Lack of IL-10 alters inflammatory and immune responses during pulmonary Mycobacterium tuberculosis infection

Higgins, David M.; Sánchez-Campillo, Joaquín; Rosas-Taraco, Adrián G.; Lee, Eric J.; Orme, Ian M.; Gonzalez-Juarrero, Mercedes

doi:10.1016/j.tube.2009.01.001

Cited by 95 publications

(88 citation statements)

References 34 publications

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“…Despite the overwhelming evidence to support a direct role of mycobacterial infection in inducing IL-10 production by APCs, [37][38][39]62 it is plausible for us to consider the possibility that some level of IL-10 may be actively induced as part of host immune regulatory mechanisms as a means to limit immunopathology, a concession that could be exploited by mycobacteria and has recently been suggested by others. 66 Although our current findings and a large body of literature information support the immune suppressive role of IL-10 in mycobacterial infection, one study shows the addition of exogenous IL-10 to enhance macrophage activation. 67 In conclusion, our study, for the first time, has examined the profile and characteristics of granuloma APCs and T cells in a model of pulmonary mycobacterial infection and compared them with those located in the extragranulomatous bronchoalveolar space of the same host.…”

Section: Discussionmentioning

confidence: 46%

Pulmonary Mycobacterial Granuloma

Shaler

Kugathasan

McCormick

et al. 2011

The American Journal of Pathology

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The granuloma, a hallmark of host defense against pulmonary mycobacterial infection, has long been believed to be an active type 1 immune environment. However, the mechanisms regarding why granuloma fails to eliminate mycobacteria even in immune-competent hosts, have remained largely unclear. By using a model of pulmonary Mycobacterium bovis Bacillus Calmette-Guerin (BCG) infection, we have addressed this issue by comparing the immune responses within the airway luminal and granuloma compartments. We found that despite having a similar immune cellular profile to that in the airway lumen, the granuloma displayed severely suppressed type 1 immune cytokine but enhanced chemokine responses. Both antigen-presenting cells (APCs) and T cells in granuloma produced fewer type 1 immune molecules including tumor necrosis factor-␣ (TNF-␣), interferon-␥ (IFN-␥), and nitric oxide. As a result, the granuloma APCs developed a reduced capacity to phagocytose mycobacteria and to induce T-cell proliferation. To examine the molecular mechanisms, we compared the levels of immune suppressive cytokine IL-10 in the airway lumen and granuloma and found that both granuloma APCs and T cells produced much more IL-10. Thus, IL-10 deficiency restored type 1 immune activation within the granuloma while having a minimal effect within the airway lumen. Hence, our study provides the first experimental evidence that, contrary to the conventional belief, the BCG-induced lung granuloma represents a symbiotic host-microbe microenvironment characterized by suppressed type 1 immune activation.

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Section: Discussionmentioning

confidence: 46%

Pulmonary Mycobacterial Granuloma

Shaler

Kugathasan

McCormick

et al. 2011

The American Journal of Pathology

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“…TNF-␣, together with IFN-␥, mediates the activation of macrophages, which is required to control the growth of M. tuberculosis, and it was shown that TNF Ϫ/Ϫ mice have significantly more CFU in their lungs than wild-type mice and succumb during early stages of disease (28). Mice deficient in IL-10 generally have an enhanced ability to control M. tuberculosis; however, it was shown that these mice succumb to the disease due to severe immunopathology (40). Mice deficient in IL-6 are able to initiate the formation of granulomas but fail to maintain them and have a decreased ability to produce proinflammatory mediators during the early stages of the infection (41).…”

Section: Discussionmentioning

confidence: 99%

The Contraceptive Depot Medroxyprogesterone Acetate Impairs Mycobacterial Control and Inhibits Cytokine Secretion in Mice Infected with Mycobacterium tuberculosis

et al. 2013

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dThe contraceptive depot medroxyprogesterone acetate (DMPA), with progestin as the single active compound, possesses selective glucocorticoid activity and can alter the expression of glucocorticoid receptor-regulated genes. We therefore propose that pharmacological doses of DMPA used for endocrine therapy could have significant immune modulatory effects and impact on susceptibility to, as well as clinical manifestation and outcome of, infectious diseases. We investigated the effect of contraceptive doses of DMPA in two different murine Mycobacterium tuberculosis models. Multiplex bead array analysis revealed that DMPA altered serum cytokine levels of tumor necrosis factor alpha (TNF-␣), granulocyte colony-stimulating factor (G-CSF), and interleukin 10 (IL-10) in C57BL/6 mice and gamma interferon (IFN-␥) in BALB/c mice. DMPA also suppressed antigen-specific production of TNF-␣, G-CSF, IL-10, and IL-6 and induced the production of IP-10 in C57BL/6 mice. In BALB/c mice, DMPA altered the antigen-specific secretion of IFN-␥, IL-17, granulocyte-macrophage colony-stimulating factor (GM-CSF), IL-6, and monocyte chemotactic protein 1 (MCP-1). Furthermore, we show that C57BL/6 mice treated with doses of DMPA, which result in serum concentrations similar to those observed in contraceptive users, have a significantly higher bacterial load in their lungs. Our data show for the first time that DMPA impacts tuberculosis (TB) disease severity in a mouse model and that the effects of this contraceptive are not confined to infections of the genital tract. This could have major implications for the contraceptive policies not only in developing countries like South Africa but also worldwide.

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“…Mice deficient in IL-10 or those receiving anti-IL-10R antibodies have varied phenotypes, with reports of no effect, a transient protective effect, or a long-term beneficial effect during infection with either virulent Mycobacterium tuberculosis, the environmental mycobacterium Mycobacterium avium, or the vaccine strain Mycobacterium bovis BCG (28,51,52,58,89). The outcome of infection in the absence of IL-10 can be linked to the species/substrain of mycobacteria or the particular strain of mouse being used, and this impact of host variation will be discussed below.…”

Section: Pathogen-induced Il-10 Production Via Prrsmentioning

confidence: 99%

Interleukin-10 and Immunity against Prokaryotic and Eukaryotic Intracellular Pathogens

2011

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2The generation of an effective immune response against an infection while also limiting tissue damage requires a delicate balance between pro-and anti-inflammatory responses. Interleukin-10 (IL-10) has potent immunosuppressive effects and is essential for regulation of immune responses. However, the immunosuppressive properties of IL-10 can also be exploited by pathogens to facilitate their own survival. In this minireview, we discuss the role of IL-10 in modulating intracellular bacterial, fungal, and parasitic infections. Using information from several different infection models, we bring together and highlight some common pathways for IL-10 regulation and function that cannot be fully appreciated by studies of a single pathogen.

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Lack of IL-10 alters inflammatory and immune responses during pulmonary Mycobacterium tuberculosis infection

Cited by 95 publications

References 34 publications

Pulmonary Mycobacterial Granuloma

Pulmonary Mycobacterial Granuloma

The Contraceptive Depot Medroxyprogesterone Acetate Impairs Mycobacterial Control and Inhibits Cytokine Secretion in Mice Infected with Mycobacterium tuberculosis

Interleukin-10 and Immunity against Prokaryotic and Eukaryotic Intracellular Pathogens

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