Degrandi Daniel, Hoffmann Reinhard, Beuter-Gunia Cornelia, Pfeffer Klaus
Institute of Medical Microbiology and Hospital Hygiene, Heinrich-Heine-University of Duesseldorf, Germany.
J Interferon Cytokine Res. 2009 Jan;29(1):55-67. doi: 10.1089/jir.2008.0013.
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.
干扰素-γ（IFN-γ）和肿瘤坏死因子（TNF）是成功清除微生物感染所必需的细胞因子。这些细胞因子的协同作用激活巨噬细胞，导致诱导抗菌效应系统，如活性氧和活性氮中间体。引人注目的是，IFN-γR（-/-）和TNFRp55（-/-）小鼠比诱导型一氧化氮合酶（-/-）和p47phox（-/-）小鼠对感染更敏感。因此，我们应用转录组分析研究来鉴定巨噬细胞中被IFN-γ和TNF协同上调的基因，这些基因可能参与抵抗细胞内病原体的防御。在总共234个受调控的基因中，我们发现35个基因被IFN-γ和TNF的联合作用上调，且至少被诱导2倍。这些基因中的大多数参与信号转导和转录调控。然而，我们发现有几个基因在免疫功能方面的特征尚不明确。作为TNF和IFN-γ共同调控基因的典型例子，我们对免疫反应基因1（IRG1）在小鼠巨噬细胞中的表达和亚细胞定位进行了表征。IRG1在小鼠ANA-1巨噬细胞中被几种促炎细胞因子和Toll样受体（TLR）激动剂高度上调，在单核细胞增生李斯特菌或刚地弓形虫感染小鼠的脾脏和肺中也分别被上调。此外，本研究鉴定了35个构成先天免疫中IFN-γ/TNF触发效应程序的基因。
