Interferon-gamma (IFN-gamma) 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-gammaR(-/-) 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-gamma 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-gamma 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 TNF- and 
IFN-gamma-coregulated gene we characterized the expression and the subcellular 
localization of immunoresponsive gene 1 (IRG1) in murine macrophages. IRG1 is 
highly upregulated in murine ANA-1 macrophages by several proinflammatory 
cytokines and Toll-like receptor (TLR) agonists, as well as in spleen and lung 
of Listeria monocytogenes or Toxoplasma gondii infected mice, respectively. 
Furthermore, this study identifies 35 genes that constitute the 
IFN-gamma/TNF-triggered effector program in innate immunity.