Regulation of Interleukin‐12 by Interleukin‐10, Transforming Growth Factor‐β, Tumor Necrosis Factor‐α, and Interferon‐γ in Human Monocytes Infected with<i>Mycobacterium tuberculosis</i>H37Ra

Fulton, Scott A.; Cross, Janet V.; Toossi, Zahra; Boom, W. Henry

doi:10.1086/515698

Cited by 72 publications

(50 citation statements)

References 35 publications

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“…Dividing by the number of macrophages, we estimate that ␣ 10 ϭ 2.75 ϫ 10 Ϫ5 pg/cell day. In contrast, early treatment with an excess of IL-10 correlated with a mean decrease of 57% in IL-12 p70 protein (56). Thus, we would expect that p 5 Ͼ 0.57.…”

Section: Growth and Decay Rates (␣ 19 mentioning

confidence: 88%

“…One study (56) measured maximal rates of IL-12 (IL-12 p70) production by human macrophages in response to live H37Ra M. tuberculosis and IFN-␥ by preincubating 2 ϫ 10 6 /ml human macrophages with an excess of IFN-␥ and 10 M. tuberculosis bacteria per macrophage. IL-12 p70 protein in 24-h supernatants was measured by ELISA to be 55 pg/ml.…”

Section: Growth and Decay Rates (␣ 19 mentioning

confidence: 99%

See 1 more Smart Citation

A Model to Predict Cell-Mediated Immune Regulatory Mechanisms During Human Infection withMycobacterium tuberculosis

Wigginton

Kirschner

2001

The Journal of Immunology

214

209

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A key issue for the study of tuberculosis infection (TB) is to understand why individuals infected with Mycobacterium tuberculosis experience different clinical outcomes. Elaborating the immune mechanisms that determine whether an infected individual will suffer active TB or latent infection can aid in developing treatment and prevention strategies. To better understand the dynamics of M. tuberculosis infection and immunity, we have developed a virtual human model that qualitatively and quantitatively characterizes the cellular and cytokine control network operational during TB infection. Using this model, we identify key regulatory elements in the host response. In particular, factors affecting cell functions, such as macrophage activation and bactericidal capabilities, and effector T cell functions such as cytotoxicity and cytokine production can each be determinative. The model indicates, however, that even if latency is achieved, it may come at the expense of tissue damage if the response is not properly regulated. A balance in Th1 and Th2 immune responses governed by IFN-γ, IL-10, and IL-4 facilitate this down-regulation. These results are further explored through virtual deletion and depletion experiments.

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Section: Growth and Decay Rates (␣ 19 mentioning

confidence: 88%

Section: Growth and Decay Rates (␣ 19 mentioning

confidence: 99%

A Model to Predict Cell-Mediated Immune Regulatory Mechanisms During Human Infection withMycobacterium tuberculosis

Wigginton

Kirschner

2001

The Journal of Immunology

214

209

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“…The increased levels of serum IL-10 and TGF-␤ detected in TB patients, and the increased in vitro IL-10 and TGF-␤ secretion by the PBMC and/or monocytes of TB patients in response to M. tuberculosis Ags, also support a role for these two immune suppressive mediators (7,(52)(53)(54). The fact that M. tuberculosis can directly induce macrophage IL-10 and TGF-␤ production (36,55) and that the growth restriction of M. tuberculosis by human monocytes/macrophages is correlated inversely with the amount of stimulated IL-10 and TGF-␤ secretion (36,56) further underscores their antagonistic role in microbicidal activity in TB.…”

Section: Discussionmentioning

confidence: 99%

Tuberculosis Is Associated with a Down-Modulatory Lung Immune Response That Impairs Th1-Type Immunity

Almeida

Lago

Boéchat

et al. 2009

The Journal of Immunology

134

118

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Immune mediators associated with human tuberculosis (TB) remain poorly defined. This study quantified levels of lung immune mediator gene expression at the time of diagnosis and during anti-TB treatment using cells obtained by induced sputum. Upon comparison to patients with other infectious lung diseases and volunteers, active pulmonary TB cases expressed significantly higher levels of mediators that counteract Th1-type and innate immunity. Despite the concomitant heightened levels of Th1-type mediators, immune activation may be rendered ineffectual by high levels of intracellular (SOCS and IRAK-M) and extracellular (IL-10 and TGF-βRII, IL-1Rn, and IDO) immune suppressive mediators. These modulators are a direct response to Mycobacterium tuberculosis as, by day 30 of anti-TB treatment, many suppressive factors declined to that of controls whereas most Th1-type and innate immune mediators rose above pretreatment levels. Challenge of human immune cells with M. tuberculosis in vitro up-regulated these immune modulators as well. The observed low levels of NO synthase-2 produced by alveolar macrophages at TB diagnosis, along with the heightened amounts of suppressive mediators, support the conclusion that M. tuberculosis actively promotes down-modulatory mediators to counteract Th1-type and innate immunity as an immunopathological strategy. Our data highlight the potential application of immune mediators as surrogate markers for TB diagnosis or treatment response.

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“…Previous studies have addressed the limiting effects of TGF-b1 on IL-12 production and activity [26,27]. In the present study we characterized the effect of IL-12 on the expression of TGF-b1 in primary monocytes and macrophages, and in epithelial and erythroleukemia cell lines.…”

Section: Discussionmentioning

confidence: 92%

Modulation of Transforming Growth Factor β‐1 Gene Expression by Interleukin‐12

Wilkinson

Aung

et al. 2000

Scand J Immunol

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The interaction of cytokines and their net balance with regard to macrophage activation (or deactivation) and immune stimulation (or suppression), ultimately determines the success of host-immune response at sites of active infection. A regulatory role for interleukin (IL)-12 in production of transforming growth factor (TGF)-b1 has been suggested, however, remains controversial. In this study, we analyzed the effect of IL-12 on TGFb1 expression in the human lines, K562 and A549, and in primary human monocytes and macrophages. We found that IL-12 down-regulates TGF-b1 mRNA expression in K562, monocytes and bone marrow cells, and to a lesser extent in the A549 cells. Using constructs containing different regions of the ®rst promoter of the TGF-b1 gene and a reporter gene, we also demonstrate that this effect is mediated through the TGF-b1 gene promoter in the K562 and monocytic cell types. In conclusion, the critical role of IL-12 in the early activation of the immune response to pathogens may include down-modulation of TGF-b1 gene activity.

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Regulation of Interleukin‐12 by Interleukin‐10, Transforming Growth Factor‐β, Tumor Necrosis Factor‐α, and Interferon‐γ in Human Monocytes Infected withMycobacterium tuberculosisH37Ra

Cited by 72 publications

References 35 publications

A Model to Predict Cell-Mediated Immune Regulatory Mechanisms During Human Infection withMycobacterium tuberculosis

A Model to Predict Cell-Mediated Immune Regulatory Mechanisms During Human Infection withMycobacterium tuberculosis

Tuberculosis Is Associated with a Down-Modulatory Lung Immune Response That Impairs Th1-Type Immunity

Modulation of Transforming Growth Factor β‐1 Gene Expression by Interleukin‐12

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