Inhibition of <i>Mycobacterium tuberculosis</i>‐Induced Signalling by Transforming Growth Factor‐β in Human Mononuclear Phagocytes

Wu, Mianda; Aung, Htin; Hirsch, Christina S.; Toossi, Zahra

doi:10.1111/j.1365-3083.2011.02668.x

Cited by 21 publications

(17 citation statements)

References 15 publications

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“…Concomitantly, the levels of suppressor cytokines IL-10 and TGF-b were up-regulated. Although IFN-g and IL-17 are important for control of M. tuberculosis infection [31][32][33], high levels of IL-10 and TGF-b increase susceptibility to M. tuberculosis infection [32,34].…”

Section: Discussionmentioning

confidence: 99%

Suppression of Toll-like receptor 2–mediated proinflammatory responses by Mycobacterium tuberculosis protein Rv3529c

Bandyopadhyay

Chadha

Gupta

et al. 2017

Journal of Leukocyte Biology

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Microorganisms are known to devise various strategies to thwart protective responses by the host. One such strategy is to incorporate sequences and domains in their genes/proteins that have similarity to various domains of the host proteins. In this study, we report that protein Rv3529c exhibits significant similarity to the death domain of the TLR pathway adaptor protein MyD88. Incubation of macrophages with Rv3529c specifically inhibited TLR2-mediated proinflammatory responses. This included attenuated oxidative burst, reduced phosphorylation of MAPK-ERK, reduced activation of transcription factor NF-κB and reduced secretion of proinflammatory cytokines IFN-γ, IL-6, and IL-17A with a concomitant increased secretion of suppressor cytokines IL-10 and TGF-β. Importantly, Rv3529c significantly inhibited TLR2-induced association of MyD88 with IRAK1 by competitively binding with IRAK1. Further, Rv3529c mediated inhibition of apoptosis and phagosome-lysosome fusion. Lastly, incubation of macrophages with Rv3529c increased bacterial burden inside macrophages. The data presented show another strategy evolved by toward immune evasion that centers on incorporating sequences in proteins that are similar to crucial proteins in the innate immune system of the host.

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Section: Discussionmentioning

confidence: 99%

Suppression of Toll-like receptor 2–mediated proinflammatory responses by Mycobacterium tuberculosis protein Rv3529c

Bandyopadhyay

Chadha

Gupta

et al. 2017

Journal of Leukocyte Biology

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“…TGFb, another inhibitory cytokine, has been shown to play a vital role in the immune-pathogenesis of TB [11]. Interfering with TGF-b signalling with the inhibitor SIS3 may prove to be an effective adjunct to TB therapy [33]. IL-12 is essential for the generation of a protective immune response to M. tb and promotes survival of patients with TB [34].…”

Section: Discussionmentioning

confidence: 99%

IL‐37 Expression is Upregulated in Patients with Tuberculosis and Induces Macrophages Towards an M2‐like Phenotype

et al. 2015

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Interleukin-37 (IL-37), a member of the IL-1 family, primarily functions as an anti-inflammatory cytokine, reducing inflammation and suppressing the immune response. However, the expression and role of IL-37 in tuberculosis (TB) remains unknown. We aimed to measure serum levels of IL-37 and several important cytokines in 25 patients with active TB and to analyse their association with disease activity. We found that IL-37 levels decreased in patients with TB and recovered after treatment. IL-37 levels negatively correlated with the serum concentration of IFN-c and IL-12 but positively correlated with IL-10 and TGFb levels. After IL-37, secretion was blocked in peripheral blood mononuclear cells from active patients with TB, IFN-c and IL-10 production was significantly upregulated; this was not observed in healthy donors or patients after treatment. IL-37 knockdown significantly enhanced the phagocytic activity of THP1-derived macrophages towards Mycobacterium tuberculosis (M. tb). M1/M2 polarization-associated markers were detected simultaneously, and IL-37 induced a phenotypic shift in THP1-derived macrophages towards a high CD206 + and low CD86 + macrophage subtype. Furthermore, this phenotypic shift was accompanied by upregulated mRNA levels of arginase 1, TGF-b and IL-10, which are characteristic hallmarks of M2 macrophages. In conclusion, our results suggest that increased levels of IL-37 in patients with TB are associated with IFN-c, IL-12, IL-10 and TGF-b levels and that IL-37 plays a pathological role in TB infection by inhibiting the production of pro-inflammatory cytokines and inducing macrophages towards an M2-like phenotype. Thus, IL-37 may be a novel research target to understand the pathogenesis of TB infection.

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“…Once activated, plasminogen is converted to plasmin, a serine protease that can degrade fibrin and activate complement [39]. Plasmin has also been reported to increase the activity of many proteins including matrix metalloproteinases (MMP) and TGF-β which can alter host pathology and allow the tubercle bacillus to disseminate more readily [40]–[42]. Thrombospondin-4 (TSP4) prominently appears in both the paired and unpaired analysis.…”

Section: Discussionmentioning

confidence: 99%

Elucidating Novel Serum Biomarkers Associated with Pulmonary Tuberculosis Treatment

et al. 2013

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In an unbiased approach to biomarker discovery, we applied a highly multiplexed proteomic technology (SOMAscan, SomaLogic, Inc, Boulder, CO) to understand changes in proteins from paired serum samples at enrollment and after 8 weeks of TB treatment from 39 patients with pulmonary TB from Kampala, Uganda enrolled in the Center for Disease Control and Prevention’s Tuberculosis Trials Consortium (TBTC) Study 29. This work represents the first large-scale proteomic analysis employing modified DNA aptamers in a study of active tuberculosis (TB). We identified multiple proteins that exhibit significant expression differences during the intensive phase of TB therapy. There was enrichment for proteins in conserved networks of biological processes and function including antimicrobial defense, tissue healing and remodeling, acute phase response, pattern recognition, protease/anti-proteases, complement and coagulation cascade, apoptosis, immunity and inflammation pathways. Members of cytokine pathways such as interferon-gamma, while present, were not as highly represented as might have been predicted. The top proteins that changed between baseline and 8 weeks of therapy were TSP4, TIMP-2, SEPR, MRC-2, Antithrombin III, SAA, CRP, NPS-PLA2, LEAP-1, and LBP. The novel proteins elucidated in this work may provide new insights for understanding TB disease, its treatment and subsequent healing processes that occur in response to effective therapy.

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Inhibition of Mycobacterium tuberculosis‐Induced Signalling by Transforming Growth Factor‐β in Human Mononuclear Phagocytes

Cited by 21 publications

References 15 publications

Suppression of Toll-like receptor 2–mediated proinflammatory responses by Mycobacterium tuberculosis protein Rv3529c

Suppression of Toll-like receptor 2–mediated proinflammatory responses by Mycobacterium tuberculosis protein Rv3529c

IL‐37 Expression is Upregulated in Patients with Tuberculosis and Induces Macrophages Towards an M2‐like Phenotype

Elucidating Novel Serum Biomarkers Associated with Pulmonary Tuberculosis Treatment

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