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Title: BET N-terminal bromodomain inhibition selectively blocks Th17 cell differentiation and ameliorates colitis in mice

Authors:
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Publication Date:
Research Org.:
Brookhaven National Laboratory (BNL), Upton, NY (United States)
Sponsoring Org.:
USDOE Office of Science (SC), Basic Energy Sciences (BES) (SC-22)
OSTI Identifier:
1409528
Report Number(s):
BNL-114580-2017-JA¿¿¿
Journal ID: ISSN 0027-8424
DOE Contract Number:
SC0012704
Resource Type:
Journal Article
Resource Relation:
Journal Name: Proceedings of the National Academy of Sciences of the United States of America; Journal Volume: 114; Journal Issue: 11
Country of Publication:
United States
Language:
English

Citation Formats

Cheung, Kalung, Lu, Geming, Sharma, Rajal, Vincek, Adam, Zhang, Ruihua, Plotnikov, Alexander N., Zhang, Fan, Zhang, Qiang, Ju, Ying, Hu, Yuan, Zhao, Li, Han, Xinye, Meslamani, Jamel, Xu, Feihong, Jaganathan, Anbalagan, Shen, Tong, Zhu, Hongfa, Rusinova, Elena, Zeng, Lei, Zhou, Jiachi, Yang, Jianjun, Peng, Liang, Ohlmeyer, Michael, Walsh, Martin J., Zhang, David Y., Xiong, Huabao, and Zhou, Ming-Ming. BET N-terminal bromodomain inhibition selectively blocks Th17 cell differentiation and ameliorates colitis in mice. United States: N. p., 2017. Web. doi:10.1073/pnas.1615601114.
Cheung, Kalung, Lu, Geming, Sharma, Rajal, Vincek, Adam, Zhang, Ruihua, Plotnikov, Alexander N., Zhang, Fan, Zhang, Qiang, Ju, Ying, Hu, Yuan, Zhao, Li, Han, Xinye, Meslamani, Jamel, Xu, Feihong, Jaganathan, Anbalagan, Shen, Tong, Zhu, Hongfa, Rusinova, Elena, Zeng, Lei, Zhou, Jiachi, Yang, Jianjun, Peng, Liang, Ohlmeyer, Michael, Walsh, Martin J., Zhang, David Y., Xiong, Huabao, & Zhou, Ming-Ming. BET N-terminal bromodomain inhibition selectively blocks Th17 cell differentiation and ameliorates colitis in mice. United States. doi:10.1073/pnas.1615601114.
Cheung, Kalung, Lu, Geming, Sharma, Rajal, Vincek, Adam, Zhang, Ruihua, Plotnikov, Alexander N., Zhang, Fan, Zhang, Qiang, Ju, Ying, Hu, Yuan, Zhao, Li, Han, Xinye, Meslamani, Jamel, Xu, Feihong, Jaganathan, Anbalagan, Shen, Tong, Zhu, Hongfa, Rusinova, Elena, Zeng, Lei, Zhou, Jiachi, Yang, Jianjun, Peng, Liang, Ohlmeyer, Michael, Walsh, Martin J., Zhang, David Y., Xiong, Huabao, and Zhou, Ming-Ming. Mon . "BET N-terminal bromodomain inhibition selectively blocks Th17 cell differentiation and ameliorates colitis in mice". United States. doi:10.1073/pnas.1615601114.
@article{osti_1409528,
title = {BET N-terminal bromodomain inhibition selectively blocks Th17 cell differentiation and ameliorates colitis in mice},
author = {Cheung, Kalung and Lu, Geming and Sharma, Rajal and Vincek, Adam and Zhang, Ruihua and Plotnikov, Alexander N. and Zhang, Fan and Zhang, Qiang and Ju, Ying and Hu, Yuan and Zhao, Li and Han, Xinye and Meslamani, Jamel and Xu, Feihong and Jaganathan, Anbalagan and Shen, Tong and Zhu, Hongfa and Rusinova, Elena and Zeng, Lei and Zhou, Jiachi and Yang, Jianjun and Peng, Liang and Ohlmeyer, Michael and Walsh, Martin J. and Zhang, David Y. and Xiong, Huabao and Zhou, Ming-Ming},
abstractNote = {},
doi = {10.1073/pnas.1615601114},
journal = {Proceedings of the National Academy of Sciences of the United States of America},
number = 11,
volume = 114,
place = {United States},
year = {Mon Mar 06 00:00:00 EST 2017},
month = {Mon Mar 06 00:00:00 EST 2017}
}
  • Highlights: Black-Right-Pointing-Pointer UT7 erythroleukemia cells are known to be refractory to differentiate. Black-Right-Pointing-Pointer Brief JQ1 treatment initiates the first steps of erythroid differentiation program. Black-Right-Pointing-Pointer Engaged UT7 cells then maturate in the presence of erythropoietin. Black-Right-Pointing-Pointer Sustained JQ1 treatment inhibits both proliferation and erythroid differentiation. -- Abstract: Malignant transformation is a multistep process requiring oncogenic activation, promoting cellular proliferation, frequently coupled to inhibition of terminal differentiation. Consequently, forcing the reengagement of terminal differentiation of transformed cells coupled or not with an inhibition of their proliferation is a putative therapeutic approach to counteracting tumorigenicity. UT7 is a human leukemic cell linemore » able to grow in the presence of IL3, GM-CSF and Epo. This cell line has been widely used to study Epo-R/Epo signaling pathways but is a poor model for erythroid differentiation. We used the BET bromodomain inhibition drug JQ1 to target gene expression, including that of c-Myc. We have shown that only 2 days of JQ1 treatment was required to transitory inhibit Epo-induced UT7 proliferation and to restore terminal erythroid differentiation. This study highlights the importance of a cellular erythroid cycle break mediated by c-Myc inhibition before initiation of the erythropoiesis program and describes a new model for BET bromodomain inhibitor drug application.« less
  • Members of the BET family of bromodomain containing proteins have been identified as potential targets for blocking proliferation in a variety of cancer cell lines. A two-dimensional NMR fragment screen for binders to the bromodomains of BRD4 identified a phenylpyridazinone fragment with a weak binding affinity (1, Ki = 160 μM). SAR investigation of fragment 1, aided by X-ray structure-based design, enabled the synthesis of potent pyridone and macrocyclic pyridone inhibitors exhibiting single digit nanomolar potency in both biochemical and cell based assays. Advanced analogs in these series exhibited high oral exposures in rodent PK studies and demonstrated significant tumormore » growth inhibition efficacy in mouse flank xenograft models.« less
  • Inflammatory bowel disease (IBD) is a chronic intestinal inflammation caused by hyperactivated effector immune cells that produce pro-inflammatory cytokines. Recent studies have shown that the cannabinoid system may play a critical role in mediating protection against intestinal inflammation. However, the effect of cannabinoid receptor induction after chronic colitis progression has not been investigated. Here, we investigate the effect of cannabinoid receptor-2 (CB2) agonist, JWH-133, after chronic colitis in IL-10{sup −/−} mice. JWH-133 effectively attenuated the overall clinical score, and reversed colitis-associated pathogenesis and decrease in body weight in IL-10{sup −/−} mice. After JWH-133 treatment, the percentage of CD4{sup +} Tmore » cells, neutrophils, mast cells, natural killer (NK1.1) cells, and activated T cells declined in the intestinal lamina propria (LP) and mesenteric lymph nodes (MLN) of mice with chronic colitis. JWH-133 was also effective in ameliorating dextran sodium sulfate (DSS)-induced colitis. In this model, JWH-133 reduced the number and percentage of macrophages and IFN-γ expressing cells that were induced during colitis progression. Treatment with aminoalkylindole 6-iodo-pravadoline (AM630), a CB2 receptor antagonist, reversed the colitis protection provided by JWH-133 treatment. Also, activated T cells were found to undergo apoptosis following JWH-133 treatment both in-vivo and in-vitro. These findings suggest that JWH-133 mediates its effect through CB2 receptors, and ameliorates chronic colitis by inducing apoptosis in activated T cells, reducing the numbers of activated T cells, and suppressing induction of mast cells, NK cells, and neutrophils at sites of inflammation in the LP. These results support the idea that the CB2 receptor agonists may serve as a therapeutic modality against IBD. -- Highlights: ► JWH-133, a cannnabinoid receptor-2 agonist ameliorates experimental colitis. ► JWH-133 suppressed inflammation and toxicity to colon by inducing T cell apoptosis. ► JWH-133 decreased mast cells, macrophages, NK cells, IFN-γ{sup +} cells in the LPL. ► AM630, a cannnabinoid receptor-2 antagonist inverted the colitis defense of JWH-133. ► Cannnabinoid receptor-2 may serve as a novel therapeutic target for IBD.« less
  • Tetracycline antibiotics, including doxycycli/e (DOX), have been used to treat bone resorptive diseases, partially because of their activity to suppress osteoclastogenesis induced by receptor activator of nuclear factor kappa B ligand (RANKL). However, their precise inhibitory mechanism remains unclear. Therefore, the present study examined the effect of Dox on osteoclastogenesis signaling induced by RANKL, both in vitro and in vivo. Although Dox inhibited RANKL-induced osteoclastogenesis and down-modulated the mRNA expression of functional osteoclast markers, including tartrate-resistant acid phosphatase (TRAP) and cathepsin K, Dox neither affected RANKL-induced MAPKs phosphorylation nor NFATc1 gene expression in RAW264.7 murine monocytic cells. Gelatin zymography andmore » Western blot analyses showed that Dox down-regulated the enzyme activity of RANKL-induced MMP-9, but without affecting its protein expression. Furthermore, MMP-9 enzyme inhibitor also attenuated both RANKL-induced osteoclastogenesis and up-regulation of TRAP and cathepsin K mRNA expression, indicating that MMP-9 enzyme action is engaged in the promotion of RANKL-induced osteoclastogenesis. Finally, Dox treatment abrogated RANKL-induced osteoclastogenesis and TRAP activity in mouse calvaria along with the suppression of MMP9 enzyme activity, again without affecting the expression of MMP9 protein. These findings suggested that Dox inhibits RANKL-induced osteoclastogenesis by its inhibitory effect on MMP-9 enzyme activity independent of the MAPK-NFATc1 signaling cascade.« less