A NEW BIOLOGIC ROLE FOR C3A AND C3A DESARG - REGULATION OF TNF-ALPHA AND IL-1-BETA SYNTHESIS

The complement activation products C3a and C3a desArg are generated in the course of trauma, infection, tissue injury, and ischemia. We have investigated the effects of C3a and C3a desArg on gene expression and protein synthesis of TNF-alpha and IL-1 beta in PBMC. Neither C3a nor C3a desArg alone induced detectable protein or mRNA levels for TNF-al pha and IL-1 beta. C3a modulated LPS-induced TNF-alpha and IL-1 beta s ynthesis. In nonadherent PBMC, C3a suppressed LPS-induced synthesis of TNF-alpha (20-71% decrease by 0.2-10 mu g/ml of C3a, p < 0.01) and IL -1 beta (19-57% decrease by 0.5-10 mu g/ml of C3a, p < 0.01), independ ently of endogenous production of PGE(2). C3a also suppressed LPS-indu ced mRNA levels for TNF-alpha and IL-1 beta. In contrast, in adherent PBMC, C3a at 5 to 20 mu g/ml enhanced LPS-induced TNF-alpha (75-188% i ncrease, p < 0.001) and IL-1 beta (119-274% increase, p < 0.001) synth esis. C3a enhanced TNF-alpha and IL-1 beta mRNA levels in LPS-stimulat ed adherent cells. Furthermore, C3a desArg shared with C3a the ability to modulate LPS-induced mRNA and protein synthesis for TNF-alpha and IL-1 beta. These results suggest that C3a, thought to be proinflammato ry, and C3a desArg, thought to be biologically inactive, are modulator s of inflammation. Both C3a and C3a desArg may enhance cytokine synthe sis by adherent monocytes at local inflammatory sites, while inhibitin g the systemic synthesis of proinflammatory cytokines by circulating c ells.