Signal transducer and activator of transcription 3

IntroductionIgA nephropathy is a chronic renal disease characterized by mesangial immunodeposits that contain autoantigen, which is aberrantly glycosylated IgA1 with some hinge-region O-glycans deficient in galactose. Macroscopic hematuria during an upper respiratory tract infection is common among patients with IgA nephropathy, which suggests a connection between inflammation and disease activity. Interleukin-6 (IL-6) is an inflammatory cytokine involved in IgA immune response. We previously showed that IL-6 selectively increases production of galactose-deficient IgA1 in IgA1-secreting cells from patients with IgA nephropathy.MethodsWe characterized IL-6 signaling pathways involved in the overproduction of galactose-deficient IgA1. To understand molecular mechanisms, IL-6 signaling was analyzed by kinomic activity profiling and Western blotting, followed by confirmation assays using siRNA knock-down and small-molecule inhibitors.ResultsSTAT3 was differentially activated by IL-6 in IgA1-secreting cells from patients with IgA nephropathy compared with those from healthy control subjects. Specifically, IL-6 induced enhanced and prolonged phosphorylation of STAT3 in the cells from patients with IgA nephropathy, which resulted in overproduction of galactose-deficient IgA1. This IL-6−mediated overproduction of galactose-deficient IgA1 could be blocked by small molecule inhibitors of JAK/STAT signaling.DiscussionOur results revealed that IL-6−induced aberrant activation of STAT3-mediated overproduction of galactose-deficient IgA1. STAT3 signaling pathway may thus represent a new target for disease-specific therapy of IgA nephropathy.

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“… 66 , 67 , 68 , 69 In these conditions and other diseases, treatment aimed at abnormal STAT3 signaling greatly ameliorated the symptoms. 70 , 71 …”

Section: Discussionmentioning

confidence: 99%

Inhibition of STAT3 Signaling Reduces IgA1 Autoantigen Production in IgA Nephropathy

Yamada

Huang

Raška

et al. 2017

Kidney International Reports

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“…On the other hand, STAT3 GOF mutations, inherited as autosomal dominant traits, lead to a broad spectrum of clinical phenotypes. These include early-onset T1D, autoimmune enteropathy, autoimmune cytopenia, juvenile-onset arthritis, and autoimmune interstitial lung disease (29,30). A total of six patients with STAT3 GOF and T1D have been described so far (Table 1), and five additional patients have recently been identified in Exeter, U.K. (A. Hattersley and M. Johnson, personal communication).…”

Section: T1d and Stat3 Mutationsmentioning

confidence: 99%

Type 1 Diabetes in STAT Protein Family Mutations: Regulating the Th17/Treg Equilibrium and Beyond

et al. 2019

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Improvements in the immunological, molecular, and genetic technologies such as next-generation sequencing have led to an exponential increase in the number of monogenic immune dysregulatory syndromes diagnosed, where type 1 diabetes (T1D) forms part of the autoimmune manifestations. Here, we reviewed the mutations in the signal transducer and activator of transcription (STAT) protein family, namely gain-of-function (GOF) mutations in STAT1 and STAT3 as well as STAT5b deficiency, that show strong association to T1D susceptibility. The equilibrium of T-helper 17 (Th17) and regulatory T cells (Tregs) is often found altered in patients affected by STAT GOF mutations. While the increased number of Th17 cells and the concomitant decrease in Treg cells may explain T1D in STAT3 GOF patients, the reduced number of Th17 cells found in those carrying STAT1 GOF mutations added a new level of complexity on the exact role of Th17 in the pathogenesis of T1D. Here, we describe the possible mechanisms through which STAT3 and STAT1 GOF mutations may perturb the fate and function of Th17 and Tregs and explore how this may lead to the development of T1D. We propose that the study of monogenic diseases, and in particular STAT mutations, may not only improve our understanding of the function of the human immune system but also shed light onto the pathogenic mechanisms of T1D and the genetic variants that confer predisposition to the disease.

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“…These data suggest that the pneumatocele phenotype may be due STAT3's role in mediating lung repair apart from its role in Th17 cell development. Pneumatoceles can be colonized and infected with fungi such as Aspergillus fumigatus (A. fumigatus) , which can cause significant morbidity in these subjects . The cell‐intrinsic roles of these genes are important to understand as this may aid in determining the role of bone marrow transplantation for some of these disorders.…”

Section: Lessons From Human Il‐17 Deficiency Syndromesmentioning

confidence: 99%

Updates on T helper type 17 immunity in respiratory disease

Iwanaga

Kolls

2018

Immunology

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Interleukin-17 (IL-17)-producing cells play a critical role in mucosal immunity including the respiratory tract. This review will highlight recent advances in our understanding of these cells in mucosal immunity in the lung as well as their potential pathogenic roles in respiratory diseases. The IL-17-producing cells include cd T cells, natural killer cells, group 3 innate lymphoid cells, and T helper type 17 (Th17) cells. There have been recent advances in our understanding of these cell populations in the lung as well as emerging data on how these cells are regulated in the lung. Moreover, Th17 cells may be a key component of tissue-resident memory cells that may be acquired over time or elicited by mucosal immunization that provides the host with enhanced immunity against certain pathogens.

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Signal transducer and activator of transcription 3

Cited by 58 publications

References 42 publications

Inhibition of STAT3 Signaling Reduces IgA1 Autoantigen Production in IgA Nephropathy

Inhibition of STAT3 Signaling Reduces IgA1 Autoantigen Production in IgA Nephropathy

Type 1 Diabetes in STAT Protein Family Mutations: Regulating the Th17/Treg Equilibrium and Beyond

Updates on T helper type 17 immunity in respiratory disease

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