Regulation of macrophage growth and function by IFN-gamma
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Abstract
Macrophages play a major role in the immune response against invading pathogens and are uniquely regulated by interferon gamma {dollar}{lcub}{dollar}IFN {dollar}\gamma{rcub}{dollar}. A somatic cell genetic approach was used to analyze the pleiotropic effects of IFN {dollar}\gamma{dollar} on macrophages, e.g. antiviral, anti-proliferative effects, and activation of the respiratory burst, and to determine whether the effects are mediated by the same signals and/or the same effector mechanisms. Somatic variants in a murine macrophage-like cell line were selected that had defects in specific IFN {dollar}\gamma{dollar} regulated functions. The anti-proliferative and antiviral activities of IFN {dollar}\gamma{dollar} could be formally dissociated. Biochemical analysis of variants revealed that both IFN {dollar}\alpha{dollar} and IFN {dollar}\gamma{dollar} utilize the dsRNA dependent eukaryotic initiation factor-2 {dollar}{lcub}{dollar}eIF-2{dollar}{rcub}{dollar} kinase system to effect the antiviral state against infection with vesicular stomatitis virus and encephalomyocarditis virus, although they can each regulate the eIF-2 kinase system via different pathways.;Unexpectedly, a genetic association existed between the respiratory burst and the anti-proliferative effects of IFN {dollar}\gamma{dollar}. Variants selected for their inability to produce O{dollar}\sb{lcub}2{rcub}\sp{lcub}-{rcub}{dollar} in response to phorbol esters were resistant to the anti-proliferative effects of IFN {dollar}\gamma{dollar}. It thus appears, a protein kinase C mediated pathway is implicated in the anti-proliferative effects of IFN {dollar}\gamma{dollar} in the mouse macrophages. Finally, Northern analysis of a variant defective in the oxidative burst revealed the absence of the transcript for the chronic granulomatous disease {dollar}{lcub}{dollar}CGD{dollar}{rcub}{dollar} gene. This variant should be useful to study the structure function relationships and/or the gene regulation of the CGD gene locus.