Interleukin 10 suppresses Th17 cytokines secreted by macrophages and T cells

Gu, Yongpeng; Yang, Jianfei; Ouyang, Xinshou; Liu, Weicheng; Li, Hongxing; Yang, Jianjun; Bromberg, Jonathan S.; Chen, Shu‐Hsia; Mayer, Lloyd; Unkeless, Jay C.; Xiong, Huabao

doi:10.1002/eji.200838331

Cited by 208 publications

(189 citation statements)

References 18 publications

(20 reference statements)

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“…IL-2 or IL-10 signaling has been shown to modulate Th17 cell generation (19,20); however, in the present study, impaired IL-17 production in Myd88 −/− CD4 + T cells was not related to increased IL-2 or IL-10 production (Fig. S2).…”

Section: Resultscontrasting

confidence: 69%

MyD88 is essential to sustain mTOR activation necessary to promote T helper 17 cell proliferation by linking IL-1 and IL-23 signaling

Chang

Burkett

Borges

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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Myeloid differentiation primary response protein 88 (MyD88) is classically known as an adaptor, linking TLR and IL-1R to downstream signaling pathways in the innate immune system. In addition to its role in innate immune cells, MyD88 has been shown to play an important role in T cells. How MyD88 regulates helper T-cell differentiation remains largely unknown, however. Here we demonstrate that MyD88 is an important regulator of IL-17-producing CD4 + T helper cells (Th17) cell proliferation. MyD88-deficient CD4 + T cells showed a defect in Th17 cell differentiation, but not in Th1 cell or Th2 cell differentiation. The impaired IL-17 production from MyD88-deficient CD4 + T cells is not a result of defective RAR-related orphan receptor γt (RORγt) expression. Instead, MyD88 is essential for sustaining the mammalian target of rapamycin (mTOR) activation necessary to promote Th17 cell proliferation by linking IL-1 and IL-23 signaling. MyD88-deficient CD4 + T cells showed impaired mTOR activation and, consequently, reduced Th17 cell proliferation. Importantly, the absence of MyD88 in T cells ameliorated disease in the experimental autoimmune encephalomyelitis model. Taken together, our results demonstrate that MyD88 has a dual function in Th17 cells by delivering IL-1 signaling during the early differentiation stage and integrating IL-23 signaling to the mTOR complex to expand committed Th17 cells.

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Section: Resultscontrasting

confidence: 69%

MyD88 is essential to sustain mTOR activation necessary to promote T helper 17 cell proliferation by linking IL-1 and IL-23 signaling

Chang

Burkett

Borges

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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“…However, new cellular sources have been proposed, such as macrophages, neutrophils, and CD8, NK, ab, and gd T cells (13)(14)(15). In this study, we demonstrated that among the IL-17A-producing cells recruited upon silica treatment in the lung, only gd + and CD4 + T cells significantly expressed IL-17A.…”

Section: Discussionmentioning

confidence: 56%

“…CD4 + T cells are not the only source of IL-17 and -22; gd T lymphocytes also produce considerable quantities of these cytokines in different neutrophilic reactions. NK T cells and CD8 T cells were also identified as IL-17-producing cells that contribute to neutrophil recruitment through IL-17 secretion (13)(14)(15).…”

mentioning

confidence: 99%

IL-17A–Producing γδ T and Th17 Lymphocytes Mediate Lung Inflammation but Not Fibrosis in Experimental Silicosis

Re¹,

Dumoutier

Couillin

et al. 2010

The Journal of Immunology

131

107

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IL-17–producing T lymphocytes play a crucial role in inflammation, but their possible implication in fibrosis remains to be explored. In this study, we examined the involvement of these cells in a mouse model of lung inflammation and fibrosis induced by silica particles. Upregulation of IL-17A was associated with the development of experimental silicosis, but this response was markedly reduced in athymic, γδ T cell-deficient or CD4+ T cell-depleted mice. In addition, γδ T lymphocytes and CD4+ T cells, but not macrophages, neutrophils, NK cells or CD8 T cells, purified from the lungs of silicotic mice markedly expressed IL-17A. Depletion of alveolar macrophages or neutralization of IL-23 reduced upregulation of IL-17A in the lung of silicotic mice. IL-17R–deficient animals (IL-17R−/−) or IL-17A Ab neutralization, but not IL-22−/− mice, developed reduced neutrophil influx and injury during the early lung response to silica. However, chronic inflammation, fibrosis, and TGF-β expression induced by silica were not attenuated in the absence of IL-17R or -22 or after IL-17A Ab blockade. In conclusion, a rapid lung recruitment of IL-17A–producing T cells, mediated by macrophage-derived IL-23, is associated with experimental silicosis in mice. Although the acute alveolitis induced by silica is IL-17A dependent, this cytokine appears dispensable for the development of the late inflammatory and fibrotic lung responses to silica.

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“…Furthermore, exposure of human macrophages to IL-10 induces IL-10R mRNA transcription [22]. Most recently, the production of Th17 cytokines by macrophages and its suppression by IL-10 was shown in vitro using IL-10R2 deficient macrophages [23]. By using IL-10R1 knock-out mice, we could confirm that the suppression of IL-17 production is IL-10 specific and that monocytes/macrophages are the main targets of IL-10 in the regulation of the Th17 cytokine production.…”

Section: Conditional Inactivation Of the Il-10r1 Genementioning

confidence: 99%

Monocytes/macrophages and/or neutrophils are the target of IL‐10 in the LPS endotoxemia model

et al. 2010

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IL-10 is a potent regulator of the innate and adaptive immune responses. Several cell types produce IL-10 and its receptor chains and these may regulate different immune responses. Here we report that inactivation of the IL-10 receptor (IL-10R1) gene in mice leads to an increased susceptibility to chemically induced colitis as in the classical IL-10-deficient mutant. To identify the cells regulated by IL-10 in immune responses, we generated several cell type specific IL-10R1-deficient mutants. We show that, in an IL-10-dependent LPS model of endotoxemia, dampening of the immune response requires expression of IL-10R1 in monocytes/macrophages and/or neutrophils but not in T cells nor B cells. As the macrophage and/or neutrophil-specific IL-10-deficient mutants also display the same phenotype, our results suggest that an autocrine loop in monocytes/macrophages is the most probable mechanism for the regulation of an LPS-induced septic shock. In contrast, in an IL-10-regulated T-cell response to Trichuris muris infection, IL-10 acting on T cells or monocytes/macrophages/neutrophils is not critical for the control of the infection.

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Interleukin 10 suppresses Th17 cytokines secreted by macrophages and T cells

Cited by 208 publications

References 18 publications

MyD88 is essential to sustain mTOR activation necessary to promote T helper 17 cell proliferation by linking IL-1 and IL-23 signaling

MyD88 is essential to sustain mTOR activation necessary to promote T helper 17 cell proliferation by linking IL-1 and IL-23 signaling

IL-17A–Producing γδ T and Th17 Lymphocytes Mediate Lung Inflammation but Not Fibrosis in Experimental Silicosis

Monocytes/macrophages and/or neutrophils are the target of IL‐10 in the LPS endotoxemia model

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