Modulation of STAT‐3 in rheumatoid synovial T cells suppresses Th17 differentiation and increases the proportion of Treg cells

Ju, Ji Hyeon; Heo, Yu-Jung; Cho, Mi‐La; Jhun, JooYeon; Park, Jin‐Sil; Lee, Seon‐Yeong; Oh, Hye-Jwa; Moon, Su‐Jin; Kwok, Seung‐Ki; Park, Kyung-Su; Park, Sung-Hwan; Kim, Ho-Youn

doi:10.1002/art.34601

Cited by 72 publications

(48 citation statements)

References 34 publications

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“…The inhibition of STAT5 has the counter effects [108,109]. In the same study, no change was found to be induced by STAT3 or STAT5 siRNA in the production of Th1 versus Th2 signature cytokines [108], suggesting that these signalling pathways could provide novel target molecules for the control of Treg cells in the treatment of autoimmune disease, including vitiligo.…”

Section: Regulatory T Cell/th17 Cell Balancementioning

confidence: 93%

Section: Regulatory T Cell/th17 Cell Balancementioning

confidence: 99%

“…Inhibiting STAT3 using siRNA has been shown to significantly increase the proportion of Treg cells and decrease the proportion of Th17 cells in the CD4 + T cell population from the peripheral blood and synovial fluid of patients with rheumatoid arthritis [108,109]. The inhibition of STAT5 has the counter effects [108,109]. In the same study, no change was found to be induced by STAT3 or STAT5 siRNA in the production of Th1 versus Th2 signature cytokines [108], suggesting that these signalling pathways could provide novel target molecules for the control of Treg cells in the treatment of autoimmune disease, including vitiligo.…”

Section: Regulatory T Cell/th17 Cell Balancementioning

confidence: 99%

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Regulatory T cells in vitiligo: Implications for pathogenesis and therapeutics

Dwivedi

Kemp

Laddha

et al. 2015

Autoimmunity Reviews

111

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Vitiligo is a hypomelanotic autoimmune skin disease arising from a breakdown in immunological self-tolerance, which leads to aberrant immune responses against melanocytes.Regulatory T cells (Tregs) are crucial to the development of self-tolerance and so are major foci in the study of autoimmune pathogenesis of vitiligo. This review will summarise recent findings concerning the role of Tregs in the pathogenesis of vitiligo. In addition, as antigen-specific Tregs are a potential route for the reinstatement of immune tolerance, new strategies that expand or induce de novo generation of Tregs and which are currently being investigated as therapies for other autoimmune diseases, will be discussed. These approaches will highlight the opportunities for Treg cell-based therapeutics in vitiligo.4

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Section: Regulatory T Cell/th17 Cell Balancementioning

confidence: 93%

Section: Regulatory T Cell/th17 Cell Balancementioning

confidence: 99%

Section: Regulatory T Cell/th17 Cell Balancementioning

confidence: 99%

See 1 more Smart Citation

Regulatory T cells in vitiligo: Implications for pathogenesis and therapeutics

Dwivedi

Kemp

Laddha

et al. 2015

Autoimmunity Reviews

111

View full text Add to dashboard Cite

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“…A decreased miR-21 expression was found to be associated closely with decreased mRNA levels of STAT-5, which is an important transcription factor for T reg differentiation [75]. In addition, miR-21 can target the STAT-3 gene, which plays a pivotal role in determining Th17 differentiation during RA [76,77]. Therefore, under-expression of miR-21 in RA patients could increase STAT-3 and decrease STAT-5 expression and, in turn, facilitate the differentiation of Th17 and inhibit the differentiation of T reg cells.…”

Section: Aberrant Expression Of Mirnasmentioning

confidence: 99%

Immunopathogenesis of systemic lupus erythematosus and rheumatoid arthritis: the role of aberrant expression of non-coding RNAs in T cells

Lai

Koo

et al. 2017

Clinical and Experimental Immunology

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Summary Non-coding RNAs (ncRNAs), including microRNAs (miRNAs) and long non-coding RNAs (lncRNAs), are RNA molecules that do not translate into protein. Both miRNAs and lncRNAs are known to regulate gene expression and to play an essential role in T cell differentiation and function. Both systemic lupus erythematosus (SLE), a prototypic systemic autoimmune disease, and rheumatoid arthritis (RA), a representative disease of inflammatory arthritis, are characterized by a complex dysfunction in the innate and adaptive immunity. T cells play a central role in cell-mediated immune response and multiple defects in T cells from patients with SLE and RA have been observed. Abnormality in T cell signalling, cytokine and chemokine production, T cell activation and apoptosis, T cell differentiation and DNA methylation that are associated closely with the aberrant expression of a number of miRNAs and lncRNAs have been implicated in the immunopathogenesis of SLE and RA. This review aims to provide an overview of the current state of research on the abnormal expression of miRNAs and lncRNAs in T cells and their roles in the immunopathogenesis of SLE and RA. In addition, by comparing the differences in aberrant expression of miRNAs and lncRNAs in T cells between patients with SLE and RA, controversial areas are highlighted that warrant further investigation.

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“…In addition, the development of pathogenic Th17 cell responses, causing colitis/inflammatory bowel disease, is dependent on STAT3 (24). In RA patients, STAT3 expression positively correlates with synovitis and enhances the Th17-differentiation potential of RA synovial T cells (25). Chromatin immunoprecipitation sequencing studies revealed that STAT3 directly regulates a number of Th17 cell response genes, including RORC, RORa, IL-17F, IL-21, and IL-17A itself, explaining its critical role in promoting Th17 responses (24).…”

Section: T Helper 17 Cells Are a Subset Of Cd4mentioning

confidence: 99%

A Negative Feedback Loop Mediated by STAT3 Limits Human Th17 Responses

Purvis

Anderson

Young

et al. 2014

The Journal of Immunology

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The transcription factor STAT3 is critically required for the differentiation of Th17 cells, a T cell subset involved in various chronic inflammatory diseases. In this article, we report that STAT3 also drives a negative-feedback loop that limits the formation of IL-17–producing T cells within a memory population. By activating human memory CD4+CD45RO+ T cells at a high density (HiD) or a low density (LoD) in the presence of the pro-Th17 cytokines IL-1β, IL-23, and TGF-β, we observed that the numbers of Th17 cells were significantly higher under LoD conditions. Assessment of STAT3 phosphorylation revealed a more rapid and stronger STAT3 activation in HiD cells than in LoD cells. Transient inhibition of active STAT3 in HiD cultures significantly enhanced Th17 cell numbers. Expression of the STAT3-regulated ectonucleotidase CD39, which catalyzes ATP hydrolysis, was higher in HiD, than in LoD, cell cultures. Interestingly, inhibition of CD39 ectonucleotidase activity enhanced Th17 responses under HiD conditions. Conversely, blocking the ATP receptor P2X7 reduced Th17 responses in LoD cultures. These data suggest that STAT3 negatively regulates Th17 cells by limiting the availability of ATP. This negative-feedback loop may provide a safety mechanism to limit tissue damage by Th17 cells during chronic inflammation. Furthermore, our results have relevance for the design of novel immunotherapeutics that target the STAT3-signaling pathway, because inhibition of this pathway may enhance, rather than suppress, memory Th17 responses.

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Modulation of STAT‐3 in rheumatoid synovial T cells suppresses Th17 differentiation and increases the proportion of Treg cells

Abstract: Objective. To investigate the impact of STAT-3-mediated regulation on Th17 differentiation in patients with rheumatoid arthritis (RA).Methods. CD4؉ T cells isolated from peripheral blood (

Cited by 72 publications

References 34 publications

Regulatory T cells in vitiligo: Implications for pathogenesis and therapeutics

Regulatory T cells in vitiligo: Implications for pathogenesis and therapeutics

Immunopathogenesis of systemic lupus erythematosus and rheumatoid arthritis: the role of aberrant expression of non-coding RNAs in T cells

A Negative Feedback Loop Mediated by STAT3 Limits Human Th17 Responses

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