CGRP inhibits antigen presentation by Langerhans cells (LC) and macrophages (Mφ). To examine whether CGRP effects might be mediated, in part, by modulation of cytokine expression, we examined the ability of CGRP to alter IL-1β, IL-12, and IL-10 expression by LC and peritoneal exudate cells (PEC). Exposure of thioglycollate-elicited PEC to 100 nM rat CGRP-I + 1 μg/ml of LPS for 3 h resulted in inhibition of mRNA expression for IL-1β, and the p40 and p35 subunits of IL-12, (by RT-PCR) compared to PEC treated with LPS alone. Culture of PEC for 24 h in LPS + CGRP resulted in significantly less IL-1β production than seen with cells incubated in LPS alone while IL-10 production induced by LPS was augmented by co-culture with CGRP (by ELISA). CGRP also potentiated the LPS-induced increase in IL-10 mRNA. LC were enriched to 85% from BALB/c epidermal cells using immunomagnetic techniques. Culture in CGRP + LPS inhibited induction of mRNA for the p40 subunit of IL-12 compared to culture in LPS alone (by RT-PCR). mRNA for IL-10 could not be detected in LC under these conditions. These results suggest that some of the effects of CGRP on LC and Mφ function may be mediated by effects on cytokines.