Down-Modulation of Lung Immune Responses by Interleukin-10 and Transforming Growth Factor β (TGF-β) and Analysis of TGF-β Receptors I and II in Active Tuberculosis

Bonecini-Almeida, Maria da Glória; Ho, John L.; Boéchat, Neio; Huard, Richard C.; Chitale, Sadhana; Doo, Howard; Geng, Juan; Rego, Lorena; Lazzarini, Luiz Claudio Oliveira; Kritski, Afrânio Lineu; Johnson, Warren D.; McCaffrey, Timothy A.; Silva, José Roberto Lapa e

doi:10.1128/iai.72.5.2628-2634.2004

Cited by 137 publications

(126 citation statements)

References 52 publications

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“…Nevertheless, in our in vitro model, the blocking of IL-10 in the Mtb-derived conditioned media seems to be sufficient to impair STAT3 activation and the establishment of M2-like phenotype. This is in line with the fact that IL-10 is considered to be an important clinical biomarker of disease progression [54], increased levels for this cytokine are reported in both the blood [31,55] and in the bronchoalveolar lavage of active TB patients [56], and in the tuberculous granuloma context in NHP model [57]. The fact that we observed elevated levels of activated STAT3 in monocyte-macrophages in both TB patients and in the NHP tuberculous granuloma context, suggests that overactive production of IL-10 may be responsible.…”

Section: Discussionmentioning

confidence: 53%

Tuberculosis is associated with expansion of a motile, permissive and immunomodulatory CD16+ monocyte population via the IL-10/STAT3 axis

et al. 2015

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The human CD14 + monocyte compartment is composed by two subsets based on CD16 expression. We previously reported that this compartment is perturbed in tuberculosis (TB) patients, as reflected by the expansion of CD16 + monocytes along with disease severity. Whether this unbalance is beneficial or detrimental to host defense remains to be elucidated. Here in the context of active TB, we demonstrate that human monocytes are predisposed to differentiate towards an anti-inflammatory (M2-like) macrophage activation program characterized by the CD16 + CD163 + MerTK + pSTAT3 + phenotype and functional properties such as enhanced protease-dependent motility, pathogen permissivity and immunomodulation. This process is dependent on STAT3 activation, and loss-of-function experiments point towards a detrimental role in host defense against TB. Importantly, we provide a critical correlation between the abundance of the CD16 + CD163 + MerTK + pSTAT3 + cells and the progression of the disease either at the local level in a non-human primate tuberculous granuloma context, or at the systemic level through the detection of the soluble form of CD163 in human sera. Collectively, this study argues for the pathogenic role of the CD16 + C-D163 + MerTK + pSTAT3 + monocyte-to-macrophage differentiation program and its potential as a target for TB therapy, and promotes the detection of circulating CD163 as a potential biomarker for disease progression and monitoring of treatment efficacy.

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Section: Discussionmentioning

confidence: 53%

Tuberculosis is associated with expansion of a motile, permissive and immunomodulatory CD16+ monocyte population via the IL-10/STAT3 axis

et al. 2015

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“…9,36 In addition to earlier reports that BAL fluids from a significant number of tested tuberculosis patients contained elevated IL-10 levels and bioactive TGF-b, 7 recent reports showed that lung cells from induced sputum expressed significantly high levels of IL-10, TGF-bRI and TGF-bRII. 37 In the present study, we found that the addition of anti-IL-10 or anti-TGF-b could partially reverse IFN-c production, suggesting that local IL-10 and TGF-b in PF may promote a cytokine microenvironment where resident and newly recruited immune cells become refractory to appropriate activating signals.…”

Section: Pf Inhibits the Functions Of T Cells And Differentiation Ofmentioning

confidence: 92%

“…IL-10 and TGF-b, the two classical regulatory cytokines, are known to not only inhibit T-cell activity in response to Mtb, 7 but also promote T-cell anergy possibly by downregulating the cell surface expression of the costimulatory and antigen-presenting molecules on Mtb-infected monocytes. 9,36 In addition to earlier reports that BAL fluids from a significant number of tested tuberculosis patients contained elevated IL-10 levels and bioactive TGF-b, 7 recent reports showed that lung cells from induced sputum expressed significantly high levels of IL-10, TGF-bRI and TGF-bRII.…”

Section: Pf Inhibits the Functions Of T Cells And Differentiation Ofmentioning

confidence: 99%

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Pleural fluid from tuberculous pleurisy inhibits the functions of T cells and the differentiation of Th1 cells via immunosuppressive factors

Liu

et al. 2011

Cell Mol Immunol

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Immunosuppressive mediators in tuberculosis pleurisy (pleural fluid (PF)) are associated with the course of disease, but they remain poorly defined. To study the local immune status of patients with tuberculosis pleurisy, we examined the effect of PF on the functions of T cells and the differentiation of Th1 cells. PF could inhibit the ability of T cells to produce cytokines. However, tumor-necrosis factor (TNF)-a derived from non-T cells was not impaired. Further analysis indicated that cell activation and cell cycle progression were also suppressed. Moreover, PF could inhibit Th1 cell differentiation. Importantly, we found that inhibitors of indoleamine 2,3-dioxygenase (IDO) and adenosine and neutralizing antibodies against IL-10 and transforming growth factor (TGF)-b could reverse cytokine production, suggesting that IDO, adenosine, IL-10 and Transforming growth factor-b1 in PF might take part in impairing T-cell functions. Taken together, our data demonstrate for the first time that several immunopathological factors participate in the downregulation of T-cell functions in local PF.

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“…Some intracellular bacteria down-regulate MHC class I or MHC class II surface expression (28 -31). Mycobacterium tuberculosis skews the cytokine response from a pro-to an antiinflammatory response (32,33). Legionella pneumophila causes IFN-␥-stimulated macrophages to produce PGE 2 , and blocks IFN-␥ secretion from CD4 ϩ T cells (34).…”

mentioning

confidence: 99%

Francisella tularensis-Infected Macrophages Release Prostaglandin E2 that Blocks T Cell Proliferation and Promotes a Th2-Like Response

Woolard

Wilson

Hensley

et al. 2007

The Journal of Immunology

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Francisella tularensis is a highly infectious bacterial pathogen, and is likely to have evolved strategies to evade and subvert the host immune response. In this study, we show that F. tularensis infection of macrophages alters T cell responses in vitro, by blocking T cell proliferation and promoting a Th2-like response. We demonstrate that a soluble mediator is responsible for this effect and identify it as PGE2. Supernatants from F. tularensis-infected macrophages inhibited IL-2 secretion from both MHC class I and MHC class II-restricted T cell hybridomas, as well as enhanced a Th2-like response by inducing increased production of IL-5. Furthermore, the soluble mediator blocked proliferation of naive MHC class I-restricted T cells when stimulated with cognate tetramer. Indomethacin treatment partially restored T cell proliferation and lowered IL-5 production to wild-type levels. Macrophages produced PGE2 when infected with F. tularensis, and treatment of infected macrophages with indomethacin, a cyclooxygenase-1/cyclooxygenase-2 inhibitor, blocked PGE2 production. To further demonstrate that PGE2 was responsible for skewing of T cell responses, we infected macrophages from membrane PGE synthase 1 knockout mice (mPGES1−/−) that cannot produce PGE2. Supernatants from F. tularensis-infected membrane PGE synthase 1−/− macrophages did not inhibit T cell proliferation. Furthermore, treatment of T cells with PGE2 recreated the effects seen with infected supernatant. From these data, we conclude that F. tularensis can alter host T cell responses by causing macrophages to produce PGE2. This study defines a previously unknown mechanism used by F. tularensis to modulate adaptive immunity.

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Down-Modulation of Lung Immune Responses by Interleukin-10 and Transforming Growth Factor β (TGF-β) and Analysis of TGF-β Receptors I and II in Active Tuberculosis

Cited by 137 publications

References 52 publications

Tuberculosis is associated with expansion of a motile, permissive and immunomodulatory CD16+ monocyte population via the IL-10/STAT3 axis

Tuberculosis is associated with expansion of a motile, permissive and immunomodulatory CD16+ monocyte population via the IL-10/STAT3 axis

Pleural fluid from tuberculous pleurisy inhibits the functions of T cells and the differentiation of Th1 cells via immunosuppressive factors

Francisella tularensis-Infected Macrophages Release Prostaglandin E2 that Blocks T Cell Proliferation and Promotes a Th2-Like Response

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