SELECTIVE SUPPRESSION OF INTERLEUKIN-12 INDUCTION AFTER MACROPHAGE RECEPTOR LIGATION

Interleukin (IL)-12 is a monocyte- and macrophage-derived cytokine tha t plays a crucial role in both the innate and the acquired immune resp onse. In this study, we examined the effects that ligating specific ma crophage receptors had on the induction of IL-12 by lipopolysaccharide (LPS). We report that ligation of the macrophage Fc gamma, complement , or scavenger receptors inhibited the induction of IL-12 by LPS. Both mRNA synthesis and protein secretion were diminished to near-undetect able levels following receptor ligation. Suppression was specific to I L-12 since IL-10 and tumor necrosis factor-alpha (TNF-alpha) productio n were not inhibited by ligating macrophage receptors. The results of several different experimental approaches suggest that IL-12 downregul ation was due to extracellular calcium influxes that resulted from rec eptor ligation. First, preventing extracellular calcium influxes, by p erforming the assays in EGTA, abrogated Fc gamma R-mediated IL-12(p40) mRNA suppression. Second, exposure of macrophages to the calcium iono phores, ionomycin or A23187, mimicked receptor ligation and inhibited IL-12(p40) mRNA induction by LPS. Finally, bone marrow-derived macroph ages from FcR gamma chain-deficient mice, which fail to nux calcium af ter receptor ligation, failed to inhibit IL-12(p40) mRNA induction. Th ese results indicate that the calcium influxes that occur as a result of receptor ligation are responsible for inhibiting the induction of I L-12 by LPS. Hence, the ligation of phagocytic receptors on macrophage s can lead to a dramatic decrease in IL-12 induction. This downregulat ion may be a way of limiting proinflammatory responses of macrophages to extracellular pathogens, or suppressing the development of cell-med iated immunity to intracellular pathogens.