Jun Wang, Julia Wakeham, Robin Harkness, Zhou Xing
J Clin Invest.
1999;
103(7):1023–1029
doi:10.1172/JCI6224
This article Copyright © 1999, The American Society for Clinical Investigation
Abstract
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T
-helper 1 (Th1) cells are believed to be the major producer of the type 1 cytokine interferon-γ (IFN-γ) 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-γ, and tumor necrosis factor-α (TNF-α), and expressed surface activation markers. However, macrophages in infected IL-12–/– mice released TNF-α but not IFN-γ and lacked surface activation makers. In freshly isolated lung macrophages from naive IL-2–/– mice, mycobacteria alone released TNF-α but not IFN-γ, whereas exogenously added IL-12 alone released a minimum of IFN-γ. However, these macrophages released large quantities of IFN-γ upon stimulation with both mycobacteria and IL-12. In contrast, mycobacteria and exogenous IFN-γ released only a minimum of endogenous IFN-γ. Endogenous IL-18 (IFN-γ–inducing factor) played little role in IFN-γ 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-γ but not TNF-α. These findings suggest that macrophages regulate cell-mediated immunity by releasing not only IL-12 and TNF-α but also IFN-γ and that full activation of IFN-γ response in macrophages is tightly regulated.
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