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

ABSTRACT: 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

ORGANISM(S): Mus musculus

SUBMITTER: Junpei Suzuki

PROVIDER: E-GEOD-42131 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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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.

2013-04-30 | GSE42131 | GEO

Genome-wide analysis reveals unique regulation of transcription of Th2-specific genes by GATA3

Project description:Differentiation of naive CD4 T cells into type 2 helper (Th2) cells is accompanied by chromatin remodeling and increased expression of a set of Th2-specific genes including those encoding Th2 cytokines. IL-4-mediated STAT6 activation induces high levels of transcription of GATA3, a master regulator of Th2 cell differentiation, and enforced expression of GATA3 induces Th2 cytokine expression. However, it remains unclear whether the expression of other Th2-specific genes is induced directly by GATA3. A genome-wide unbiased ChIP-seq analysis revealed that GATA3 bound to 1,279 genes selectively in Th2 cells, and 101 genes in both Th1 and Th2 cells. Simultaneously, we identified 26 highly Th2-specific STAT6-dependent inducible genes by a DNA microarray analysis-based three-step selection processes, and among them 17 genes showed GATA3 binding. We assessed dependency on GATA3 for the transcription of these 26 Th2-specific genes, and 10 genes showed increased transcription in a GATA3-dependent manner while 16 genes showed no significant responses. The transcription of the 16 GATA3-nonresponding genes was clearly increased by the introduction of an active form of STAT6, STAT6VT. Therefore, although GATA3 has been recognized as a master regulator of Th2 cell differentiation, many Th2-specific genes are not regulated by GATA3 itself but in collaboration with STAT6. Th1 and Th2 subsets are profiled for mRNA expression Examination of GATA3-binding and 3 different histone modifications in Th1 and Th2 cells.

2011-03-31 | E-GEOD-28292 | biostudies-arrayexpress

Identification of a new pathway for Th1 cell development induced by cooperative stimulation with IL-4 and TGFbeta [Affymetrix]

Project description:IL-4 plays an important role in the induction of Th2 and Th9 cells as well as in the inhibition of Th1 cell generation. We herein show that a combination of IL-4 and TGFbeta augment the development of Th1 cells that express CD103 (CD103+ Th1 cells) if IFNgamma is present. The T-box containing transcription factor, eomesodermin (Eomes) is preferentially expressed in CD103+ Th1 cells, and is involved in IFNgamma production. The induction of T-bet during early T cell activation is essential for the formation of the active chromatin at both the Eomes and IFNgamma gene loci. TGFbeta is required for the induction of Eomes and CD103, as well as the inhibition of Th2 cytokine expression. In addition, IL-4 induces Eomes transcription through activation of the Stat6 signaling pathway. IFNgamma-producing CD103+ Th1 cells are detected in the IEL of normal mice, and their numbers significantly decrease in Tbet- and Stat6-deficient mice. These results represent the first molecular mechanism of IL-4/TGFbeta-dependent augmentation of Th1 cell generation, and raise the possibility that IL-4 and TGFbeta may simultaneously enhance the Th1 cell-mediated immune responses under certain cytokine conditions. CD103+ Th1 and Th1 cells are profiled for mRNA expression

2012-03-17 | E-GEOD-36520 | biostudies-arrayexpress

Genome-wide gene expression profiling revealed a critical role for GATA3 in the maintenance of the Th2 cell identity

Project description:Functionally polarized CD4+ T helper (Th) cells such as Th1, Th2 and Th17 cells are central to the regulation of acquired immunity. However, the molecular mechanisms governing the maintenance of the polarized functions of Th cells remain unclear. GATA3, a master regulator of Th2 cell differentiation, initiates the expressions of Th2 cytokine genes and other Th2-specific genes. GATA3 also plays important roles in maintaining Th2 cell function and in continuous chromatin remodeling of Th2 cytokine gene loci. However, it is unclear whether continuous expression of GATA3 is required to maintain the expression of various other Th2-specific genes. In this report, genome-wide DNA gene expression profiling revealed that GATA3 expression is critical for the expression of a certain set of Th2-specific genes. We demonstrated that GATA3 dependency is reduced for some Th2-specific genes in fully developed Th2 cells compared to that observed in effector Th2 cells, whereas it is unchanged for other genes. Moreover, effects of a loss of GATA3 expression in Th2 cells on the expression of cytokine and cytokine receptor genes were examined in detail. A critical role of GATA3 in the regulation of Th2-specific gene expression is confirmed in in vivo generated antigen-specific memory Th2 cells. Therefore, GATA3 is required for the continuous expression of the majority of Th2-specific genes involved in maintaining the Th2 cell identity. Mock-transfected and GATA3 siRNA-transfected Th2 and Th2-4th cells are profiled for mRNA expression

2013-04-19 | E-GEOD-46185 | biostudies-arrayexpress

Identification of a new pathway for Th1 cell development induced by cooperative stimulation with IL-4 and TGFbeta [Agilent]

Project description:IL-4 plays an important role in the induction of Th2 and Th9 cells as well as in the inhibition of Th1 cell generation. We herein show that a combination of IL-4 and TGFbeta augment the development of Th1 cells that express CD103 (CD103+ Th1 cells) if IFNgamma is present. The T-box containing transcription factor, eomesodermin (Eomes) is preferentially expressed in CD103+ Th1 cells, and is involved in IFNgamma production. The induction of T-bet during early T cell activation is essential for the formation of the active chromatin at both the Eomes and IFNgamma gene loci. TGFbeta is required for the induction of Eomes and CD103, as well as the inhibition of Th2 cytokine expression. In addition, IL-4 induces Eomes transcription through activation of the Stat6 signaling pathway. IFNgamma-producing CD103+ Th1 cells are detected in the IEL of normal mice, and their numbers significantly decrease in Tbet- and Stat6-deficient mice. These results represent the first molecular mechanism of IL-4/TGFbeta-dependent augmentation of Th1 cell generation, and raise the possibility that IL-4 and TGFbeta may simultaneously enhance the Th1 cell-mediated immune responses under certain cytokine conditions. Th9+IFNgamma and Th9 cells are profiled for mRNA expression

2012-03-17 | E-GEOD-36554 | biostudies-arrayexpress

A regulatory CD9+ B cell subset controls HDM-induced allergic airway inflammation

Project description:Background: A specific subset of regulatory IL-10 producing B cells has been extensively studied in autoimmune and inflammatory pathologies. These cells are able to constrain exacerbated inflammation by inhibiting T cell mediated responses and maturation of antigen presenting cells. In allergic diseases, observations that increase of regulatory B cells is necessary for allergen tolerance suggest that development of allergic asthma would be associated with a defect in the regulatory B cells compartment. Objective: We sought to (i) characterize regulatory IL-10+ regulatory B cell subset in Balb/c mice by microarray and flow cytometry and (ii) investigate their regulatory capacity in vivo in a house dust mite model of allergic asthma. Results: We identified an IL-10 producing B cells subset able to control T cell proliferation in vitro in both control and asthmatic mice. This subset is decreased in allergic mice. IL-10+ Breg cells express high levels of CD9 and upregulate CD70 and CD73 after activation. Expression of CD9 allows identifying more than 50% of Bregs. Interestingly CD9+ B cells inhibit TH2-TH17 allergic airway inflammation in vivo after adoptive transfer in an IL-10 dependent manner. Conclusions: Herein, we demonstrate that induction of allergic asthma dampens the generation of Bregs contributing to exacerbated airway inflammation. We identified a distinct CD9+ Breg-cell population decreased in lung of HDM mice and able to control asthma and allergic airway inflammation by producing IL-10 after adoptive transfer. This study points B cells as an interesting therapeutic target in allergic asthma. IL-10+ B cells (n=3) and 3 IL-10- B cells (n=3) in control mice + IL-10+ B cells (n=3) and 3 IL-10- B cells (n=3) from asthmatic allergic (HDM) mice

2015-03-01 | E-GEOD-57772 | biostudies-arrayexpress

The Menin–Bach2 axis is critical for regulating CD4 T cell senescence and homeostasis

Project description:Although CD4 T cell senescence plays an important role in immunosenescence, the mechanisms remain unclear. We found that T cell-specific Menin deficiency results in the premature senescence of CD4 T cells, accompanied by the senescence-associated secretory phenotype (SASP) after antigenic stimulation. TH1 and TH2 differentiation was dysregulated in Menin-knockout CD4 T cells. Bach2, which regulates SASP and TH differentiation, was identified as a Menin target. Menin binds to the Bach2 locus, and controls its expression through maintenance of histone acetylation. These findings reveal a critical role of the Menin-Bach2 pathway in regulating CD4 T cell senescence and homeostasis, thus indicating the involvement of this pathway in the inhibition of age-associated development of inflammatory diseases, which are induced by immunosenescence. Examination of transcriptional factor Menin binding and histone modefications in Menin WT and KO CD4 T cells

2014-03-27 | E-GEOD-53831 | biostudies-arrayexpress

Identification of a new pathway for Th1 cell development induced by cooperative stimulation with IL-4 and TGFbeta

Project description:This SuperSeries is composed of the following subset Series: GSE36520: Identification of a new pathway for Th1 cell development induced by cooperative stimulation with IL-4 and TGFbeta [Affymetrix] GSE36554: Identification of a new pathway for Th1 cell development induced by cooperative stimulation with IL-4 and TGFbeta [Agilent] Refer to individual Series

2012-03-17 | E-GEOD-36556 | biostudies-arrayexpress

IL-5+ and IL-5- memory Th2

Project description:We used microarray analysis to identify specific molecular mechanisms controlling IL-5 transcription in memory Th2 cells. IL-5+ and IL-5- memory Th2 cells were selected for RNA extraction and hybridization on Affymetrix microarrays.

2011-11-07 | E-GEOD-33516 | biostudies-arrayexpress

Specification of innate type-2 lymphocytes by the transcriptional determinant Gfi1

Project description:Innate type-2 lymphoid cells (ILC2s) function in immune responses against helminth parasites and are implicated in allergic inflammation and asthma. ILC2s are activated by the epithelial-derived cytokines IL-33 and IL-25 and are major sources of the type-2 cytokines IL-5 and IL-13. We show that the transcription factor Gfi1 promotes the generation of ILC2s and controls their responsiveness during Nippostrongylus brasiliensis infection as well as IL-33- or IL-25-instigated inflammation. Gfi1 directly activates Il1rl1, which encodes the IL-33 receptor. IL- 33 signaling upregulates Gfi1, thereby constituting a positive feedback loop that enables rapid and robust expansion of ILC2s in response to IL-33 signaling. Loss of Gfi1 in activated ILC2s results in an unusual effector state involving derepression of the IL-17 inflammatory program and co-expression of IL-13 with IL-17. ChIPseq reveals key Gfi1 targeted genes that are activated or repressed to maintain ILC2 identity. We propose that Gfi1 functions as a shared determinant within innate and adaptive immune cells to specify type-2 responses, while actively repressing the IL-17 effector state. ILC2s (~3 x 10^7 cells) were sorted from the MLN of IL-25-treated mice. Chromatin fragments bound by Gfi1 were subject to ChIP using Gfi1 antibodies and followed by high-throughput sequencing.

2013-09-13 | E-GEOD-50806 | biostudies-arrayexpress

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