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

We characterized the IL-12 response of mouse macrophages in terms of mlodul ation of IFN-gamma production by cytokines (IFN-alpha and IL-18) and regula tion of IL-12 receptor expression, pi and beta2 IL-12R chain mRNA expressio n increased with, time in culture in the absence of exogenous stimulation, with concomitant acquisition of responsiveness to IL-12 for IFN-gamma produ ction. Expression of the IL-12R beta1 chain mRNA was increased further foll owing IL-12 treatment as a consequence of IFN-gamma expression, IL-12 respo nse was regulated differentially by IFN-alpha and IL-18, Neutralization of endogenous type I IFN increased IFN-gamma secretion, whereas exogenous IFN- alpha reduced it. In contrast, IL-18 enhanced IFN-gamma mRNA accumulation a nti. IFN-gamma secretion in IL-12-stimulated, hut not -untreated, cultures. The opposite effects exerted by IFN-alpha and IL-18 mirror their mutual ca pacity of regulating-in a negative or positive manner, respectively-the exp ression of the IL-12R beta1 drain. We suggest that differential regulation of IL-12 response by IFN-alpha and IL-18 can represent previously unrecogni zed regulatory mechanisms for maintaining suitable levels of differentiatio n/activation in macrophages.