Induction of gamma interferon production in human alveolar macrophages by Mycobacterium tuberculosis

Fenton, Matthew J.; Vermeulen, Mary W.; Kim, Sue; Burdick, Marie D.; Strieter, Robert M.; Kornfeld, Hardy

doi:10.1128/iai.65.12.5149-5156.1997

Cited by 195 publications

(68 citation statements)

References 44 publications

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“…21 Earlier, IFN-g was considered to be of lymphoid origin only, but lately many reports have come to describe a myeloid origin of IFN-g as well. 4,22 In the present study, we demonstrate that alveolar epithelial cells have full armour to respond to M. tuberculosis infection and release IFN-g. Secretion of IFN-g by A549 cells in the culture supernatant following infection with M. tuberculosis demonstrated a statistically significant higher level of IFN-g at 48 h as compared with the concentration in uninfected cell supernatant. This level almost tripled at 72 h post-infection.…”

Section: Discussionsupporting

confidence: 56%

Pulmonary epithelial cells are a source of interferon‐γ in response to Mycobacterium tuberculosis infection

Sharma

Roy

et al. 2007

Immunol Cell Biol

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Recent report from our laboratory showed that A549 cells representing alveolar epithelial cells produce chemokine interleukin-8 and nitric oxide (NO) when challenged with Mycobacterium tuberculosis. Interferon-gamma (IFN-gamma) played a critical role in priming these cells to generate NO in vitro. In the present study, we report that M. tuberculosis-infected A549 cells are capable of elaborating IFN-gamma as shown by enzyme-linked immunosorbent assay and intracellular staining for IFN-gamma. Secretion profile indicated that M. tuberculosis-infected A549 released significantly high concentration of IFN-gamma at 48 and 72 h post-infection. Low level of IFN-gamma release was also seen to be induced by gamma-irradiated M. tuberculosis and subcellular components of M. tuberculosis. Cell surface receptor analysis showed that the M. tuberculosis-infected A549 cells expressed enhanced levels of IFN-gamma receptors. This observation suggests that the endogenously produced IFN-gamma in response to M. tuberculosis infection plays a role in intracellular regulation of innate immunity against intracellular pathogen such as M. tuberculosis. This observation is further strengthened by the fact that infected A549 cells expressed signal transducer and activator of transcription 1 (STAT1), an important mediator for IFN-gamma signaling pathway, leading to expression of inducible NO synthase and subsequent release of NO in sufficient concentration to be mycobactericidal. Our results show that production of IFN-gamma and enhanced expression of IFN-gamma receptors by infected A549 cells is a local phenomenon occurring as de novo intracellular activity, in response to M. tuberculosis infection. To the best of our knowledge, this is the first report to show that A549 cells interact actively with M. tuberculosis to produce IFN-gamma that might play an important role in innate immunity against tuberculosis.

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Section: Discussionsupporting

confidence: 56%

Pulmonary epithelial cells are a source of interferon‐γ in response to Mycobacterium tuberculosis infection

Sharma

Roy

et al. 2007

Immunol Cell Biol

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“…It has been shown that macrophages are an important source of IFN-c, under physiological or pathological conditions, 34 particularly in response to Mtb infection. 35,36 Since it has been demonstrated that Mtb may counteract the host's defence mechanisms, inhibiting the macrophage response to the exogenous IFN-c, 37 it could be interesting to investigate the effect of the endogenous IFN-c on the same macrophage's antimicrobial activities. Interestingly, among the up-regulated genes, we reported a significant increase of MMP-7 transcripts.…”

Section: Discussionmentioning

confidence: 99%

Gene expression profiling of human macrophages at late time of infection with Mycobacterium tuberculosis

et al. 2006

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Summary Macrophages play an essential role in the immune response to Mycobacterium tuberculosis (Mtb). Previous transcriptome surveys, by means of micro‐ and macroarrays, investigated the cellular gene expression profile during the early phases of infection (within 48 hr). However, Mtb remains within the host macrophages for a longer period, continuing to influence the macrophage gene expression and, consequently, the environment in which it persists. Therefore, we studied the transcription patterns of human macrophages for up to 7 days after infection with Mtb. We used a macroarray approach to study 858 human genes involved in immunoregulation, and we confirmed by quantitative real‐time reverse transcriptase polymerase chain reaction (q‐rt RT‐PCR) and by enzyme‐linked immunosorbent assay the most relevant modulations. We constantly observed the up‐regulation in infected macrophages versus uninfected, of the following genes: interleukin‐1β and interleukin‐8, macrophage inflammatory protein‐1α, growth‐related oncogene‐β, epithelial cell‐derived neutrophil‐activating peptide‐78, macrophage‐derived chemokine, and matrix metalloproteinase‐7; whereas macrophage colony‐stimulating factor‐receptor and CD4 were down‐regulated in infected macrophages. Mtb is able to withstand this intense cytokine microenvironment and to survive inside the human macrophage. Therefore we simultaneously investigated by q‐rt RT‐PCR the modulation of five mycobacterial genes: the alternative sigma factors sigA, sigE and sigG, the α‐crystallin (acr) and the superoxide dismutase C (sodC) involved in survival mechanisms. The identified host and mycobacterial genes that were expressed until 7 days after infection, could have a role in the interplay between the host immune defences and the bacterial escape mechanisms.

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“…Activated macrophages release effector molecules, which help them control the growth of intracellular mycobacteria (18)(19)(20)(21)(22)(23). In view of the possibility that verapamil activates macrophages, we assessed the activation levels of BCG-infected macrophages cultured in the presence or absence of 100 M verapamil or norverapamil by measuring the levels of nitric oxide and several cytokines present in the culture supernatants.…”

Section: Verapamil and Norverapamil Inhibit Intracellular Mycobacterimentioning

confidence: 99%

New Verapamil Analogs Inhibit Intracellular Mycobacteria without Affecting the Functions of Mycobacterium-Specific T Cells

Abate

Ruminiski

Kumar

et al. 2016

Antimicrob Agents Chemother

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eThere is a growing interest in repurposing mycobacterial efflux pump inhibitors, such as verapamil, for tuberculosis (TB) treatment. To aid in the design of better analogs, we studied the effects of verapamil on macrophages and Mycobacterium tuberculosis-specific T cells. Macrophage activation was evaluated by measuring levels of nitric oxide, tumor necrosis factor alpha (TNF-␣), interleukin-1 beta (IL-1␤), and gamma interferon (IFN-␥). Since verapamil is a known autophagy inducer, the roles of autophagy induction in the antimycobacterial activities of verapamil and norverapamil were studied using bone marrow-derived macrophages from ATG5 flox/flox (control) and ATG5 flox/flox Lyz-Cre mice. Our results showed that despite the well-recognized effects of verapamil on calcium channels and autophagy, its action on intracellular M. tuberculosis does not involve macrophage activation or autophagy induction. Next, the effects of verapamil and norverapamil on M. tuberculosis-specific T cells were assessed using flow cytometry following the stimulation of peripheral blood mononuclear cells from TB-skin-test-positive donors with M. tuberculosis whole-cell lysate for 7 days in the presence or absence of drugs. We found that verapamil and norverapamil inhibit the expansion of M. tuberculosis-specific T cells. Additionally, three new verapamil analogs were found to inhibit intracellular Mycobacterium bovis BCG, and one of the three analogs (KSV21) inhibited intracellular M. tuberculosis replication at concentrations that did not inhibit M. tuberculosis-specific T cell expansion. KSV21 also inhibited mycobacterial efflux pumps to the same degree as verapamil. More interestingly, the new analog enhances the inhibitory activities of isoniazid and rifampin on intracellular M. tuberculosis. In conclusion, KSV21 is a promising verapamil analog on which to base structureactivity relationship studies aimed at identifying more effective analogs.

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Induction of gamma interferon production in human alveolar macrophages by Mycobacterium tuberculosis

Cited by 195 publications

References 44 publications

Pulmonary epithelial cells are a source of interferon‐γ in response to Mycobacterium tuberculosis infection

Pulmonary epithelial cells are a source of interferon‐γ in response to Mycobacterium tuberculosis infection

Gene expression profiling of human macrophages at late time of infection with Mycobacterium tuberculosis

New Verapamil Analogs Inhibit Intracellular Mycobacteria without Affecting the Functions of Mycobacterium-Specific T Cells

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