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(Journal of Leukocyte Biology. 2000;68:707-714.)
© 2000 by Society for Leukocyte Biology

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

Laura Fantuzzi^*, Patrizia Puddu, Barbara Varano^*, Manuela Del Cornò^*, Filippo Belardelli^* and Sandra Gessani^*

Laboratories of
^* Virology and
Immunology, Istituto Superiore di Sanità, Viale Regina Elena 299, 00161 Rome, Italy

Correspondence: Dr. Sandra Gessani, Laboratory of Virology, Istituto Superiore di Sanità, Viale Regina Elena 299, 00161 Rome, Italy. E-mail: gessani{at}iss.it

We characterized the IL-12 response of mouse macrophages in terms of modulation of IFN- production by cytokines (IFN- and IL-18) and regulation of IL-12 receptor expression. ß1 and ß2 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- production. Expression of the IL-12R ß1 chain mRNA was increased further following IL-12 treatment as a consequence of IFN- expression. IL-12 response was regulated differentially by IFN- and IL-18. Neutralization of endogenous type I IFN increased IFN- secretion, whereas exogenous IFN- reduced it. In contrast, IL-18 enhanced IFN- mRNA accumulation and IFN- secretion in IL-12-stimulated, but not -untreated, cultures. The opposite effects exerted by IFN- and IL-18 mirror their mutual capacity of regulating—in a negative or positive manner, respectively—the expression of the IL-12R ß1 chain. We suggest that differential regulation of IL-12 response by IFN- and IL-18 can represent previously unrecognized regulatory mechanisms for maintaining suitable levels of differentiation/activation in macrophages.

Key Words: monocytes/macrophages • IL-12 • type I IFN • IL-18

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