title: 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.
authors: Department of Pathology, Microbiology, and Immunology, University of South Carolina School of Medicine, Columbia, SC 29209, USA. cory.robinson@uscmed.sc.edu
authors: Cory M
authors: CM
authors: Robinson
authors: Joo-Yong
authors: JY
authors: Jung
authors: Gerard J
authors: GJ
authors: Nau
mesh_terms: D001119:Arginase / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D002478:Cells, Cultured; D015870:Gene Expression / Q000187:drug effects; D054884:Host-Pathogen Interactions / Q000276:immunology; D006801:Humans; D015151:Immunoblotting; D007371:Interferon-gamma / Q000276:immunology* / Q000378:metabolism / Q000494:pharmacology; D018664:Interleukin-12 / Q000494:pharmacology; D020382:Interleukin-18 / Q000276:immunology* / Q000378:metabolism; D008264:Macrophages / Q000276:immunology* / Q000378:metabolism / Q000382:microbiology; D018613:Microscopy, Confocal; D009169:Mycobacterium tuberculosis / Q000276:immunology* / Q000502:physiology; D052247:Nitric Oxide Synthase Type II / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D017471:Receptors, Interferon / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D053724:Receptors, Interleukin-18 / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics / Q000276:immunology; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology* / Q000378:metabolism / Q000494:pharmacology; D000096743:Interferon gamma Receptor
chemical_list: D001119:Arginase; D007371:Interferon-gamma; D018664:Interleukin-12; D020382:Interleukin-18; D052247:Nitric Oxide Synthase Type II; D017471:Receptors, Interferon; D053724:Receptors, Interleukin-18; D014409:Tumor Necrosis Factor-alpha; D000096743:Interferon gamma Receptor; C496319:NOS2 protein, human; C574619:ARG1 protein, human