Recent data have shown the ability of bombesin-related peptides to stimulate murine macrophage functions. In the present study, we have investigated the effect of bombesin, gastrin-releasing peptide (GRP), and neuromedin C on the proliferative response of lymphocytes from murine axillary nodes, spleen, and thymus. The results show that these neuropeptides at 10(-9), 10(-10), and 10(-11) M concentrations modulate the lymphoproliferative response, stimulating to a small but significant extent the spontaneous proliferation and inhibiting to a great extent the lymphoproliferative response to the mitogen concanavalin A (Con A). This regulation is probably mediated through adherent accessory cells, since their presence for the neuropeptides to produce their effect. The increased interleukin-1 beta production by Con A in cultures of peritoneal macrophages (a model of adherent accessory cells) decreased after the addition of bombesin, GRP, and neuromedin C; this diminution is a possible mechanism for their inhibitory action on the lymphoproliferative response to Con A. In addition, these neuropeptides caused a significant protein kinase C activation in total leukocyte population and T-enriched lymphocytes from axillary nodes, as well as in peritoneal macrophages.