The secretion of IL-6 after stimulation of macrophages has been found to play a central role in the regulation of defense mechanism, haematopoiesis, and acute phase reaction. It was reported that cAMP is involved in the regulation of IL-6 production. Since calcitonin gene-related peptide (CGRP) is known to increase cAMP accumulation in mouse macrophages, we examined whether CGRP would induce IL-6 release in macrophages. Macrophages were obtained from the peritoneal exudate of male Balb/c mouse. The cells were plated on culture dishes at a density of 2.5 x 10(5) cells per well and allowed to adhere for 2 h. After incubation for 48 h with two changes of PRMI-1640, the macrophages were cultured with CGRP and LPS 1 microg/ml for 12 h. The IL-6 level in medium was measured by ELISA kits. The results showed that CGRP had no direct effects on IL-6 production, but it potentiated LPS-induced IL-6 production in a concentration-dependent manner. When CGRP was at a concentration of 10(-10) M, the LPS-induced IL-6 production was increased from 5.16 +/- 0.48 to 8.88 +/- 0.48 ng/ml. The effect of CGRP 10(-10) M was reversed by hCGRP(8-37) 10(-8) M, an antagonist of CGRP1 receptor. The LPS-induced IL-6 production from macrophages was also potentiated by forskolin 5 microM, an activator of adenylate cyclase. Furthermore, pretreatment with H-89 1 microM or Rp-cAMPS 100 microM, the inhibitors of cAMP-dependent protein kinase, inhibited the effect of CGRP by 31% and 98%, respectively. These results demonstrate that the LPS-induced IL-6 release is potentiated by CGRP via the activation of cAMP pathway in mouse resident peritoneal macrophages.