The anaphylatoxin C3a has been reported to have immunomodulatory effects on a number of different cell types. In this study we investigated the effects of C3a and C3a desArg on gene expression and protein secretion of IL-6 in human PBMCs, either alone or in combination with LPS or IL-1β. C3a or C3a desArg alone exhibited no effect on the expression or secretion of IL-6. However, when PBMC were stimulated with LPS or IL-1β, both C3a and C3a desArg were found to enhance IL-6 release by PBMC in a dose-dependent manner. Since C3a has been shown to induce PGE 2 production by monocytes, and PGE 2 has been shown to influence cytokine production, we investigated the potential role of PGE 2 in C3a-mediated enhancement of LPS-and IL-1β-induced IL-6 production. Indomethacin blocked PGE 2 release, but had no influence on the observed effects of C3a, suggesting that the effects of C3a on IL-6 production are independent of PGE 2 formation by monocytes. Northern blot analysis showed that C3a as well as C3a desArg enhanced LPS-induced mRNA levels for IL-6. Pretreatment of PBMCs with pertussis toxin blocked the functions of C3a and C3a desArg, indicating that the actions of these two molecules are mediated by a G protein-coupled pathway. Furthermore, we investigated the effects of C3a and C3a desArg on induction of NF-κB and activating protein-1 binding. Both molecules enhanced LPS-induced NF-κB and activating protein-1 binding activity. These results demonstrate the capacity of intact C3a and its circulating des-Arg form to exert immunmodulatory effects in vitro.