Macrophages are a significant source of type 1 cytokines during mycobacterial infection


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Abstract

T-helper 1 (Th1) cells are believed to be the major producer of the type 1 cytokine interferon-[small gamma, Greek] (IFN-[small gamma, Greek]) 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-Guerin (BCG) in wild-type mice, lung macrophages released interleukin-12 (IL-12), IFN-[small gamma, Greek], and tumor necrosis factor-[small alpha, Greek] (TNF-[small alpha, Greek]), and expressed surface activation markers. However, macrophages in infected IL-12-/- mice released TNF-[small alpha, Greek] but not IFN-[small gamma, Greek] and lacked surface activation makers. In freshly isolated lung macrophages from naive IL-2-/- mice, mycobacteria alone released TNF-[small alpha, Greek] but not IFN-[small gamma, Greek], whereas exogenously added IL-12 alone released a minimum of IFN-[small gamma, Greek]. However, these macrophages released large quantities of IFN-[small gamma, Greek] upon stimulation with both mycobacteria and IL-12. In contrast, mycobacteria and exogenous IFN-[small gamma, Greek] released only a minimum of endogenous IFN-[small gamma, Greek]. Endogenous IL-18 (IFN-[small gamma, Greek]-inducing factor) played little role in IFN-[small gamma, Greek] 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-[small gamma, Greek] but not TNF-[small alpha, Greek]. These findings suggest that macrophages regulate cell-mediated immunity by releasing not only IL-12 and TNF-[small alpha, Greek] but also IFN-[small gamma, Greek] and that full activation of IFN-[small gamma, Greek] response in macrophages is tightly regulated.J.Clin. Invest. 103:1023-1029 (1999).

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