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

We characterized the IL-12 response of mouse macrophages in terms of modulation of IFN-g production by cytokines (IFN-a and IL-18) and regulation of IL-12 receptor expression. b1 and b2 IL-12R chain mRNA expression increased with time in culture in the absence of exogenous stimulation, with concomitant acquisition of re- sponsiveness to IL-12 for IFN-g production. Ex- pression of the IL-12R b1 chain mRNA was in- creased further following IL-12 treatment as a con- sequence of IFN-g expression. IL-12 response was regulated differentially by IFN-a and IL-18. Neu- tralization of endogenous type I IFN increased IFN-g secretion, whereas exogenous IFN-a re- duced it. In contrast, IL-18 enhanced IFN-g mRNA accumulation and IFN-g secretion in IL-12- stimulated, but not -untreated, cultures. The oppo- site effects exerted by IFN-a and IL-18 mirror their mutual capacity of regulating—in a negative or positive manner, respectively—the expression of the IL-12R b1 chain. We suggest that differen- tial regulation of IL-12 response by IFN-a and IL-18 can represent previously unrecognized reg- ulatory mechanisms for maintaining suitable levels of differentiation/activation in macrophages. J. Leukoc. Biol. 68: 707-714; 2000.