mammalian bombesin-related peptides, gastrin-releasing peptide (GRP) and neuromedin C, at physiological concentrations ranging from 10(-11) M to 10(-9) M have been shown in this study to significantly stimulate in vitro the antibody-dependent cellular cytotoxicity (ADCC) and natural killer (NK) activities in BALB/c mouse leukocytes from axillary nodes, spleen and thymus. The three neuropeptides studied induced no change in interleukin-2 production. In addition, these neuropeptides induced in leukocytes from axillary nodes a rapid, transient and significant decrease of intracellular cyclic AMP at 30 s, but a significant transient increase of inositol 1,4,5-trisphosphate levels at 30 and 60 s and a stimulation of protein kinase C activity in membrane fractions after 5 min incubation. These results suggest that inositol phospholipid signalling and cAMP messenger systems are involved in the increase of NK and ADCC activities when leukocytes are incubated in the presence of bombesin, GRP or neuromedin C.