Cooper AM, Magram J, Ferrante J, and Orme IM. Interleukin 12 (IL-12) is crucial to the development of protective immunity in mice intravenously infected with Mycobacterium tuberculosis. J Exp Med 186:39-45

Department of Microbiology, Colorado State University, Fort Collins, Colorado 80523, USA.
Journal of Experimental Medicine (Impact Factor: 12.52). 08/1997; 186(1):39-45. DOI: 10.1084/jem.186.1.39
Source: PubMed

ABSTRACT Immunity to Mycobacterium tuberculosis infection is associated with the emergence of protective CD4 T cells that secrete cytokines, resulting in activation of macrophages and the recruitment of monocytes to initiate granuloma formation. The cytokine-mediating macrophage activation is interferon-gamma (IFN-gamma), which is largely dependent on interleukin-12 (IL-12) for its induction. To address the role of IL-12 in immunity to tuberculosis, IL-12 p40(-/-) mice were infected with M. tuberculosis and their capacity to control bacterial growth and other characteristics of their immune response were determined. The IL-12 p40(-/-) mice were unable to control bacterial growth and this appeared to be linked to the absence of both innate and acquired sources of IFN-gamma. T cell activation as measured by delayed type hypersensitivity and lymphocyte accumulation at the site of infection were both markedly reduced in the IL-12 p40(-/-) mice. Therefore, IL-12 is essential to the generation of a protective immune response to M. tuberculosis, with its main functions being the induction of the expression of IFN-gamma and the activation of antigen-specific lymphocytes capable of creating a protective granuloma.

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Available from: Andrea M Cooper, Sep 26, 2015
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    • "IL-12, known to stimulate the growth of NK cells and T-cells, enhances the production of cytokines, and connects innate and adaptive immune responses against mycobacterial infections (Trinchieri, 1995). IL-12 has been reported to exert its protective effects in M. tuberculosis-infected mice, mainly through IFN-γ (Cooper et al., 1997). Therapeutic effect of transgenic tomato over-expressing IL-12 has been reported in a murine model of progressive pulmonary TB (Elías-López et al., 2008). "
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    ABSTRACT: Human tuberculosis (TB), a chronic inflammatory disease is caused by Mycobacterium tuberculosis, a facultative intramacrophage pathogen. The highly complex interactions between mycobacteria and macrophages (MΦs), characterized in part by the induction and elaboration of several cytokines including IL-1, IL-6, IL-10, IL-12 p40 and IL-12 p70 are not yet fully understood. The cytokines are known to have important bearing on the pathogenesis and host defense during TB. We thus studied different patterns of cytokines elaborated by mouse peritoneal macrophages (PMs) following their interaction with live and heat-killed, virulent and avirulent, and pathogenic and non-pathogenic mycobacteria, in vitro. Pathogenic M. tuberculosis H37Rv (virulent) and M. tuberculosis H37Ra (avirulent), and non-pathogenic M. smegmatis were grown in complete Middle Brook 7H9 broth. For some experiments, mycobacteria were heat-killed (80°C; 20 min). The supernatants of cultured PMs, having ingested mycobacteria for 6 h, 24 h, 4 days and 7 days, were harvested for the quantification of IL-1, IL-6, IL-10, IL-12 p40 and IL-12 p70 by using a multiplex suspension cytokine array system. The PMs infected with heat-killed mycobacteria, as compared to their respective live counterparts, invariably elaborated significantly (p < 0.001) increased (approximately 2-3-fold) amounts of IL-6, at all the time-points studied, in vitro. Further, PMs infected with M. tuberculosis H37Ra, as compared to M. tuberculosis H37Rv, elaborated 4-5-fold more (p < 0.001) IL-6. Non-pathogenic M. smegmatis, as compared to pathogenic M. tuberculosis H37Ra and M. tuberculosis H37Rv, following infection, induced the PMs to elaborate highest (p < 0.001) amounts of IL-6 at all the time-points studied. Curiously, none of these mycobacteria-infected PMs elaborated IL-1, IL-10, IL-12 p40 and IL-12 p70, significantly. IL-6 appears to be the only major cytokine elaborated by mycobacteria-infected PMs, in vitro, and thus may function as a potent biomarker of mycobacterial infection, either stand-alone or along with other cytokines.
    SpringerPlus 12/2013; 2(1):686. DOI:10.1186/2193-1801-2-686
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    • "These patients lacking effective IL-12 and IL-12 receptor show a reduced capacity of IFNγ production. In fact, IL-12 exerts its protective roles against mycobacterial infection mainly through induction of IFNγ, thus serving as a link between innate and adaptive host immune responses [132]. "
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    ABSTRACT: Tuberculosis, an infectious disease caused by Mycobacterium tuberculosis (Mtb), remains a major cause of human death worldwide. Innate immunity provides host defense against Mtb. Phagocytosis, characterized by recognition of Mtb by macrophages and dendritic cells (DCs), is the first step of the innate immune defense mechanism. The recognition of Mtb is mediated by pattern recognition receptors (PRRs), expressed on innate immune cells, including toll-like receptors (TLRs), complement receptors, nucleotide oligomerization domain like receptors, dendritic cell-specific intercellular adhesion molecule grabbing nonintegrin (DC-SIGN), mannose receptors, CD14 receptors, scavenger receptors, and FCγ receptors. Interaction of mycobacterial ligands with PRRs leads macrophages and DCs to secrete selected cytokines, which in turn induce interferon-γ- (IFNγ-) dominated immunity. IFNγ and other cytokines like tumor necrosis factor-α (TNFα) regulate mycobacterial growth, granuloma formation, and initiation of the adaptive immune response to Mtb and finally provide protection to the host. However, Mtb can evade destruction by antimicrobial defense mechanisms of the innate immune system as some components of the system may promote survival of the bacteria in these cells and facilitate pathogenesis. Thus, although innate immunity components generally play a protective role against Mtb, they may also facilitate Mtb survival. The involvement of selected PRRs and cytokines on these seemingly contradictory roles is discussed.
    11/2013; 2013(5):179174. DOI:10.1155/2013/179174
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    • "Since protective immunity against M. tuberculosis is dependent on IL-12p40 production [20], we wanted to determine the main source of IL-12p40 in the M. tuberculosis-infected lungs three to six weeks p.i. (Figure 8). The single cell suspensions prepared from total lung tissue were kept in media alone, or stimulated with LPS or M. tuberculosis cell wall extract. "
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    ABSTRACT: Non-hematopoietic cells, including lung epithelial cells, influence host immune responses. By co-culturing primary alveolar epithelial cells and monocytes from naïve donor mice, we show that alveolar epithelial cells support monocyte survival and differentiation in vitro, suggesting a role for non-hematopoietic cells in monocyte differentiation during the steady state in vivo. CD103(+) dendritic cells (αE-DC) are present at mucosal surfaces. Using a murine primary monocyte adoptive transfer model, we demonstrate that αE-DC in the lungs and pulmonary lymph nodes are monocyte-derived during pulmonary tuberculosis. The tissue localization may influence the functional potential of αE-DC that accumulate in Mycobacterium tuberculosis-infected lungs. Here, we confirm the localization of αE-DC in uninfected mice beneath the bronchial epithelial cell layer and near the vascular wall, and show that αE-DC have a similar distribution in the lungs during pulmonary tuberculosis and are detected in the bronchoalveolar lavage fluid from infected mice. Lung DC can be targeted by M. tuberculosis in vivo and play a role in bacterial dissemination to the draining lymph node. In contrast to other DC subsets, only a fraction of lung αE-DC are infected with the bacterium. We also show that virulent M. tuberculosis does not significantly alter cell surface expression levels of MHC class II on infected cells in vivo and that αE-DC contain the highest frequency of IL-12p40(+) cells among the myeloid cell subsets in infected lungs. Our results support a model in which inflammatory monocytes are recruited into the M. tuberculosis-infected lung tissue and, depending on which non-hematopoietic cells they interact with, differentiate along different paths to give rise to multiple monocyte-derived cells, including DC with a distinctive αE-DC phenotype.
    PLoS ONE 07/2013; 8(7):e69287. DOI:10.1371/journal.pone.0069287 · 3.23 Impact Factor
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