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Generation of nitric oxide and induction of major histocompatibility complex class II antigen in macrophages from mice lacking the interferon gamma receptor



Generation of nitric oxide and induction of major histocompatibility complex class II antigen in macrophages from mice lacking the interferon gamma receptor



Proceedings of the National Academy of Sciences of the United States of America 90(14): 6626-6630



Availability of mice with a targeted disruption of the interferon gamma (IFN-gamma) receptor gene (IFN-gamma-R-0/0 mice) made it possible to examine parameters of macrophage activation in the absence of a functional IFN-gamma receptor. We asked to what extent other cytokines could replace IFN-gamma in the induction of nitric oxide or major histocompatibility complex class II antigen (Ia) expression in peritoneal macrophages. In thioglycollate-elicited macrophages from wild-type mice, tumor necrosis factor (TNF) alone was virtually ineffective in inducing release of NO-2- (the endproduct of nitric oxide generation), but TNF enhanced NO-2- release in the presence of IFN-gamma. In macrophages from IFN-gamma-R-0/0 mice, which were unresponsive to IFN-gamma, TNF completely failed to stimulate NO-2- release. The stimulatory actions of IFN-alpha/beta on NO-2- release were indistinguishable in wild-type and IFN-gamma-R-0/0 macrophages: IFN-alpha/beta was ineffective on its own, showed marginal stimulation of NO-2- release in combination with TNF, and was moderately effective in the presence of lipopolysaccharide. The level of constitutive Ia antigen expression was not significantly different in peritoneal macrophages from wild-type and IFN-gamma-R-0/0 mice. An increased Ia expression was induced by IL-4 and granulocyte-macrophage colony-stimulating factor in both wild-type and IFN-gamma-R-0/0 macrophages, but the magnitude of this induction was less than with optimal concentrations of IFN-gamma in macrophages from wild-type mice. IFN-alpha/beta showed only a minor stimulatory effect on Ia expression in both wild-type and IFN-gamma-R-0/0 macrophages. Simultaneous treatment of wild-type macrophages with IFN-alpha/beta and IFN-gamma reduced the IFN-gamma-induced Ia expression in wild-type macrophages, but IFN-alpha/beta did not show an inhibitory effect on IL-4- or granulocyte-macrophage-colony-stimulating factor-induced Ia expression in either wild-type or IFN-gamma-R-0/0 macrophages. The important role of IFN-gamma in the regulation of the induced expression of major histocompatibility complex clam H antigen was confirmed by showing that after systemic infection with the BCG strain of Mycobacterium bovis resident peritoneal macrophages from IFN-gamma-R-0/0 mice had a lower level of la expression than macrophages from wild-type mice. The inability of other cytokines to substitute fully for IFN-gamma in macrophage activation helps to explain the earlier observed decreased resistance of IFN-gamma-R-0/0 mice to some infections.

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Accession: 002390010

Download citation: RISBibTeXText

PMID: 8341679

DOI: 10.1073/pnas.90.14.6626


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