IFNγ inhibits Th17 differentiation and function via Tbet-dependent and Tbet-independent mechanisms

Yeh, Wen-I; McWilliams, Ian; Harrington, Laurie E.

doi:10.1016/j.jneuroim.2013.12.001

Cited by 39 publications

(33 citation statements)

References 40 publications

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“…Supporting this concept, it has been reported recently that IFN-γ inhibits IL-17 production in a STAT1-dependent manner, thus representing one mechanism favoring the development of Th1 cells and silencing the Th17 program [42]. Furthermore, Ortiz et al .…”

Section: Discussionmentioning

confidence: 92%

STAT6 and STAT1 Pathway Activation in Circulating Lymphocytes and Monocytes as Predictor of Treatment Response in Rheumatoid Arthritis

Kuuliala

Koivuniemi

et al. 2016

PLoS ONE

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ObjectiveTo find novel predictors of treatment response to disease-modifying antirheumatic drugs (DMARDs), we studied activation of STAT (signal transducers and activators of transcription) 6 and 1 in circulating leukocytes of patients with rheumatoid arthritis (RA).Methods19 patients with untreated recent-onset RA, 16 patients with chronic RA irresponsive to synthetic DMARDs and 37 healthy volunteers provided blood samples for whole blood flow cytometric determination of intracellular STAT6 and STAT1 phosphorylation, expressed as relative fluorescence units, in response to IL-4 and IFN-γ, respectively. Phosphorylation was restudied and treatment response (according to European League Against Rheumatism) determined after 1-year treatment with synthetic DMARDs in recent-onset RA and with biological DMARD in synthetic DMARD-irresponsive RA. Estimation-based exact logistic regression was used to investigate relation of baseline variables to treatment response. 95% confidence intervals of means were estimated by bias-corrected bootstrapping and the significance between baseline and follow-up values was calculated by permutation test.ResultsAt baseline, levels of phosphorylated STAT6 (pSTAT6) induced by IL-4 in monocytes were higher in those who achieved good treatment response to synthetic DMARDs than in those who did not among patients with untreated RA (OR 2.74, 95% CI 1.05 to 9.47), and IFN-γ -stimulated lymphocyte pSTAT1 levels were higher in those who achieved good treatment response to a biological drug than in those who did not among patients with chronic RA (OR 3.91, 95% CI 1.12 to 20.68). During follow-up, in recent-onset RA patients with good treatment response to synthetic DMARDS, the lymphocyte pSTAT6 levels decreased (p = 0.011), and, consequently, the ratio of pSTAT1/pSTAT6 in lymphocytes increased (p = 0.042).ConclusionCytokine-stimulated STAT6 and STAT1 phosphorylation in circulating leukocytes was associated with treatment response to DMARDs in this pilot study. The result, if confirmed in larger studies, may aid in developing personalized medicine in RA.

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Section: Discussionmentioning

confidence: 92%

STAT6 and STAT1 Pathway Activation in Circulating Lymphocytes and Monocytes as Predictor of Treatment Response in Rheumatoid Arthritis

Kuuliala

Koivuniemi

et al. 2016

PLoS ONE

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“…IFN-γ from T H 1 cell responses can suppress T H 2 and T H 17 cell responses. 38,39 However, increased T H 1 cell responses are not likely the direct the mechanism of diminished T H 2 cell responses because neutralization of IFN-γ did not restore T H 2 cell responses in RORγt-deficient T cells in vitro , as well as in UA-treated mice in vivo . Of note, we observed that the level of Bcl6 transcript was increased in RORγt-deficient T cells stimulated under T H 2-skewing conditions and that the expression of BCL6 in CD44 hi CD4 + T cells was increased in RORγt-deficient mice at steady state.…”

Section: Discussionmentioning

confidence: 99%

Concomitant suppression of TH2 and TH17 cell responses in allergic asthma by targeting retinoic acid receptor–related orphan receptor γt

Lim

Choi

et al. 2018

Journal of Allergy and Clinical Immunology

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Background Allergic asthma is a heterogeneous chronic inflammatory disease of the airways with a massive infiltration of eosinophils or neutrophils mediated by allergen-specific TH2 and TH17 cells, respectively. Therefore successful treatment of allergic asthma will require suppression of both TH2 and TH17 cells. Objective We sought to investigate the role of the TH17 cell pathway in regulating TH2 cell responses in allergic asthma. Methods Allergic asthma was induced by intranasal challenge with proteinase allergens in C57BL/6, Il17a−/−Il17f−/−, and retinoic acid receptor–related orphan receptor γt (RORγt)gfp/gfp mice. A pharmacologic RORγt inhibitor was used to evaluate its preventive and therapeutic effects in allergic asthma. Characteristics of allergic airway inflammation were analyzed by using flow cytometry, histology, quantitative real-time PCR, and ELISA. Mixed bone marrow chimeric mice, fate mapping analysis, short hairpin RNA transduction, and in vitro T-cell differentiation were used for mechanistic studies. Results Mice deficient in IL-17A and IL-17F, as well as RORγt, exhibited a significant reduction not only in TH17 cell responses but also in TH2 cell responses in an animal model of allergic asthma. Similarly, mice treated with an RORγt inhibitor had significantly diminished TH17 and TH2 cell responses, leading to reduced neutrophil and eosinophil numbers in the airway. RORγt-deficient T cells were intrinsically defective in differentiating into TH2 cells and expressed increased levels of B-cell lymphoma 6 (Bcl6). Bcl6 knockdown resulted in a remarkable restoration of TH2 cell differentiation in RORγt- deficient T cells. Blockade of RORγt also significantly hampered the differentiation of human TH2 and TH17 cells from naive CD4+ T cells. Conclusion RORγt in T cells is required for optimal TH2 cell differentiation by suppressing Bcl6 expression; this finding suggests that targeting RORγt might be a promising approach for the treatment of allergic asthma by concomitantly suppressing TH17 and TH2 cell responses in the airway.

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“…Negative control over Th17 differentiation is regulated through four distinct mechanisms: IL-27 and IFN-γ through STAT1 activation (9,46,51,70,71); IL-2 and IL-4 through STAT5 activation (72,73); IL-13 through stimulation of IL-10 production by Th17 cells, leading to IL-6 downregulation and thus diminished IL-17 production (74); loss of the inhibition of RORγt by Foxp3 when IL-6 is present (75,76). The balance between Foxp3 and RORγt is therefore a very important factor in the Th17/iTreg equilibrium.…”

Section: Th17 Subsetmentioning

confidence: 99%

The role of Th17 and Treg responses in the pathogenesis of RSV infection

et al. 2015

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IFNγ inhibits Th17 differentiation and function via Tbet-dependent and Tbet-independent mechanisms

Cited by 39 publications

References 40 publications

STAT6 and STAT1 Pathway Activation in Circulating Lymphocytes and Monocytes as Predictor of Treatment Response in Rheumatoid Arthritis

STAT6 and STAT1 Pathway Activation in Circulating Lymphocytes and Monocytes as Predictor of Treatment Response in Rheumatoid Arthritis

Concomitant suppression of TH2 and TH17 cell responses in allergic asthma by targeting retinoic acid receptor–related orphan receptor γt

The role of Th17 and Treg responses in the pathogenesis of RSV infection

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