A mouse model of HIES reveals pro- and anti-inflammatory functions of STAT3

Steward-Tharp, Scott; Laurence, Arian; Kanno, Yuka; Kotlyar, A.G.; Villarino, Alejandro V.; Sciumé, Giuseppe; Kuchen, Stefan; Resch, Wolfgang; Wohlfert, Elizabeth A.; Jiang, Kan; Hirahara, Kiyoshi; Vahedi, Golnaz; Sun, Hongwei; Feigenbaum, Lionel; Milner, Joshua D.; Holland, Steven M.; Casellas, Rafael; Powrie, Fiona; O’Shea, John J.

doi:10.1182/blood-2013-09-523167

Cited by 76 publications

(78 citation statements)

References 47 publications

(51 reference statements)

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“…Wild type (WT) C57Bl/6, mice were obtained from Jackson Laboratory (Bar Harbor, ME) and mut- Stat3 (AD-HIES) mice with their corresponding WT littermate controls were kindly provided by Dr. J. O’Shea 29 . Mice received daily i.p.…”

Section: Methodsmentioning

confidence: 99%

Diminution of signal transducer and activator of transcription 3 signaling inhibits vascular permeability and anaphylaxis

Hox

O’Connell

Lyons

et al. 2016

Journal of Allergy and Clinical Immunology

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Background During IgE-mediated immediate hypersensitivity reactions, vascular endothelial cells permeabilize in response to mast cell mediators. We have previously demonstrated that patients and mice with STAT3 mutations (autosomal dominant-hyper IgE syndrome; AD-HIES) are partially protected from anaphylaxis. Objectives To further study the mechanism by which STAT3 contributes to anaphylaxis, and determine whether small molecule inhibition of STAT3 can prevent anaphylaxis. Methods Using unaffected and STAT3-inhibited or genetic loss of function samples, we performed histamine skin prick testing, investigated the contribution of STAT3 to animal models of anaphylaxis, measured endothelial cell permeability, gene and protein expression, and histamine receptor-mediated signaling. Results While mouse mast cell degranulation was minimally affected by STAT3 blockade, mast cell mediator-induced anaphylaxis was blunted in Stat3 mutant AD-HIES mice and in wild-type mice subjected to small molecule STAT3 inhibition. Histamine skin prick responses were diminished in AD-HIES patients. Human umbilical vein vascular endothelial cells (HUVECs) derived from patients with AD-HIES or treated with a STAT3 inhibitor failed to properly signal through Src or to appropriately dissolute the adherens junctions made up of the proteins vascular endothelial (VE)-cadherin and β-catenin. Further, we found that diminished STAT3-target mir17–92 expression in AD-HIES HUVECS is associated with increased PTEN expression, which inhibits Src, and increased E2F1 expression, which regulates β-catenin cellular dynamics. Conclusions These data demonstrate that STAT3-dependent transcriptional activity regulates critical components for the architecture and functional dynamics of endothelial junctions thus permitting vascular permeability.

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Section: Methodsmentioning

confidence: 99%

Diminution of signal transducer and activator of transcription 3 signaling inhibits vascular permeability and anaphylaxis

Hox

O’Connell

Lyons

et al. 2016

Journal of Allergy and Clinical Immunology

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“…Job’s Syndrome). A similar dichotomy is evident in mice; IL-10- and IL-10R-deficient animals develop colitis while those bearing a hypomorphic STAT3 allele common in HIES patients do not (65). Adding further complexity, the recent identification of patients with gain-of-function STAT3 mutations highlights the central role of this pathway in promoting autoimmune disease.…”

Section: Jaks and Stats In Immunity And Diseasementioning

confidence: 83%

Mechanisms of Jak/STAT Signaling in Immunity and Disease

Villarino

Kanno

Ferdinand

et al. 2015

The Journal of Immunology

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451

358

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More than 2 decades ago, experiments on the antiviral mechanisms of interferons led to the discovery of Janus kinases (JAK) and their downstream effectors, the signal transducer of activation (STAT) proteins. This pathway has since become a paradigm for membrane to nucleus signaling and has come to explain how a broad range of soluble factors, including cytokines and hormones, mediate their diverse functions. Jak/STAT research has not only impacted basic science, particularly in the context of intercellular communication and cell-extrinsic control of gene expression, but has also become a prototype for transition from bench to bedside, culminating in the development and clinical implementation of pathway-specific therapeutics. This brief review will synthesize current understanding of Jak/STAT biology while taking stock of the lessons learned and the challenges that lie ahead.

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“…A recent report described the generation of a mouse model of AD-HIES that recapitulated several aspects of human AD-HIES including elevated IgE, low Th17 cells [59], and resistance to anaphylaxis [44]. …”

Section: Germline Stat3 Loss-of-function: Hyper-ige Syndromementioning

confidence: 99%

The Ying and Yang of STAT3 in Human Disease

2015

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The transcription factor signal transducer and activator of transcription 3 (STAT3) is a critical regulator of multiple, diverse cellular processes. Heterozgyous, germline, loss-of-function mutations in STAT3 lead to the primary immune deficiency Hyper-IgE syndrome. Heterozygous, somatic, gain-of-function mutations in STAT3 have been reported in malignancy. Recently, germline, heterozygous mutations in STAT3 that confer a gain-of-function have been discovered and result in early-onset, multi-organ autoimmunity. This review summarizes what is known about the role of STAT3 in human disease.

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A mouse model of HIES reveals pro- and anti-inflammatory functions of STAT3

Cited by 76 publications

References 47 publications

Diminution of signal transducer and activator of transcription 3 signaling inhibits vascular permeability and anaphylaxis

Diminution of signal transducer and activator of transcription 3 signaling inhibits vascular permeability and anaphylaxis

Mechanisms of Jak/STAT Signaling in Immunity and Disease

The Ying and Yang of STAT3 in Human Disease

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