Wang J, Wakeham J, Harkness R, Xing Z
Department of Pathology and Molecular Medicine, and Division of Infectious Diseases, Centre for Gene Therapeutics, McMaster University, Hamilton, Ontario, Canada L8N 3Z5.
J Clin Invest. 1999 Apr;103(7):1023-9. doi: 10.1172/JCI6224.
T-helper 1 (Th1) cells are believed to be the major producer of the type 1 cytokine interferon-gamma (IFN-gamma) in cell-mediated immunity against intracellular infection. We have investigated the ability of macrophages to release type 1 cytokines and their regulatory mechanisms using both in vivo and in vitro models of pulmonary mycobacterial infection. During pulmonary infection by live Mycobacterium bovis bacilli Calmette-Guérin (BCG) in wild-type mice, lung macrophages released interleukin-12 (IL-12), IFN-gamma, and tumor necrosis factor-alpha (TNF-alpha), and expressed surface activation markers. However, macrophages in infected IL-12(-/-) mice released TNF-alpha but not IFN-gamma and lacked surface activation makers. In freshly isolated lung macrophages from naive IL-2(-/-) mice, mycobacteria alone released TNF-alpha but not IFN-gamma, whereas exogenously added IL-12 alone released a minimum of IFN-gamma. However, these macrophages released large quantities of IFN-gamma upon stimulation with both mycobacteria and IL-12. In contrast, mycobacteria and exogenous IFN-gamma released only a minimum of endogenous IFN-gamma. Endogenous IL-18 (IFN-gamma-inducing factor) played little role in IFN-gamma responses by macrophages stimulated by mycobacteria and IL-12. Our data reveal that macrophages are a significant source of type 1 cytokines during mycobacterial infection and that both IL-12 and intracellular pathogens are required for the release of IFN-gamma but not TNF-alpha. These findings suggest that macrophages regulate cell-mediated immunity by releasing not only IL-12 and TNF-alpha but also IFN-gamma and that full activation of IFN-gamma response in macrophages is tightly regulated.
辅助性T细胞1（Th1）被认为是细胞介导的针对细胞内感染的免疫中1型细胞因子γ干扰素（IFN-γ）的主要产生者。我们使用肺部分枝杆菌感染的体内和体外模型，研究了巨噬细胞释放1型细胞因子的能力及其调节机制。在野生型小鼠被活的卡介苗（BCG）肺部感染期间，肺巨噬细胞释放白细胞介素-12（IL-12）、IFN-γ和肿瘤坏死因子-α（TNF-α），并表达表面活化标志物。然而，感染的IL-12基因敲除小鼠中的巨噬细胞释放TNF-α但不释放IFN-γ，并且缺乏表面活化标志物。在来自未感染的IL-2基因敲除小鼠的新鲜分离的肺巨噬细胞中，单独的分枝杆菌释放TNF-α但不释放IFN-γ，而单独外源性添加的IL-12释放的IFN-γ最少。然而，这些巨噬细胞在受到分枝杆菌和IL-12刺激后释放大量IFN-γ。相比之下，分枝杆菌和外源性IFN-γ仅释放少量内源性IFN-γ。内源性IL-18（IFN-γ诱导因子）在分枝杆菌和IL-12刺激的巨噬细胞的IFN-γ反应中作用很小。我们的数据表明，巨噬细胞是分枝杆菌感染期间1型细胞因子的重要来源，并且IL-12和细胞内病原体都是释放IFN-γ而非TNF-α所必需的。这些发现表明，巨噬细胞不仅通过释放IL-12和TNF-α，还通过释放IFN-γ来调节细胞介导的免疫，并且巨噬细胞中IFN-γ反应的完全激活受到严格调控。
