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

Abstract

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.

Protective Role for Protease-Activated Receptor-2 against Influenza Virus Pathogenesis via an IFN-γ-Dependent Pathway

“…Thus, a balance between inhibitory and activating signals could determine the release of IFN-␥ after IAV infection, and full activation of PAR 2 would overcome IAV-induced-inhibition of IFN-␥ release. This is also in agreement with the potential of A549 cells to produce IFN-␥ after some but not all pathogen infections (32,49).…”

The Role of Non-Phagocytic Cells in Mycobacterial Infections

“…These authors established that one of the mechanisms involved in the response induced by IFN-is expression of indoleamine-2,3-dioxygenase (IDO) and regulation of the expression of IL-17 (Desvignes & Ernst, 2009). The capacity of epithelial cells to improve their response after IFN-exposure is supported by the observation that cells infected by M. tuberculosis express elevated levels of the receptor specific for this cytokine (Sharma et al, 2007 …”

“…Also the ability of mycobacterium to enter into non-phagocytic cells is another mechanism of immunological evasion, since mycobacteria "hided" in these cells could skip hostile environment of the macrophages and create an ideal niche for its replication and establishment. Nevertheless, recent evidences suggest that non-phagocytic cells have an important role in the immune response against mycobacteria and these cells have the potentially to exert potent antimycobacterial mechanisms (Garcia-Perez et al, 2011;Kwon et al, 1998;Sharma et al, 2007). Besides, we demonstrated that the intracellular destiny of M. tuberculosis will be dictated by the cell type infected, hence while in epithelial cells M. tuberculosis survives and replicates, in the endothelial cells tends to persist without showing replication (Garcia-Perez et al, 2011).…”

Prime-boost vaccination with Bacillus Calmette Guerin and a recombinant adenovirus co-expressing CFP10, ESAT6, Ag85A and Ag85B of Mycobacterium tuberculosis induces robust antigen-specific immune responses in mice

“…Cytokines have also been demonstrated to have important roles in host defense against Mtb infection. For example, IFN-γ was reported to activate infected macrophages and directly inhibit intracellular replication and growth of Mtb (47,48). By contrast, TNF-α was demonstrated to be essential for the initiation of the immune response against Mtb infection (49).…”