The transcription factor Sox4 is a downstream target of signaling by the cytokine TGF-β and suppresses TH2 differentiation

Kuwahara, Makoto; Yamashita, Masakatsu; Shinoda, Kenta; Tofukuji, Soichi; Onodera, Atsushi; Shinnakasu, Ryo; Motohashi, Shinichiro; Hosokawa, Hiroyuki; Tumes, Damon J.; Iwamura, Chiaki; Lefebvre, Véronique; Nakayama, Toshinori

doi:10.1038/ni.2362

Cited by 154 publications

(147 citation statements)

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“…Numerous studies have suggested that SOX4 is over expressed in different cancers and correlative with tumor development [29,30]. The regulation effect of Sox4 on EMT is mainly related to TGF-β/Smad pathway, Wnt signaling pathway and its own transcription factor activity [31,32]. Similarly, we then performed luciferase reporter assays to determine whether miR-130a-3p could directly bind to the 3'-UTR of SOX4.…”

Section: H19 and Sox4 Are Target Genes Of Mir-130a-3pmentioning

confidence: 99%

H19 Functions as a Competing Endogenous RNA to Regulate EMT by Sponging miR-130a-3p in Glioma

Yin

Zeng

et al. 2018

Cell Physiol Biochem

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Background/Aims: Glioma is one of the most devasting tumors and confers dismal prognosis. Long noncoding RNAs(lncRNAs) have emerged as important regulators in various tumors including glioma. A classic lncRNA-H19, which is found to be highly expressed in human glioma tissues and cell lines, and is associated with tumor progression thus predicating clinical outcomes in glioma patients. However, the overall biological functions and their mechanism of H19 in glioma are not fully understood. Methods: Firstly, we analyzed H19 alterations in different grades of glioma tissues through an analysis of 5 sequencing datasets and qRT-PCR was performed to confirm the results. Next, we evaluated the effect of H19 on glioma cells migration, invasion and EMT process. Luciferase assays and RIP assays were employed to figure out the correlation of H19 and SOX4. Results: H19 was overexpressed in glioma tissues. Down-regulation of H19 led to the inhibition of migration, invasion and EMT process with a reduction in N-cadherin and Vimentin. H19 and SOX4 are both direct target of miR-130a-3p. H19 could compete with SOX4 via sponging miR-130a-3p. Conclusion: Taken together, these results provide a possible function of H19 as an oncogene in glioma tissues and provide a potential new therapeutic strategy for human glioma.

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Section: H19 and Sox4 Are Target Genes Of Mir-130a-3pmentioning

confidence: 99%

H19 Functions as a Competing Endogenous RNA to Regulate EMT by Sponging miR-130a-3p in Glioma

Yin

Zeng

et al. 2018

Cell Physiol Biochem

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“…The Smad pathway also contributes to the inhibition of Th2-cell differentiation by TGF-b, by inducing the expression of Sox4, a transcription factor that can bind to GATA-3 (Kuwahara et al 2012). Retroviral expression of wild-type Sox4, but not Sox4 mutants lacking the ability to interact with GATA-3, inhibits Th2 cytokine production in CD4 þ T cells (Kuwahara et al 2012).…”

Section: Peripheral Homeostasismentioning

confidence: 99%

Regulation of the Immune Response by TGF-β: From Conception to Autoimmunity and Infection

Sanjabi

2017

Cold Spring Harb Perspect Biol

451

306

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Transforming growth factor b (TGF-b) is a pleiotropic cytokine involved in both suppressive and inflammatory immune responses. After 30 years of intense study, we have only begun to elucidate how TGF-b alters immunity under various conditions. Under steady-state conditions, TGF-b regulates thymic T-cell selection and maintains homeostasis of the naïve T-cell pool. TGF-b inhibits cytotoxic T lymphocyte (CTL), Th1-, and Th2-cell differentiation while promoting peripheral ( p)Treg-, Th17-, Th9-, and Tfh-cell generation, and T-cell tissue residence in response to immune challenges. Similarly, TGF-b controls the proliferation, survival, activation, and differentiation of B cells, as well as the development and functions of innate cells, including natural killer (NK) cells, macrophages, dendritic cells, and granulocytes. Collectively, TGF-b plays a pivotal role in maintaining peripheral tolerance against self-and innocuous antigens, such as food, commensal bacteria, and fetal alloantigens, and in controlling immune responses to pathogens.

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“…A few studies [122,123] have shown that TGFβ-mediated prevention of Th2-cell development is due to suppressed expression of the transcription factor GATA-3, a key transcriptional activator of Th2-cell differentiation [124] . Moreover, TGFβ is able to induce the transcription factor Sox-4 and therefore negatively regulate GATA-3 function indirectly by two distinct mechanisms [125] . First, Sox-4 binds directly to GATA-3, preventing its transcriptional activity, and second, Sox-4 binds to the promoter of IL-5, a Th2 cytokine, and prevents GATA-3-mediated induction of gene expression [125] .…”

Section: Transforming Growth Factor Betamentioning

confidence: 99%

“…Moreover, TGFβ is able to induce the transcription factor Sox-4 and therefore negatively regulate GATA-3 function indirectly by two distinct mechanisms [125] . First, Sox-4 binds directly to GATA-3, preventing its transcriptional activity, and second, Sox-4 binds to the promoter of IL-5, a Th2 cytokine, and prevents GATA-3-mediated induction of gene expression [125] . In addition to suppressing proliferation, TGFβ has also been demonstrated to inhibit CD8+ T-cell effector functions through down-regulation of the expression of several essential CTL effector molecules such as perforin [126] , Fas ligand (FasL) [127] and IFNγ [128,129] .…”

Section: Transforming Growth Factor Betamentioning

confidence: 99%

Secretion of immunoregulatory cytokines by mesenchymal stem cells

Kyurkchiev

Bochev

Ivanova‐Todorova

et al. 2014

WJSC

520

392

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According to the minimal criteria of the International Society of Cellular Therapy, mesenchymal stem cells (MSCs) are a population of undifferentiated cells defined by their ability to adhere to plastic surfaces when cultured under standard conditions, express a certain panel of phenotypic markers and can differentiate into osteogenic, chondrogenic and adipogenic lineages when cultured in specific inducing media. In parallel with their major role as undifferentiated cell reserves, MSCs have immunomodulatory functions which are exerted by direct cell-to-cell contacts, secretion of cytokines and/or by a combination of both mechanisms. There are no convincing data about a principal difference in the profile of cytokines secreted by MSCs isolated from different tissue sources, although some papers report some quantitative but not qualitative differences in cytokine secretion. The present review focuses on the basic cytokines secreted by MSCs as described in the literature by which the MSCs exert immunodulatory effects. It should be pointed out that MSCs themselves are objects of cytokine regulation. Hypothetical mechanisms by which the MSCs exert their immunoregulatory effects are also discussed in this review. These mechanisms may either influence the target immune cells directly or indirectly by affecting the activities of predominantly dendritic cells. Chemokines are also discussed as participants in this process by recruiting cells of the immune systems and thus making them targets of immunosuppression. This review aims to present and discuss the published data and the personal experience of the authors regarding cytokines secreted by MSCs and their effects on the cells of the immune system. © 2014 Baishideng Publishing Group Inc. All rights reserved.Key words: Mesenchymal stem cells; Immunomodulation; Cytokines; Chemokines; Dendritic cells Core tip: Autoimmune diseases affect approximately 5% of the human population, leading to serious disability and effective methods to treat these diseases are still not perfect. Mesenchymal stem cells (MSCs) are assumed to be promising agents, both for regenerative medicine and cell therapy for autoimmune disorders. Under the influence of some factors, mesenchymal stem cells secrete cytokines which induce suppression of the immune response. Studies on the secreted cytokines and the precise mechanisms involved in these suppressive mechanisms would create possibilities for efficient application of MSCs as a therapeutic means for treatment of autoimmune diseases.Kyurkchiev D, Bochev I, Ivanova-Todorova E, Mourdjeva M, REVIEWSubmit a

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The transcription factor Sox4 is a downstream target of signaling by the cytokine TGF-β and suppresses TH2 differentiation

Cited by 154 publications

References 50 publications

H19 Functions as a Competing Endogenous RNA to Regulate EMT by Sponging miR-130a-3p in Glioma

H19 Functions as a Competing Endogenous RNA to Regulate EMT by Sponging miR-130a-3p in Glioma

Regulation of the Immune Response by TGF-β: From Conception to Autoimmunity and Infection

Secretion of immunoregulatory cytokines by mesenchymal stem cells

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