Byrd T F
Division of Infectious Diseases, Department of Medicine, West Los Angeles Veterans Affairs Medical Center, UCLA School of Medicine, Los Angeles, California 90073, USA.
J Clin Invest. 1997 May 15;99(10):2518-29. doi: 10.1172/JCI119436.
The human immune response to Mycobacterium tuberculosis is not well characterized. To better understand the cellular immune response to tuberculosis, a human mononuclear phagocyte culture system using a low-infecting inoculum of M. tuberculosis to mimic in vivo conditions was developed. Using this system, monocytes treated with IFNgamma/TNFalpha/ calcitriol (CytD) were permissive for the growth of virulent M. tuberculosis. In the presence of iron, however, these monocytes suppressed the growth of M. tuberculosis. The enhanced permissiveness of CytD-preincubated monocytes was found to be due to TNFalpha, however, the ability of iron to suppress M. tuberculosis growth also required preincubation with TNFalpha. Iron-mediated growth suppression was correlated with selective suppression of TNFalpha release from infected monocytes. In addition, removal of TNFalpha from CytD-treated monocytes 2 d after infection mimicked the suppressive effect of iron, suggesting that iron may also be decreasing monocyte sensitivity to exogenously added TNFalpha. In the absence of iron, permissive, CytD-treated monocytes formed large infected cellular aggregates. With iron treatment, aggregation was suppressed, suggesting that the iron-suppressive effect on M. tuberculosis growth may be related to suppression of monocyte aggregation and diminished cell-to-cell spread of M. tuberculosis. The results of this study indicate that TNFalpha preincubation is required for human monocytes to exert an iron-mediated suppressive effect on M. tuberculosis growth. In the absence of iron, however, the continued presence of TNFalpha has a growth-promoting effect on M. tuberculosis in human monocytes. Iron may be an important early modulator of M. tuberculosis growth via its effects on TNFalpha.
人类对结核分枝杆菌的免疫反应尚未得到充分表征。为了更好地理解对结核病的细胞免疫反应，开发了一种人类单核吞噬细胞培养系统，该系统使用低感染接种量的结核分枝杆菌来模拟体内条件。使用该系统，用IFNγ/TNFα/骨化三醇（CytD）处理的单核细胞允许有毒力的结核分枝杆菌生长。然而，在有铁存在的情况下，这些单核细胞会抑制结核分枝杆菌的生长。发现CytD预孵育的单核细胞的易感性增强是由于TNFα，然而，铁抑制结核分枝杆菌生长的能力也需要与TNFα预孵育。铁介导的生长抑制与感染的单核细胞中TNFα释放的选择性抑制相关。此外，感染后2天从CytD处理的单核细胞中去除TNFα模拟了铁的抑制作用，表明铁也可能降低单核细胞对外源添加的TNFα的敏感性。在没有铁的情况下，允许生长的、CytD处理的单核细胞形成大的感染细胞聚集体。经过铁处理后，聚集受到抑制，这表明铁对结核分枝杆菌生长的抑制作用可能与单核细胞聚集的抑制以及结核分枝杆菌细胞间传播的减少有关。这项研究的结果表明，人类单核细胞要对结核分枝杆菌生长发挥铁介导的抑制作用需要TNFα预孵育。然而，在没有铁的情况下，TNFα的持续存在对人类单核细胞中的结核分枝杆菌有促生长作用。铁可能通过其对TNFα的作用成为结核分枝杆菌生长的重要早期调节剂。
