GENERATION OF NITRIC-OXIDE AND INDUCTION OF MAJOR HISTOCOMPATIBILITY COMPLEX CLASS-II ANTIGEN IN MACROPHAGES FROM MICE LACKING THE INTERFERON-GAMMA RECEPTOR

Availability of mice with a targeted disruption of the interferon gamm a (IFN-gamma) receptor gene (IFN-gammaR0/0 mice) made it possible to e xamine parameters of macrophage activation in the absence of a functio nal IFN-gamma receptor. We asked to what extent other cytokines could replace IFN-gamma in the induction of nitric oxide or major histocompa tibility complex class II antigen (Ia) expression in peritoneal macrop hages. In thioglycollate-elicited macrophages from wild-type mice, tum or necrosis factor (TNF) alone was virtually ineffective in inducing r elease of NO2- (the endproduct of nitric oxide generation), but TNF en hanced NO2- release in the presence of IFN-gamma. In macrophages from IFN-gammaR0/0 mice, which were unresponsive to IFN-gamma, TNF complete ly failed to stimulate NO2- release. The stimulatory actions of IFN-al pha/beta on NO2- release were indistinguishable in wild-type and IFN-g ammaR0/0 macrophages: IFN-alpha/beta was ineffective on its own, showe d marginal stimulation of NO2- release in combination with TNF, and wa s moderately effective in the presence of lipopolysaccharide. The leve l of constitutive Is antigen expression was not significantly differen t in peritoneal macrophages from wild-type and IFN-gammR0/0 mice. An i ncreased Ia expression was induced by IL-4 and granulocyte-macrophage colony-stimulating factor in both wild-type and IFN-gammaR0/0 macropha ges, but the magnitude of this induction was less than with optimal co ncentrations of IFN-gamma in macrophages from wild-type mice. IFN-alph a/beta showed only a minor stimulatory effect on Ia expression in both wild-type and IFN-gammaR0/0 macrophages. Simultaneous treatment of wi ld-type macrophages with IFN-alpha/beta and IFN-gama reduced the IFN-g amma-induced Ia expression in wild-type macrophages, but IFN-alpha/bet a did not show an inhibitory effect on IL-4- or granulocyte-macrophage -colony-stimulating factor-induced Ia expression in either wild-type o r IFN-gamma-R0/0 macrophages. The important role of IFN-gamma in the r egulation of the induced expression of major histocompatibility comple x class II antigen was confirmed by showing that after system infectio n with the BCG strain of Mycobacterium bovis resident peritoneal macro phages from IFN-gammaR0/0 mice had a lower level of Ia expression than macrophages from wild-type mice. The inability of other cytokines to substitute fully for IFN-gamma in macrophage activation helps to expla in the earlier observed decreased resistance of IFN-gammaR0/0 mice to some infections.