IFN-α and IL-18 exert opposite regulatory effects on the IL-12 receptor expression and IL-12-induced IFN-γ production in mouse macrophages: novel pathways in the regulation of the inflammatory response of macrophages

Abstract We characterized the IL-12 response of mouse macrophages in terms of modulation of IFN-γ production by cytokines (IFN-α and IL-18) and regulation of IL-12 receptor expression. β1 and β2 IL-12R chain mRNA expression increased with time in culture in the absence of exogenous stimulation, with concomitant acquisition of responsiveness to IL-12 for IFN-γ production. Expression of the IL-12R β1 chain mRNA was increased further following IL-12 treatment as a consequence of IFN-γ expression. IL-12 response was regulated differentially by IFN-α and IL-18. Neutralization of endogenous type I IFN increased IFN-γ secretion, whereas exogenous IFN-α reduced it. In contrast, IL-18 enhanced IFN-γ mRNA accumulation and IFN-γ secretion in IL-12-stimulated, but not -untreated, cultures. The opposite effects exerted by IFN-α and IL-18 mirror their mutual capacity of regulating—in a negative or positive manner, respectively—the expression of the IL-12R β1 chain. We suggest that differential regulation of IL-12 response by IFN-α and IL-18 can represent previously unrecognized regulatory mechanisms for maintaining suitable levels of differentiation/activation in macrophages.