Cutting Edge: STAT6 Signaling in Eosinophils Is Necessary for Development of Allergic Airway Inflammation

Stokes, Kindra; LaMarche, Nelson M.; Islam, Nasif; Wood, Amie; Huang, Weishan; August, Avery

doi:10.4049/jimmunol.1402096

Cited by 23 publications

(18 citation statements)

References 31 publications

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“…Gingras et al suggest that the transactivation domain of Stat6 makes contact with the basal transcription machinery by binding to p300/CBP 14 . Stokes et al indicate that STAT6 signaling in eosinophils is necessary for development of allergic airway inflammation 19 . In line with those pioneer studies, our data also show that STAT6 plays a critical role in the expression of TIM4 by DCs, in which Inhibition of STAT6 abolished the CT-induced TIM4 expression.…”

Section: Discussionmentioning

confidence: 99%

Histone acetyltransferease p300 modulates TIM4 expression in dendritic cells

Yang

et al. 2016

Sci Rep

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TIM4 (T cell immunoglobulin mucin domain molecule-4) plays a critical role in the initiation of skewed T helper (Th) 2 polarization. The factors regulating TIM4 expression are unclear. This study tests a hypothesis that p300 and STAT6 (signal transducer and activator transcription-6) regulates TIM4 expression in dendritic cells (DC). In this study, a food allergy mouse model was developed with ovalbumin (a specific antigen) and cholera toxin (CT; an adjuvant). The chromatin immunoprecipitation assay was performed to evaluate the chromatin changes at TIM4 and STAT6 promoters. The TIM4 expression was evaluated by real time RT-PCR and Western blotting. The results showed that high levels of p300 and TIM4 were detected in the intestinal DCs of mice with intestinal allergy. p300 is involved in the CT-induced TIM4 expression in DCs. p300 interacts with the chromatin at the TIM4 promoter locus in DCs isolated from allergic mice. CT increases p300 expression to regulate STAT6 levels in DCs. STAT6 mediates the CT-induced TIM4 expression in DCs. In conclusion, p300 and STAT6 mediate the microbial product CT-induced TIM4 expression in DCs.

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Section: Discussionmentioning

confidence: 99%

Histone acetyltransferease p300 modulates TIM4 expression in dendritic cells

Yang

et al. 2016

Sci Rep

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“…STAT1 mRNA in CLNs decreased by 48.5% ( P < 0.05, n = 6) in WSX‐1 −/− ‐EAC mice (Figure A), and the cells expressing phosphorylated P‐STAT1 were reduced significantly in WSX‐1 −/− ‐EAC mice (Figure B). In contrast, STAT6 signaling, which is critical to differentiation of Th2 effector cells and hyperresponsiveness in allergic disease, was upregulated and activated significantly in EAC model. STAT6 transcripts in CLNs increased by 1.9‐fold ( P < 0.05) in wild‐type C57BL/6‐EAC and by 4.1‐fold ( P < 0.01) in WSX‐1 −/− EAC mice (Figure C).…”

Section: Resultsmentioning

confidence: 86%

“…IL‐27 has been known to regulate Th1 and foxp3 via inducing STAT1, and IL‐27 was recently reported to attenuate airway inflammation in a mouse asthma model via STAT1 . STAT6 signaling has been recognized to be necessary for the development of Th2 response and allergic inflammation . However, it is not clear how IL‐27 regulates STAT1 and STAT6 both in allergic disease.…”

Section: Discussionmentioning

confidence: 99%

IL‐27 signaling deficiency develops Th17‐enhanced Th2‐dominant inflammation in murine allergic conjunctivitis model

Chen

Deng

Chi

et al. 2019

Allergy

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Background: While most studies focus on pro-allergic cytokines, the protective role of immunosuppressive cytokines in allergic inflammation is not well elucidated. This study was to explore a novel anti-inflammatory role and cellular/molecular mechanism of IL-27 in allergic inflammation. Methods:A murine model of experimental allergic conjunctivitis (EAC) was induced in BALB/c, C57BL/6 or IL-27Rα-deficient (WSX-1 −/− ) mice by short ragweed pollen, with untreated or PBS-treated mice as controls. The serum, eyeballs, conjunctiva, cervical lymph nodes (CLNs) were used for study. Gene expression was determined by RT-qPCR, and protein production and activation were evaluated by immunostaining, ELISA and Western blotting. Results: Typical allergic manifestations and stimulated thymic stromal lymphopoietin (TSLP) signaling and Th2 responses were observed in ocular surface of EAC models in BALB/c and C57BL/6 mice. The decrease of IL-27 at mRNA (IL-27/EBI3) and protein levels were detected in serum, conjunctiva and CLN, as evaluated by RT-qPCR, immunofluorescent staining, ELISA and Western blotting. EAC induced in WSX-1 −/− mice showed aggravated allergic signs with higher TSLP-driven Th2-dominant inflammation, accompanied by stimulated Th17 responses, including IL-17A, IL-17F, and transcription factor RORγt. In contrast, Th1 cytokine IFNγ and Treg marker IL-10, with their respective transcription factors T-bet and foxp3, were largely suppressed. Interestingly, imbalanced activation between reduced phosphor (P)-STAT1 and stimulated P-STAT6 were revealed in EAC, especially WSX-1 −/− -EAC mice. Conclusion: These findings demonstrated a natural protective mechanism by IL-27, of which signaling deficiency develops a Th17-type hyperresponse that further aggravates Th2-dominant allergic inflammation. K E Y W O R D S allergy, anti-inflammatory cytokine, IL-27, Th17, Th2

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“…STAT6 signaling in asthma is well characterized. In mouse models of allergic airway disease, a model of asthma, STAT6 phosphorylation is critical for Th2 differentiation (135), eosinophil migration (136, 137), mucus production and airway hyper-reactivity (138). More recently, IL-13 derived from NKT cells promotes ulcerative colitis through the activation of STAT6 (139).…”

Section: Il-4 and Il-13 Signaling In Health And Diseasementioning

confidence: 99%

Commentary: IL-4 and IL-13 receptors and signaling

2015

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Interleukin (IL)-4 and IL-13 were discovered approximately 30 years ago and were immediately linked to allergy and atopic diseases. Since then, new roles for IL-4 and IL-13 and their receptors in normal gestation, fetal development, neurological function and in the pathogenesis of cancer and fibrosis have been appreciated. Studying IL-4/-13 and their receptors has revealed important clues about cytokine biology and lead to the development of numerous experimental therapeutics. Here we aim to highlight new discoveries and consolidate concepts in the field of IL-4 and IL-13 structure, receptor regulation, signaling and experimental therapeutics.

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Cutting Edge: STAT6 Signaling in Eosinophils Is Necessary for Development of Allergic Airway Inflammation

Cited by 23 publications

References 31 publications

Histone acetyltransferease p300 modulates TIM4 expression in dendritic cells

Histone acetyltransferease p300 modulates TIM4 expression in dendritic cells

IL‐27 signaling deficiency develops Th17‐enhanced Th2‐dominant inflammation in murine allergic conjunctivitis model

Commentary: IL-4 and IL-13 receptors and signaling

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