Analysis of TGFβ1 and IL-10 Transcriptional Regulation in CTCL Cells by Chromatin Immunoprecipitation

Chang, Tzu‐Pei; Kim, Myra; Vancurova, Ivana

doi:10.1007/978-1-4939-0928-5_30

Cited by 10 publications

(12 citation statements)

References 26 publications

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“…45 DMF treatment inhibits CTCL tumor growth in subcutaneous and orthotopic xenograft mouse models To confirm our findings in vivo, we established a subcutaneous and an intradermal orthotopic CTCL xenograft mouse model by injecting HH cells into NSG mice. The latter model closely represents CTCL cell localization in humans.…”

Section: Dmf Induces Cell Death In Patient-derived Ctcl and Ctcl Cellmentioning

confidence: 57%

Dimethyl fumarate restores apoptosis sensitivity and inhibits tumor growth and metastasis in CTCL by targeting NF-κB

Nicolay

Müller‐Decker

Schroeder

et al. 2016

Blood

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Key Points• DMF induces specific cell death in CTCL cells and inhibits CTCL tumor growth and metastasis in vivo via inhibition of NF-kB.• DMF therefore represents a promising, nontoxic novel therapeutic approach to treating CTCL.Despite intensive efforts in recent years, a curative therapy for cutaneous T-cell lymphoma (CTCL) has not yet been developed. Therefore, the establishment of new therapeutic approaches with higher efficacy rates and milder side effects is strongly desired. A characteristic feature of the malignant T-cell population in CTCL is resistance toward cell death resulting from constitutive NF-kB activation. Therefore, NF-kBdependent cell death resistance represents an interesting therapeutic target in CTCL because an NF-kB-directed therapy would leave bystander T cells widely unaffected. We investigated the effects of dimethyl fumarate (DMF) on CTCL cells in vitro and in vivo. DMF induced cell death in primary patient-derived CD4 1 cells and CTCL cell lines, but hardly in T cells from healthy donors. DMF-induced cell death was linked specifically to NF-kB inhibition. To study the impact of DMF in vivo, we developed 2 CTCL xenograft mouse models with different cutaneous localizations of the T-cell infiltrate. DMF treatment delayed the growth of CTCL tumors and prevented formation of distant metastases. In addition, DMF induced increased cell death in primary CTCL tumors and in liver metastases. In summary, DMF treatment represents a remarkable therapeutic option in CTCL because it restores CTCL apoptosis in vitro and in preclinical models in vivo and prevents spreading of the disease to distant sites. DMF treatment is of particular promise in CTCL because DMF is already in successful clinical use in the treatment of psoriasis and multiple sclerosis allowing fast translation into clinical studies in CTCL. (Blood. 2016;128(6):805-815)

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Section: Dmf Induces Cell Death In Patient-derived Ctcl and Ctcl Cellmentioning

confidence: 57%

Dimethyl fumarate restores apoptosis sensitivity and inhibits tumor growth and metastasis in CTCL by targeting NF-κB

Nicolay

Müller‐Decker

Schroeder

et al. 2016

Blood

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“…ChIP analysis was performed as described (51). Briefly, proteins and DNA were cross-linked by formaldehyde, cells were washed and sonicated.…”

Section: Methodsmentioning

confidence: 99%

Bortezomib Inhibits Expression of TGF-β1, IL-10, and CXCR4, Resulting in Decreased Survival and Migration of Cutaneous T Cell Lymphoma Cells

Chang

Poltoratsky

Vancurova

2015

The Journal of Immunology

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Increased expression of the immuno-suppressive cytokines, transforming growth factor-β1 (TGFβ1) and interleukin-10 (IL-10), is a hallmark of the advanced stages of cutaneous T cell lymphoma (CTCL), where it has been associated with suppressed immunity, increased susceptibility to infections, and diminished antitumor responses. Yet, little is known about the transcriptional regulation of TGFβ1 and IL-10 in CTCL, and about their function in regulating the CTCL cell responses. Here, we show that TGFβ1 and IL-10 expression in CTCL cells is regulated by NFκB, and suppressed by bortezomib (BZ), which has shown promising results in the treatment of CTCL. However, while the TGFβ1 expression is IκBα-dependent and is regulated by the canonical pathway, the IL-10 expression is IκBα-independent, and its inhibition by BZ is associated with increased promoter recruitment of p52 that characterizes the non-canonical pathway. TGFβ1 suppression decreases CTCL cell viability and increases apoptosis, and adding exogenous TGFβ1 increases viability of BZ-treated CTCL cells, indicating TGFβ1 pro-survival function in CTCL cells. In addition, TGFβ1 suppression increases expression of the pro-inflammatory cytokines IL-8 and IL-17 in CTCL cells, suggesting that TGFβ1 also regulates the IL-8 and IL-17 expression. Importantly, our results demonstrate that BZ inhibits expression of the chemokine receptor CXCR4 in CTCL cells, resulting in their decreased migration, and that the CTCL cell migration is mediated by TGFβ1. These findings provide the first insights into the BZ-regulated TGFβ1 and IL-10 expression in CTCL cells, and indicate that TGFβ1 has a key role in regulating CTCL survival, inflammatory gene expression, and migration.

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“…IL‐10‐producing B cells have immune regulatory functions. Patients with allergic, autoimmune, or other inflammatory diseases may benefit from the IL‐10‐producing B cells, while patients with tumours do not; IL‐10 suppresses the antitumour immune response to promote tumour growth . Thus, to find the causative factors of the aberrant IL‐10 expression in B cells is of significance.…”

Section: Discussionmentioning

confidence: 99%

“…Patients with allergic, 18 autoimmune, 19 or other inflammatory diseases 20 may benefit from the IL-10-producing B cells, 21 while patients with tumours do not; IL-10 suppresses the antitumour immune response to promote tumour growth. 22 VitD is an activator of VDR. 24 The data also show that using VDR agonists down regulated the IL-10 expression in the peripheral B cells collected from PGT patients, suggesting that the IL-10 expression in B cells of patients with PGT is reversible, and to use VDR agonists may improve the immunologic environment in PGT patients.…”

Section: Discussionmentioning

confidence: 99%

Vitamin D insufficiency correlates with peripheral B10 cells in patients with pituitary tumours

Wang

et al. 2017

Cell Biochemistry & Function

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The mechanism of pituitary gland tumour (PGT) is unclear. Aberrant immune tolerance is associated with the pathogenesis of tumour. Vitamin D and vitamin D receptor (VDR) are involved in the immune regulation. Interleukin (IL)-10 is one of the important immune regulatory molecules. This study aims to elucidate the role of VDR in the regulation of IL-10 in peripheral B cells of PGT patients. In this study, the peripheral blood samples were collected from PGT patients and healthy subjects. B cells were purified from the blood samples and analysed by RT-qPCR and Western blotting. The correlation between the expression of IL-10 and VDR in the B cells was assessed. We observed that the serum VitD levels were negatively correlated with IL-10 expression in peripheral B cells of patients with PGT. Low levels of VDR expression were found in peripheral B cells of PGT patients. Exposure to VitD suppressed the expression of IL-10 in B cells. The VDR bounds the transcription factor of IL-10 to interfere with the expression of IL-10 in B cells. The VDR agonists inhibited IL-10 expression in B cells from PGT patients. In conclusion, modulation of the expression of VDR can regulate the expression of IL-10 in peripheral B cells of PGT patients, which may contribute to the treatment of PGT.

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Analysis of TGFβ1 and IL-10 Transcriptional Regulation in CTCL Cells by Chromatin Immunoprecipitation

Cited by 10 publications

References 26 publications

Dimethyl fumarate restores apoptosis sensitivity and inhibits tumor growth and metastasis in CTCL by targeting NF-κB

Dimethyl fumarate restores apoptosis sensitivity and inhibits tumor growth and metastasis in CTCL by targeting NF-κB

Bortezomib Inhibits Expression of TGF-β1, IL-10, and CXCR4, Resulting in Decreased Survival and Migration of Cutaneous T Cell Lymphoma Cells

Vitamin D insufficiency correlates with peripheral B10 cells in patients with pituitary tumours

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