Interferon-γ, tumor necrosis factor, and interleukin-18 cooperate to control growth of Mycobacterium tuberculosis in human macrophages

Abstract

Mycobacterium tuberculosis (MTB) remains a leading infectious threat to human health. Macrophages are the cells targeted for infection by the bacterium as well as key effector cells for clearance of the pathogen. Interleukin (IL)-27 opposes macrophage-mediated control of MTB because supplying IL-12 and blocking the activity of IL-27 limits bacterial growth in primary human macrophages. The purpose of this study was to determine the immunological regulators of this macrophage mechanism to restrict MTB growth. Interferon (IFN)-γ, TNF-α, and IL-18 were all demonstrated to be important to the environment that limits bacterial growth when IL-12 is supplied and IL-27 is neutralized. We find IL-18 works in conjunction with IL-12 to achieve optimal IFN-γ production in this system. We also demonstrate novel interactions between these cytokines to influence the expression or responsiveness to one another. Quantitative assays show that IFN-γ enhances expression of the IL-18 receptor signaling chain, as well as TNF expression and secretion. In turn, TNF-α augments expression of the receptor for IFN-γ the amount at the cell surface, and the extent of IFN-γ-induced signaling. We further define how the cytokine environment supports an enhanced state of classical macrophage activation. Collectively, these results describe novel immunological mechanisms that provide additional insights into the effects of IL-12 and IL-27 on macrophage regulation during MTB infection.

IL-27 inhibits IFN-γ induced autophagy by concomitant induction of JAK/PI3 K/Akt/mTOR cascade and up-regulation of Mcl-1 in Mycobacterium tuberculosis H37Rv infected macrophages

“…Increased lymphocytic character of TB granuloma and decrease in bacterial number were observed in IL-27R knockout mice (Pearl et al, 2004). Robinson et al (2012) reported that neutralization of IL-27 enhances mycobacterial clearance in infected human macrophages.…”

Ficolin-2 Defends against Virulent Mycobacteria Tuberculosis Infection In Vivo, and Its Insufficiency Is Associated with Infection in Humans

“…Our data showed that ficolin-2 stimulated macrophages to produce high levels of IFN-γ, TNF-α, and NO, indicating that ficolin-2 might activate M1 macrophages (characteristic of Th1-type immunity), therefore stimulating cell-mediated responses that play major roles in the defense against intracellular pathogens [38]. Robinson et al [39] showed that IFN-γ, TNF-α, and interleukin (IL)-18 cooperated to control the growth of Mtb in human macrophages. Several recent reports demonstrated that IL-17A increased protection against Mtb infection [40].…”

The Intracellular Environment of Human Macrophages That Produce Nitric Oxide Promotes Growth of Mycobacteria

“…We previously demonstrated constitutive arginase-1 protein expression in unstimulated human macrophages (37). A competition for pools of available substrate could curtail NO production.…”