The Proinflammatory Cytokine-Induced IRG1 Protein Associates with Mitochondria

Interferon-γ (IFN-γ) and tumor necrosis factor (TNF) are essential cytokines for successful clearance of microbial infections. Activation of macrophages by synergistic effects of these cytokines leads to induction of antimicrobial effector systems like reactive oxygen and reactive nitrogen intermediates. Strikingly, IFN-γR−/− and TNFRp55−/− mice are considerably more susceptible to infections than inducible nitric oxide synthase−/− and p47phox−/− mice. Thus we applied transcriptome-profiling studies to identify genes synergistically upregulated by IFN-γ and TNF in macrophages which are potentially involved in the defense against intracellular pathogens. From a total of 234 regulated genes we found 35 genes that were upregulated by combined effects of IFN-γ and TNF and were at least 2-fold induced. The majority of these genes are involved in signal transduction and transcriptional regulation. However, we found several genes were poorly characterized with regard to immunological functions. As a prototypic T...