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STAT4 activation by leukemia inhibitory factor confers a therapeutic effect on intestinal inflammation [array]

ABSTRACT: STAT4 activation by leukemia inhibitory factor confers a therapeutic effect on intestinal inflammation [array]

PROVIDER: PRJNA510667 | ENA |

REPOSITORIES: ENA

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STAT4 activation by leukemia inhibitory factor confers a therapeutic effect on intestinal inflammation

Project description:STAT4 activation by leukemia inhibitory factor confers a therapeutic effect on intestinal inflammation

| PRJNA510664 | ENA

STAT4 activation by leukemia inhibitory factor confers a therapeutic effect on intestinal inflammation [array]

Project description:T helper 17 (Th17) cell differentiation triggered by interleukin-6 (IL-6) via STAT3 activation promotes inflammation in inflammatory bowel disease (IBD) patients. However, leukemia inhibitory factor (LIF), an IL-6 family cytokine, restricts inflammation by blocking Th17 cell differentiation via an unknown mechanism. Here, we report that microbiota dysregulation promotes LIF secretion by intestinal epithelial cells (IECs) in a mouse colitis model. LIF greatly activates STAT4 phosphorylation on multiple SPXX elements within the C-terminal transcription regulation domain. STAT4 and STAT3 act reciprocally on both canonical cis-inducible elements (SIEs) and noncanonical “AGG” elements at different loci. In lamina propria lymphocytes (LPLs), STAT4 activation by LIF blocks STAT3-dependent Il-17a/Il-17f promoter activation, whereas in IECs, LIF bypasses the extraordinarily low level of STAT4 to induce YAP gene expression via STAT3 activation. In addition, we found that the administration of LIF is sufficient to restore microbiome homeostasis. Thus, LIF effectively inhibits Th17 accumulation and promotes repair of damaged intestinal epithelium in inflamed colon, and serves as a potential therapy for IBD.

2019-12-18 | GSE124078 | GEO

STAT4 activation by leukemia inhibitory factor confers a therapeutic effect on intestinal inflammation [RNA-Seq]

Project description:STAT4 activation by leukemia inhibitory factor confers a therapeutic effect on intestinal inflammation [RNA-Seq]

| PRJNA510663 | ENA

STAT4 activation by leukemia inhibitory factor confers a therapeutic effect on intestinal inflammation [RNA-Seq]

Project description:We report that microbiota dysregulation promotes LIF secretion by intestinal epithelial cells (IECs) in a mouse colitis model. LIF greatly activates STAT4 phosphorylation on multiple SPXX elements within the C-terminal transcription regulation domain. STAT4 and STAT3 act reciprocally on both canonical cis-inducible elements (SIEs) and noncanonical “AGG” elements at different loci. In lamina propria lymphocytes (LPLs), STAT4 activation by LIF blocks STAT3-dependent Il-17a/Il-17f promoter activation, whereas in IECs, LIF bypasses the extraordinarily low level of STAT4 to induce YAP gene expression via STAT3 activation. In addition, we found that the administration of LIF is sufficient to restore microbiome homeostasis. Thus, LIF effectively inhibits Th17 accumulation and promotes repair of damaged intestinal epithelium in inflamed colon, and serves as a potential therapy for IBD.

2019-12-18 | GSE124077 | GEO

STAT4 activation by leukemia inhibitory factor confers a therapeutic effect on intestinal inflammation

Project description:T helper 17 (Th17) cell differentiation triggered by interleukin-6 (IL-6) via STAT3 activation promotes inflammation in inflammatory bowel disease (IBD) patients. However, leukemia inhibitory factor (LIF), an IL-6 family cytokine, restricts inflammation by blocking Th17 cell differentiation via an unknown mechanism. Here, we report that microbiota dysregulation promotes LIF secretion by intestinal epithelial cells (IECs) in a mouse colitis model. LIF greatly activates STAT4 phosphorylation on multiple SPXX elements within the C-terminal transcription regulation domain. STAT4 and STAT3 act reciprocally on both canonical cis-inducible elements (SIEs) and noncanonical "AGG" elements at different loci. In lamina propria lymphocytes (LPLs), STAT4 activation by LIF blocks STAT3-dependent Il-17a/Il-17f promoter activation, whereas in IECs, LIF bypasses the extraordinarily low level of STAT4 to induce YAP gene expression via STAT3 activation. In addition, we found that the administration of LIF is sufficient to restore microbiome homeostasis. Thus, LIF effectively inhibits Th17 accumulation and promotes repair of damaged intestinal epithelium in inflamed colon, serves as a potential therapy for IBD.

| S-SCDT-EMBOJ-2018-99595 | biostudies-other

STAT4 activation by leukemia inhibitory factor confers a therapeutic effect on intestinal inflammation.

Project description:T helper 17 (Th17)-cell differentiation triggered by interleukin-6 (IL-6) via STAT3 activation promotes inflammation in inflammatory bowel disease (IBD) patients. However, leukemia inhibitory factor (LIF), an IL-6 family cytokine, restricts inflammation by blocking Th17-cell differentiation via an unknown mechanism. Here, we report that microbiota dysregulation promotes LIF secretion by intestinal epithelial cells (IECs) in a mouse colitis model. LIF greatly activates STAT4 phosphorylation on multiple SPXX elements within the C-terminal transcription regulation domain. STAT4 and STAT3 act reciprocally on both canonical cis-inducible elements (SIEs) and noncanonical "AGG" elements at different loci. In lamina propria lymphocytes (LPLs), STAT4 activation by LIF blocks STAT3-dependent Il17a/Il17f promoter activation, whereas in IECs, LIF bypasses the extraordinarily low level of STAT4 to induce YAP gene expression via STAT3 activation. In addition, we found that the administration of LIF is sufficient to restore microbiome homeostasis. Thus, LIF effectively inhibits Th17 accumulation and promotes repair of damaged intestinal epithelium in inflamed colon, serves as a potential therapy for IBD.

| S-EPMC6418461 | biostudies-literature

STAT4 activation by leukemia inhibitory factor confers a therapeutic effect on intestinal inflammation

Project description:This SuperSeries is composed of the SubSeries listed below.

2019-12-18 | GSE124079 | GEO

Divergent roles for STAT4 in shaping effector differentiation of ILC1 and NK cells during gut inflammation II

Project description:Natural killer (NK) cells and type 1 innate lymphoid cells (ILC1) require the transcription factor STAT4 to elicit rapid effector responses and protect against pathogens. Herein, by combining genetic and transcriptomic approaches, we revealed that STAT4 played an unexpected divergent role in regulating effector differentiation of murine ILC1 and NK cells, during intestinal inflammation. Stat4 deletion in Ncr1-expressing cells led to an increased generation of cytotoxic ILC1 in the inflamed large intestine. By contrast, Stat4-deficient NK cells showed impaired terminal differentiation, characterized by lower levels of IRF-8 and KLRG1. STAT4 expression in NCR+ innate lymphocytes restrained gut inflammation and controlled both systemic IFN-g levels and the number of type 2 adaptive T cells in the large intestine. Collectively our data shed light on shared and distinctive mechanisms of transcriptional regulation driven by STAT4 in NK cells and ILC1 required for protection during intestinal inflammation.

2023-09-28 | GSE210977 | GEO

Divergent roles for STAT4 in shaping effector differentiation of ILC1 and NK cells during gut inflammation I

2023-09-28 | GSE210483 | GEO

Title: An IL-23-STAT4 Axis Regulates Classical Dendritic Cell Expansion and Function in Experimental Autoimmune Encephalomyelitis

Project description:The signal transducer and activator of transcription 4 (STAT4) promotes protective immunity and autoimmunity downstream of pro-inflammatory cytokines including IL-12 and IL-23. In experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis (MS), Stat4-/- mice are resistant to the development of inflammation and paralysis. Here, we examined cell-type requirements and found that in addition to T cells, STAT4 is required in dendritic cells for development of EAE. Deficiency of STAT4 in CD11c-expressing cells resulted in decreased T cell priming and inflammation in the CNS. EAE susceptibility was recovered following adoptive transfer of wild type bone marrow-derived DC to mice with STAT4-deficient DCs, but not adoptive transfer of STAT4- or IL-23R-deficient DCs. Single cell RNA-seq identified STAT4-dependent genes in DC subsets that paralleled a signature in MS patient DCs. Together, these data define a novel IL-23/DC/STAT4 pathway in DCs that could be a key to novel therapeutic targets in MS.

2024-07-17 | GSE243202 | GEO

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