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IL-6 prevents Th2 cell polarization by promoting SOCS3-dependent suppression of IL-2 signaling

ABSTRACT: Defective interleukin-6 (IL-6) signaling has been associated with Th2 bias and elevated IgE. However, the underlying mechanism by which IL-6 may prevent the development of Th2-driven diseases remains unknown. Using a model of house-dust-mite (HDM)-induced Th2 differentiation and allergic airway inflammation, we show here that IL-6 signaling in allergen-specific T cells was required to prevent Th2 development and subsequent IgE response and allergic inflammation. Th2 cell lineage commitment required strong sustained IL-2 signaling. Importantly, we found that IL-6 turned off IL-2 signaling during early T cell activation and thus inhibited Th2 cell priming. Mechanistically, we found that IL-6-driven inhibition of IL-2 signaling in responding T cells was mediated by upregulation of suppressor of cytokine signaling 3 (SOCS3). Therapeutically, this mechanism can be mimicked by JAK1 inhibition. Collectively, our results identify an unrecognized mechanism that prevents the development of unwanted Th2 cell responses and associated diseases and outline potential preventive interventions.

ORGANISM(S): Mus musculus

PROVIDER: GSE212158 | GEO | 2023/04/07

REPOSITORIES: GEO

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Upper airway gene expression is an effective surrogate biomarker for Th2-driven inflammation in the lower airway

Project description:Molecular profiling studies in asthma cohorts have identified a Th2-driven asthma subtype, characterized by elevated lower airway expression of POSTN, CLCA1 and SERPINB2. To assess upper airway gene expression as a potential biomarker for lower airway Th2 inflammation, we assayed upper airway (nasal) and lower airway (bronchial) epithelial gene expression, serum total IgE, blood eosinophils and serum periostin in a cohort of 54 allergic asthmatics and 30 matched healthy controls. 23 of 51 asthmatics in our cohort were classified as âTh2 highâ based on lower airway Th2 gene signature expression. Consistent with this classification, âTh2 highâ subjects displayed elevated total IgE and blood eosinophil levels relative to âTh2 lowâ subjects. Upper airway Th2 signature expression was significantly correlated with lower airway Th2 signature expression (r=0.44), with similar strength of association as serum total IgE and blood eosinophils, known biomarkers of Th2 inflammation. In an unbiased genome-wide scan, we identified 8 upper airway genes more strongly correlated with lower airway Th2 gene signature expression (r=0.58), including Eotaxin-3 (CCL26), Galectin-10 (CLC) and Cathepsin-C (CTSC). Asthmatics classified as âTh2 highâ using this 8-gene signature show similar serum total IgE and blood eosinophil levels as âTh2 highâ asthmatics classified using lower airway Th2 gene signature expression. We have identified an 8-gene upper airway signature correlated with lower airway Th2 inflammation, which may be used as a diagnostic biomarker for Th2-driven asthma. Upper airway (nasal) and lower airway (bronchial) epithelial brushings obtained from a cohort of 54 allergic asthmatics and 30 matched healthy controls were profiled by gene expression by microarray. Subjects were assayed for gene expression, serum total IgE, blood eosinophils and serum periostin.

2015-10-23 | E-GEOD-41861 | biostudies-arrayexpress

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2016-10-03 | GSE64860 | GEO

The Effect of Steroid and ERa agonism on Th2 cells

Project description:Allergic asthma is a T helper 2 (Th2) cell-associated inflammatory disease, driven by cytokines such as IL-4, IL-5, and IL-13. Th2 cells express the G-protein-coupled receptor CRTh2, a receptor for prostaglandin D2 (PGD2) that influences Th2 function and survival. Inhaled glucocorticosteroids are the primary treatment of allergic asthma and improve asthma symptoms by inhibiting Th2 cytokine production. Women are more likely than men to have severe asthma and to have symptoms requiring a hospital visit. These findings lead us to consider a mechanism by which female sex hormones could influence Th2 cell response to glucocorticosteroid. Using whole-mRNA sequencing, we examined gene expression in primary Th2 cells following exposure to glucocorticosteroids (0.1µM) in the presence or absence of an estrogen mimic, PPT (10µM).

2022-10-19 | GSE132699 | GEO

A novel small compound SH-2251 suppresses Th2 cell-dependent airway inflammation through selective modulation of chromatin status at the Il5 gene locus

Project description:IL-5 is a key cytokine that plays an important role in the development of pathological conditions in chronic allergic inflammation. Identification of a strategy to inhibit IL-5 production is important for establishment of new therapies for allergic inflammation. We found that SH-2251, a novel thioamide-related compound, selectively inhibits the differentiation of IL-5-producing Th2 cells. SH-2251 inhibited the formation of the active histone modifications (H3K4me3, H3K9ac, H3K27ac) at the Il5 gene locus during Th2 cell differentiation. The recruitment of RNA polymerase II and the induction of Th2 cell-specific intergenic transcription between the Rad50 and Il5 gene locus was also inhibited. Furthermore, Th2 cell-driven airway inflammation in mice was suppressed by oral administration of SH-2251. We identified Gfi1 as a downstream target molecule of SH-2251 treatment. The expression of Gfi1 was dramatically decreased in SH-2251-treated Th2 cells. SH-2251-mediated inhibition of the IL-5-producing Th2 cell generation was restored by transduction of Gfi1. Thus, our study unearths SH-2251 as a novel therapeutic candidate for allergic inflammation that selectively inhibits IL-5 production. Gene expression in SH-2251-treated and untreated Th2 cells

2013-04-30 | E-GEOD-42131 | biostudies-arrayexpress

Upper airway gene expression is an effective surrogate biomarker for Th2-driven inflammation in the lower airway

Project description:Molecular profiling studies in asthma cohorts have identified a Th2-driven asthma subtype, characterized by elevated lower airway expression of POSTN, CLCA1 and SERPINB2. To assess upper airway gene expression as a potential biomarker for lower airway Th2 inflammation, we assayed upper airway (nasal) and lower airway (bronchial) epithelial gene expression, serum total IgE, blood eosinophils and serum periostin in a cohort of 54 allergic asthmatics and 30 matched healthy controls. 23 of 51 asthmatics in our cohort were classified as ‘Th2 high’ based on lower airway Th2 gene signature expression. Consistent with this classification, ‘Th2 high’ subjects displayed elevated total IgE and blood eosinophil levels relative to ‘Th2 low’ subjects. Upper airway Th2 signature expression was significantly correlated with lower airway Th2 signature expression (r=0.44), with similar strength of association as serum total IgE and blood eosinophils, known biomarkers of Th2 inflammation. In an unbiased genome-wide scan, we identified 8 upper airway genes more strongly correlated with lower airway Th2 gene signature expression (r=0.58), including Eotaxin-3 (CCL26), Galectin-10 (CLC) and Cathepsin-C (CTSC). Asthmatics classified as ‘Th2 high’ using this 8-gene signature show similar serum total IgE and blood eosinophil levels as ‘Th2 high’ asthmatics classified using lower airway Th2 gene signature expression. We have identified an 8-gene upper airway signature correlated with lower airway Th2 inflammation, which may be used as a diagnostic biomarker for Th2-driven asthma.

2015-10-23 | GSE41861 | GEO

The USP7-STAT3-granzyme-Par-1 axis regulates allergic inflammation by promoting differentiation of IL-5-producing Th2 cells

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