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1. Activation of Toll-Like Receptor 3 Induces Interleukin-1 Receptor Antagonist Expression by Activating the Interferon Regulatory Factor 3

Author

Yang Liu, Chun-Fen Mo, Xing-Yan Luo, Hua Li, Hui-Jie Guo, Hai Sun, Song Hu, Li-Mei Li, Yan-Tang Wang, Shu-Xia Yang, Shan Chang, and Qiang Zou

Subjects
poly(i:c), toll-like receptor 3, interleukin-1 receptor antagonist, interferon regulatory factor 3, human fibroblast-like synoviocytes, Medicine, Internal medicine, RC31-1245
Abstract

Toll-like receptor 3 (TLR3) is a sensor of endogenous cell necrosis during the process of acute inflammation. Interleukin (IL)-1 receptor antagonist (IL-1Ra) is an anti-inflammatory cytokine and can negatively regulate the pathogenesis of inflammation. However, whether and how activation of TLR3 can regulate IL-1Ra expression has not been clarified. Here, we show that poly(I:C) induces IL-1Ra expression in primarily cultured human fibroblast-like synoviocytes and other types of cells. Induction of IL-1Ra by poly(I:C) was dependent on TLR3, but was independent of melanoma differentiation-­associated protein 5 or retinoic acid-inducible gene I. Interferon regulatory factor 3 (IRF3) directly binds to the IL-1Ra promoter and promotes IL-1Ra expression in response to poly(I:C) stimulation. Induction of IL-1Ra by poly(I:C) was abolished by the inhibition of the NF-κB signaling, attenuated by the inhibition of the PI3K-Akt signaling, enhanced by inhibition of the ERK1/2 or MSK1/2 activation, but was independent of the p38 MAPK signaling. Treatment with poly(I:C) or Sendai virus elevated the levels of serum IL-1Ra in wild-type, but not in TLR3–/– or IRF3–/– mice. Our findings may provide new insights into the intrinsic anti-inflammatory function of TLR3 and double-stranded RNA-induced IL-Ra expression by TLR3 and its regulation.

Published
2019
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2. Renal function is associated with 1-month and 1-year mortality in patients with ischemic stroke

Author

I-Kuan Wang, Chung-Hsiang Liu, Tzung-Hai Yen, Jiann-Shing Jeng, Sheng-Feng Sung, Pai-Hao Huang, Jie-Yuan Li, Yu Sun, Cheng-Yu Wei, Li-Ming Lien, I-Ju Tsai, Fung-Chang Sung, Chung Y. Hsu, Chon-Haw Tsai, Wei-Shih Huang, Chung-Ta Lu, Tzung-Chang Tsai, Chun-Hung Tseng, Kang-Hsu Lin, Woei-Cherng Shyu, Yu-Wan Yang, Yen-Liang Liu, Der-Yang Cho, Chun-Chung Chen, Sung-Chun Tang, Li-Kai Tsai, Shin-Joe Yeh, Chih-Hao Chen, Hsin-Hsi Tsai, Han-Jung Chen, Kan Lu, Shih-Pin Hsu, Hung-Chang Kuo, Jung-Chi Tsou, Yan-Tang Wang, Yi-Cheng Tai, Meng-Tsang Hsieh, Po-Chao Liliang, Cheng-Loong Liang, Hao-Kuang Wang, Yu-Tun Tsai, Kuo-Wei Wang, Jui-Sheng Chen, Po-Yuan Chen, Yi-Ching Wang, Chih-Hung Chen, Pi-Shan Sung, Han-Chieh Hsieh, Hui-Chen Su, Hou-Chang Chiu, Wei-Hung Chen, Chyi-Huey Bai, Tzu-Hsuan Huang, Chi-Ieong Lau, Ya-Ying Wu, Hsu-Ling Yeh, Anna Chang, Ching-Huang Lin, Cheng-Chang Yen, Ruey-Tay Lin, Chun-Hung Chen, Gim-Thean Khor, A-Ching Chao, Hsiu-Fen Lin, Poyin Huang, Huey-Juan Lin, Der-Shin Ke, Chia-Yu Chang, Poh-Shiow Yeh, Kao-Chang Lin, Tain-Junn Cheng, Chih-Ho Chou, Chun-Ming Yang, Hsiu-Chu Shen, An-Chih Chen, Shih-Jei Tsai, Tsong-Ming Lu, Sheng-Ling Kung, Mei-Ju Lee, Hsi-Hsien Chou, Wei-Lun Chang, Pai-Yi Chiu, Min-Hsien Hsu, Po-Chi Chan, Chau-Hsiung Pan, Hai-Ming Shoung, Yi-Chen Lo, Fu-Hwa Wang, Wei-Chieh Chang, Ta-Chang Lai, Jiu-Haw Yin, Chung-Jen Wang, Kai-Chen Wang, Li-Mei Chen, Jong-Chyou Denq, Chien-Jung Lu, Cheng-Huai Lin, Chieh-Cheng Huang, Chang-Hsiu Liu, Hoi-Fong Chan, Siu-Pak Lee, Ming-Hui Sun, Li-Ying Ke, Po-Lin Chen, Yu-Shan Lee, Cheung-Ter Ong, Chi-Shun Wu, Yung-Chu Hsu, Yu-Hsiang Su, Ling-Chien Hung, Jiunn-Tay Lee, Jiann-Chyun Lin, Yaw-Don Hsu, Giia-Sheun Peng, Chang-Hung Hsu, Chun-Chieh Lin, Che-Hung Yen, Chun-An Cheng, Yueh-Feng Sung, Yuan-Liang Chen, Ming-Tung Lien, Chung-Hsing Chou, Chia-Chen Liu, Fu-Chi Yang, Yi-Chung Wu, An-Chen Tso, Yu- Hua Lai, Chun-I. Chiang, Chia-Kuang Tsai, Meng-Ta Liu, Ying-Che Lin, Yu-Chuan Hsu, Tsuey-Ru Chiang, Pin-Wen Liao, Mei-Ching Lee, Jen-Tse Chen, Sian-King Lie, Mu-Chien Sun, Pi-Ju Hsiao, Wei-Liang Chen, Ta-Cheng Chen, Chen-Shu Chang, Chien-Hsu Lai, Chieh-Sen Chuang, Yen-Yu Chen, Shinn-Kuang Lin, Yu-Chin Su, Jen-Lun Shiao, Fu-Yi Yang, Chih-Yang Liu, Han-Lin Chiang, Guei-Chiuan Chen, Po-Jen Hsu, Chun-Yuan Chang, I.-sheng Lin, Chung-Hsien Chien, Yang-Chuang Chang, Ping-Kun Chen, Yu-Jen Hsiao, Chen-Wen Fang, Yu-Wei Chen, Kuo-Ying Lee, Yun-Yu Lin, Chen-Hua Li, Hui-Fen Tsai, Chuan-Fa Hsieh, Chih-Dong Yang, Shiumn-Jen Liaw, How-Chin Liao, Shoou-Jeng Yeh, Ling-Li Wu, Liang-Po Hsieh, Yong-Hui Lee, Chung-Wen Chen, Chih-Shan Hsu, Ye-Jian Jhih, Hao-Yu Zhuang, Yan-Hong Pan, Shin-An Shih, Chin-I. Chen, Jia-Ying Sung, Hsing-Yu Weng, Hao-Wen Teng, Jing-Er Lee, Chih-Shan Huang, Shu-Ping Chao, Rey-Yue Yuan, Jau-Jiuan Sheu, Jia-Ming Yu, Chun-Sum Ho, Ting-Chun Lin, Shih-Chieh Yu, Jiunn-Rong Chen, Song-Yen Tsai, Chao-Hsien Hung, Chia Fang Lee, Sheng-Kung Yang, Chih-Lin Chen, Wei Lin, Hung-Pin Tseng, Chin-Hsiung Liu, Chun-Liang Lin, Hung-Chih Lin, Pi-Tzu Chen, Chaur-Jong Hu, Lung Chan, Nai-Fang Chi, Chang-Ming Chern, Chun-Jen Lin, Shuu-Jiun Wang, Li-Chi Hsu, Wen-Jang Wong, I-Hui Lee, Der-Jen Yen, Ching-Piao Tsai, Shang-Yeong Kwan, Bing-Wen Soong, Shih-Pin Chen, Kwong-Kum Liao, Kung-Ping Lin, Chien Chen, Din-E. Shan, Jong-Ling Fuh, Pei-Ning Wang, Yi-Chung Lee, Yu-Hsiang Yu, Hui-Chi Huang, Jui-Yao Tsai, Ming-Hsiu Wu, Szu-Yi Chiang, Chiung-Yao Wang, Ming-Chin Hsu, Chien-Chung Chen, Po-Yen Yeh, Yu-Tai Tsai, Ko-Yi Wang, Tsang-Shan Chen, Cheng-Yang Hsieh, Wei-Fen Chen, Ping-Keung Yip, Vinchi Wang, Kaw-Chen Wang, Chung-Fen Tsai, Chao-Ching Chen, Yi-Chien Liu, Shao-Yuan Chen, Zi-Hao Zhao, Zhi-Peng Wei, Shey-Lin Wu, Ching-Kuan Liu, Ryh-Huei Lin, Ching-Hua Chu, Sui-Hing Yan, Yi-Chun Lin, Pei-Yun Chen, Sheng-Huang Hsiao, Bak-Sau Yip, Pei-Chun Tsai, Ping-Chen Chou, Tsam-Ming Kuo, Yi-Chen Lee, Yi-Pin Chiu, Kun-Chang Tsai, Yi-Sheng Liao, Ming-Jun Tsai, and Hsin-Yi Kao

Subjects
Adult, Male, Stroke registry, medicine.medical_specialty, Time Factors, Adolescent, Taiwan, Renal function, 030204 cardiovascular system & hematology, Kidney, Risk Assessment, Brain Ischemia, Young Adult, 03 medical and health sciences, 0302 clinical medicine, Risk Factors, Internal medicine, Humans, Medicine, In patient, Registries, Risk factor, Stroke, Aged, Retrospective Studies, Aged, 80 and over, business.industry, Mortality rate, Middle Aged, Prognosis, medicine.disease, Ischemic stroke, Cardiology, Female, Kidney Diseases, Cardiology and Cardiovascular Medicine, business, 1 year mortality, 030217 neurology & neurosurgery, Glomerular Filtration Rate
Abstract

Background and aims Renal dysfunction is a potent risk factor for cardiovascular diseases, including stroke. This study aimed to evaluate the impact of admission estimated glomerular filtration rate (eGFR) levels on short-term (1-month) and long-term (1-year) mortality in patients with acute ischemic stroke. Methods From the Taiwan Stroke Registry data, we classified ischemic stroke patients, identified from April 2006 to December 2015, into 5 groups by eGFR at admission: ≥ 90, 60–89, 30–59, 15–29, and Results Among 52,732 ischemic stroke patients, 1480 died within one month. The 1-month mortality rate was over 5-fold greater in patients with eGFR Conclusions After acute ischemic stroke, patients with reduced eGFR are at elevated risks of short-term and long-term deaths in a graded relationship.

Published
2018
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3. Tolerogenic Dendritic Cells Induced by BD750 Ameliorate Proinflammatory T cell Responses and Experimental Autoimmune Encephalitis in Mice

Author

Qiang Zou, Hua Li, Yang Liu, Yan-Tang Wang, Tai Yang, Yan Zhou, Xiao Leng, Ying Xiong, Shu-Xia Yang, and Li-Mei Li

Subjects
0301 basic medicine, Adoptive cell transfer, Encephalomyelitis, Autoimmune, Experimental, Indazoles, Lipopolysaccharide, T cell, T-Lymphocytes, Cell, Proinflammatory cytokine, lcsh:Biochemistry, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Antigen, Genetics, medicine, Immune Tolerance, Animals, lcsh:QD415-436, Benzothiazoles, Molecular Biology, Genetics (clinical), Mice, Inbred BALB C, lcsh:RM1-950, Dendritic cell, Dendritic Cells, Oligodendrocyte, Mice, Inbred C57BL, 030104 developmental biology, medicine.anatomical_structure, lcsh:Therapeutics. Pharmacology, chemistry, Immunology, Molecular Medicine, Female, Immunosuppressive Agents, 030215 immunology, Research Article
Abstract

BD750, a novel JAK3/STAT5 inhibitor, can inhibit T cell proliferation. This study aims to evaluate whether BD750 can induce tolerogenic dendritic cells (tolDC) and their function in experimental autoimmune encephalitis (EAE) in mice. Following BD750 treatment, lipopolysaccharide (LPS)-induced maturation of DCs, allogeneic T cell proliferation, Th1 and Th17 cell functional differentiation, and STAT5 and AKT activation were determined. The effect of tolDC loaded with antigen peptide on the development and severity of EAE and splenic Th1 and Th17 cell responses was determined. In comparison with LPS-induced mature DCs (mDCs), BD750 treatment induced tolDC with lower expression levels of costimulatory molecules and proinflammatory cytokines and lower levels of STAT5 phosphorylation. TolDC inhibited allogeneic T cell proliferation and reduced Th1 and Th17 responses. Adoptive transfer of tolDC loaded with myelin oligodendrocyte glycoprotein35-55 inhibited the development and severity of EAE in mice, accompanied by reduced numbers of inflammatory infiltrates and decreased levels of demyelination in the spinal cord tissues. In addition, treatment with tolDC loaded with antigen peptide also significantly reduced the frequency of splenic Th1 and Th17 cells in EAE mice. The effects of tolDC were similar to that of JAK/STAT inhibitor CP690550-treated DCs. In conclusion, treatment with BD750 induced tolDC that inhibited proinflammatory T cell immunity in vitro and in vivo. BD750 and tolDC may be valuable for development of new therapies for EAE and other autoimmune diseases.

Published
2017
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4. Cholesterol Levels Are Associated with 30-day Mortality from Ischemic Stroke in Dialysis Patients

Author

I.-Kuan Wang, Chung-Hsiang Liu, Tzung-Hai Yen, Jiann-Shing Jeng, Shih-Pin Hsu, Chih-Hung Chen, Li-Ming Lien, Ruey-Tay Lin, An-Chih Chen, Huey-Juan Lin, Hsin-Yi Chi, Ta-Chang Lai, Yu Sun, Siu-Pak Lee, Sheng-Feng Sung, Po-Lin Chen, Jiunn-Tay Lee, Tsuey-Ru Chiang, Shinn-Kuang Lin, Chih-Hsin Muo, Henry Ma, Chi-Pang Wen, Fung-Chang Sung, Chung Y. Hsu, Chon-Haw Tsai, Wei-Shih Huang, Chung-Ta Lu, Tzung-Chang Tsai, Chun-Hung Tseng, Kang-Hsu Lin, Woei-Cherng Shyn, Yu-Wan Yang, Yen-Liang Liu, Der-Yang Cho, Chun-Chung Chen, Sung-Chun Tang, Li-Kai Tsai, Shin-Joe Yeh, Han-Jung Chen, Cheng-Sen Chang, Hung-Chang Kuo, Lian-Hui Lee, Huan-Wen Tsui, Jung-Chi Tsou, Yan-Tang Wang, Yi-Cheng Tai, Kun-Chang Tsai, Yen-Wen Chen, Kan Lu, Po-Chao Liliang, Yu-Tun Tsai, Cheng-Loong Liang, Kuo-Wei Wang, Hao-Kuang Wang, Jui-Sheng Chen, Po-Yuan Chen, Cien-Leong Chye, Wei-Jie Tzeng, Pei-Hua Wu, Pi-Shan Sung, Han-Chieh Hsieh, Hui-Chen Su, Hou-Chang Chiu, Wei-Hung Chen, Chyi-Huey Bai, Tzu-Hsuan Huang, Chi-Ieong Lau, Ya-Ying Wu, Hsu-Ling Yeh, Anna Chang, Ching-Huang Lin, Cheng-Chang Yen, Chun-Hung Chen, Gim-Thean Khor, A-Ching Chao, Hsiu-Fen Lin, Poyin Huang, Der-Shin Ke, Chia-Yu Chang, Poh-Shiow Yeh, Kao-Chang Lin, Tain-Junn Cheng, Chih-Ho Chou, Chun-Ming Yang, Hsiu-Chu Shen, Shih-Jei Tsai, Tsong-Ming Lu, Sheng-Ling Kung, Mei-Ju Lee, Hsi-Hsien Chou, Chou-Hsiung Pan, Po-Chi Chan, Min-Hsien Hsu, Wei-Lun Chang, Zhi-Zang Huang, Hai-Ming Shoung, Yi-Chen Lo, Fu-Hwa Wang, Jiu-Haw Yin, Chung-Jen Wang, Kai-Chen Wang, Li-Mei Chen, Jong-Chyou Denq, Chien-Jung Lu, Cheng-Huai Lin, Chieh-Cheng Huang, Chang-Hsiu Liu, Hoi-Fong Chan, Ming-Hui Sun, Li-Ying Ke, Yu-Shan Lee, Cheung-Ter Ong, Chi-Shun Wu, Yung-Chu Hsu, Yu-Hsiang Su, Ling-Chien Hung, Jiann-Chyun Lin, Yaw-Don Hsu, Giia-Sheun Peng, Chang-Hung Hsu, Chun-Chieh Lin, Che-Hung Yen, Chun-An Cheng, Yueh-Feng Sung, Yuan-Liang Chen, Ming-Tung Lien, Chung-Hsing Chou, Chia-Chen Liu, Fu-Chi Yang, Yi-Chung Wu, An-Chen Tso, Yu-Hua Lai, Chun-I Chiang, Chia-Kuang Tsai, Meng-Ta Liu, Ying-Che Lin, Yu-Chuan Hsu, Mei-Ching Lee, Pai-Hao Huang, Sian-King Lie, Pin-Wen Liao, Jen-Tse Chen, Mu-Chien Sun, Tien-Pao Lai, Wei-Liang Chen, Yen-Chun Chen, Ta-Cheng Chen, Wen-Fu Wang, Kwo-Whei Lee, Chen-Shu Chang, Chien-Hsu Lai, Siao-Ya Shih, Chieh-Sen Chuang, Yen-Yu Chen, Chien-Min Chen, Yu-Chin Su, Cheng-Lun Hsiao, Fu-Yi Yang, Chih-Yang Liu, Han-Lin Chiang, Chun-Yuan Chang, I-sheng Lin, Chung-Hsien Chien, Yang-Chuang Chang, Ping-Kun Chen, Pai-Yi Chiu, Yu-Jen Hsiao, Chen-Wen Fang, Yu-Wei Chen, Kuo-Ying Lee, Yun-Yu Lin, Chen-Hua Li, Hui-Fen Tsai, Chuan-Fa Hsieh, Chih-Dong Yang, Shiumn-Jen Liaw, How-Chin Liao, Shoou-Jeng Yeh, Ling-Li Wu, Liang-Po Hsieh, Yong-Hui Lee, Chung-Wen Chen, Chih-Shan Hsu, Ye-Jian Jhih, Hao-Yu Zhuang, Yan-Hong Pan, Shin-An Shih, Chin-I Chen, Jia-Ying Sung, Hsing-Yu Weng, Hao-Wen Teng, Jing-Er Lee, Chih-Shan Huang, Shu-Ping Chao, Rey-Yue Yuan, Jau- Jiuan Sheu, Jia-Ming Yu, Chun-Sum Ho, Ting-Chun Lin, Shih-Chieh Yu, Jiunn-Rong Chen, Song-Yen Tsai, Cheng-Yu Wei, Chao-Nan Yang, Chao-Hsien Hung, Ian Shih, Hung-Pin Tseng, Chin-Hsiung Liu, Chun-Liang Lin, Hung-Chih Lin, Pi-Tzu Chen, Chaur-Jong Hu, Nai-Fang Chi, Lung Chan, Chang-Ming Chern, Chun-Jen Lin, Shuu-Jiun Wang, Li-Chi Hsu, Wen-Jang Wong, I-Hui Lee, Der-Jen Yen, Ching-Piao Tsai, Shang-Yeong Kwan, Bing-Wen Soong, Shih-Pin Chen, Kwong-Kum Liao, Kung-Ping Lin, Chien Chen, Din-E Shan, Jong-Ling Fuh, Pei-Ning Wang, Yi-Chung Lee, Yu-Hsiang Yu, Hui-Chi Huang, Jui-Yao Tsai, Ming-Hsiu Wu, Shi-Cheng Chen, Szu-Yi Chiang, Chiung-Yao Wang, Ming-Chin Hsu, Chien-Chung Chen, Po-Yen Yeh, Yu-Tai Tsai, Ko-Yi Wang, Tsang-Shan Chen, Ping-Keung Yip, Vinchi Wang, Kaw-Chen Wang, Chung-Fen Tsai, Chao-Ching Chen, Chih-Hao Chen, Yi-Chien Liu, Shao-Yuan Chen, Zi-Hao Zhao, Zhi-Peng Wei, Shey-Lin Wu, Ching-Kuan Liu, Ryh-Huei Lin, Ching-Hua Chu, Sui-Hing Yan, Yi-Chun Lin, Pei-Yun Chen, Sheng-Huang Hsiao, Bak-Sau Yip, Pei-Chun Tsai, Ping-Chen Chou, Tsam-Ming Kuo, Yi-Chen Lee, Yi-Pin Chiu, Yi-Sheng Liao, Ming-Jun Tsai, and Hsin-Yi Kao

Subjects
Male, Stroke registry, medicine.medical_specialty, Time Factors, medicine.medical_treatment, Taiwan, Kaplan-Meier Estimate, 030204 cardiovascular system & hematology, Dialysis patients, Brain Ischemia, 03 medical and health sciences, chemistry.chemical_compound, Patient Admission, 0302 clinical medicine, Renal Dialysis, Risk Factors, Internal medicine, medicine, Humans, Registries, Serum cholesterol, Dialysis, Aged, Proportional Hazards Models, Aged, 80 and over, Cholesterol, business.industry, Mortality rate, Rehabilitation, Middle Aged, Prognosis, Stroke, chemistry, 30 day mortality, Ischemic stroke, Cardiology, Kidney Failure, Chronic, Female, Surgery, Neurology (clinical), Cardiology and Cardiovascular Medicine, business, Biomarkers, 030217 neurology & neurosurgery
Abstract

We investigated the impact of serum cholesterol levels on 30-day mortality after ischemic stroke in dialysis patients.From the Taiwan Stroke Registry data, we identified 46,770 ischemic stroke cases, including 1101 dialysis patients and 45,669 nondialysis patients from 2006 to 2013.Overall, the 30-day mortality was 1.46-fold greater in the dialysis group than in the nondialysis group (1.75 versus 1.20 per 1000 person-days). The mortality rates were 1.64, .62, 2.82, and 2.23 per 1000 person-days in dialysis patients with serum total cholesterol levels of 120 mg/dL, 120-159 mg/dL, 160-199 mg/dL, and ≥200 mg/dL, respectively. Compared to dialysis patients with serum total cholesterol levels of 120-159 mg/dL, the corresponding adjusted hazard ratios of mortality were 4.20 (95% confidence interval [CI] = 1.01-17.4), 8.06 (95% CI = 2.02-32.2), and 6.89 (95% CI = 1.59-29.8) for those with cholesterol levels of 120 mg/dL, 160-199 mg/dL, and ≥200 mg/dL, respectively.Dialysis patients with serum total cholesterol levels of ≥160 mg/dL or 120 mg/dL on admission are at an elevated hazard of 30-day mortality after ischemic stroke.

Published
2017
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5. A novel water-soluble benzothiazole derivative BD926 inhibits human activated T cell proliferation by down-regulating the STAT5 activation

Author

Xing-Yan Luo, Yan-Tang Wang, Zheng-Liang Chen, Jin Liu, Yi Lai, Qiang Zou, Tai Yang, Hua Li, Li-Mei Li, Liu Yang, Shu-Xia Yang, and Minhui Li

Subjects
Indazoles, T-Lymphocytes, T cell, Down-Regulation, Activated T cell proliferation, Lymphocyte Activation, Interleukin 21, Cyclin-dependent kinase, STAT5 Transcription Factor, medicine, Animals, Humans, Cytotoxic T cell, Benzothiazoles, IL-2 receptor, Cyclin D3, Phosphorylation, Cells, Cultured, Cell Proliferation, Pharmacology, Mice, Inbred BALB C, Dose-Response Relationship, Drug, biology, Cell growth, ZAP70, Water, Cyclin-Dependent Kinase 6, G1 Phase Cell Cycle Checkpoints, Disease Models, Animal, medicine.anatomical_structure, Solubility, Biochemistry, Dermatitis, Allergic Contact, Cancer research, biology.protein, Cytokines, Benzimidazoles, Dinitrofluorobenzene, Female, Immunosuppressive Agents, Signal Transduction
Abstract

Immunosuppressants are widely used for treatment of T cell-mediated autoimmune diseases and allogeneic graft rejection. However, because of the toxicity and tolerance of these drugs, novel immunosuppressants are urgently needed. We synthesized a series of novel water-soluble benzothiazole derivatives and found that BD926 [sodium 2-(benzo[d]thiazol-2-yl)-4,5,6,7-tetrahydro-2H-indazol-3-olate] had potent immunosuppressive activity. Treatment with BD926 significantly inhibited anti-CD3/anti-CD28 and alloantigen-induced human T cell proliferation as well as IL2-stimulated activated T cell proliferation in a dose-dependent manner in vitro. BD926 had no obvious cytotoxicity against human resting T cells, IL-4 treated activated T cells and fibroblast-like synoviocytes in our experimental conditions. Furthermore, BD926 induced cell cycle arrest at G0/G1 phase and inhibited the cyclin D3 and CDK 6 expression in activated T cells. BD926 inhibited the STAT5, but not Akt and p70S6K, phosphorylation in a dose-dependent manner in the IL-2-treated activated T cells. Interestingly, BD926 inhibited IFN-γ, IL-6 and IL-17, but not IL-2, IL-4 and IL-10, production in activated T cells. Finally, treatment with BD926 reduced delayed-type hypersensitivity in mice in a dose-dependent manner. Collectively, these data suggest that BD926 may be a lead compound for the design and development of new immunosuppressants for the intervention of allograft rejection and autoimmune diseases.

Published
2015
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6. 2-(1H-Benzimidazol-2-yl)-4,5,6,7-tetrahydro-2H-indazol-3-ol, a Benzimidazole Derivative, Inhibits T Cell Proliferation Involving H+/K+-ATPase Inhibition

Author

Xing-Yan Luo, Hua Li, Tai Yang, Si-Nian Liu, Li-Mei Li, Minhui Li, Ning Li, Qiang Zou, Yang Liu, Ning Huang, Jin Liu, and Yan-Tang Wang

Subjects
CD3 Complex, T-Lymphocytes, T cell, ATPase, Intracellular pH, Down-Regulation, Pharmaceutical Science, chemical and pharmacologic phenomena, Lymphocyte Activation, Article, T cell proliferation, Analytical Chemistry, lcsh:QD241-441, H(+)-K(+)-Exchanging ATPase, CD28 Antigens, lcsh:Organic chemistry, immune system diseases, Drug Discovery, medicine, Humans, Immunologic Factors, IL-2 receptor, Physical and Theoretical Chemistry, Cells, Cultured, immunomodulatory, Cell Proliferation, biology, Cell growth, Organic Chemistry, CD28, benzimidazole derivative, Proton Pump Inhibitors, hemic and immune systems, Cell Cycle Checkpoints, Hydrogen-Ion Concentration, Cell cycle, Molecular biology, Cell biology, medicine.anatomical_structure, surgical procedures, operative, Chemistry (miscellaneous), Leukocytes, Mononuclear, biology.protein, H+/K+-ATPases, Interleukin-2, Molecular Medicine, Benzimidazoles, Intracellular
Abstract

In this study, a benzimidazole derivative named BMT-1 is revealed as a potential immunomodulatory agent. BMT-1 inhibits the activity of H+/K+-ATPases from anti-CD3/CD28 activated T cells. Furthermore, inhibition the H+/K+-ATPases by use of BMT-1 should lead to intracellular acidification, inhibiting T cell proliferation. To explore this possibility, the effect of BMT-1 on intracellular pH changes was examined by using BCECF as a pH-dependent fluorescent dye. Interestingly, increases in the pHi were observed in activated T cells, and T cells treated with BMT-1 showed a more acidic intracellular pH. Finally, BMT-1 targeted the H+/K+-ATPases and inhibited the proliferative response of anti-CD3/CD28-stimulated T cells. A cell cycle analysis indicated that BMT-1 arrested the cell cycle progression of activated T cells from the G1 to the S phase without affecting CD25 expression or interleukin-2 (IL-2) production, treating IL-2-dependent PBMCs with BMT-1 also led to the inhibition of cell proliferation. Taken together, these findings demonstrate that BMT-1 inhibits the proliferation of T cells by interfering with H+/K+-ATPases and down-regulating intracellular pHi. This molecule may be an interesting lead compound for the development of new immunomodulatory agents.

Published
2014

7. BD750, a benzothiazole derivative, inhibits T cell proliferation by affecting the JAK3/STAT5 signalling pathway

Author

Yi Lai, Ping Yang, Jin Liu, Minhui Li, Yang Liu, Qiang Zou, Li-Mei Li, Shu-Xia Yang, Yan-Tang Wang, Hongyu Li, Xing-Yan Luo, Tai Yang, and Zheng J

Subjects
Pharmacology, biology, Cell growth, T cell, Janus kinase 3, Cell cycle, chemistry.chemical_compound, medicine.anatomical_structure, Biochemistry, Benzothiazole, chemistry, medicine, Cancer research, biology.protein, Signal transduction, Mode of action, STAT5
Abstract

Background and Purpose A series of benzothiazole derivatives were screened for immunosuppressive activity; of these compounds BD750 was found to be the most effective immunosuppressant. The purpose of the current study was to determine the immunosuppressive activity of BD750 on T cell proliferation and its potential mode of action.

Published
2013
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8. Tolerogenic Dendritic Cells Generated with Tofacitinib Ameliorate Experimental Autoimmune Encephalomyelitis through Modulation of Th17/Treg Balance

Author

Yang Liu, Zhiwei Su, Qiang Zou, Chun-Fen Mo, Yan Zhou, Xiao Leng, Hui-Jie Guo, Yan-Tang Wang, Shasha Luo, and Xing-Yan Luo

Subjects
0301 basic medicine, lcsh:Immunologic diseases. Allergy, Encephalomyelitis, Autoimmune, Experimental, Multiple Sclerosis, Article Subject, Encephalomyelitis, medicine.medical_treatment, Immunology, chemical and pharmacologic phenomena, Immunotherapy, Adoptive, T-Lymphocytes, Regulatory, Myelin oligodendrocyte glycoprotein, Immune tolerance, Proinflammatory cytokine, 03 medical and health sciences, Mice, Piperidines, medicine, Immune Tolerance, Immunology and Allergy, Animals, Pyrroles, Protein Kinase Inhibitors, Cells, Cultured, Janus kinase inhibitor, Tofacitinib, biology, business.industry, Experimental autoimmune encephalomyelitis, hemic and immune systems, General Medicine, Immunotherapy, Dendritic Cells, Th1 Cells, medicine.disease, CD4 Lymphocyte Count, Mice, Inbred C57BL, Disease Models, Animal, 030104 developmental biology, Pyrimidines, biology.protein, Th17 Cells, Female, business, lcsh:RC581-607, Research Article
Abstract

It is well known that dendritic cells (DCs) play a pivotal role in triggering self-specific responses. Conversely, tolerogenic DCs (tolDCs), a specialized subset, induce tolerance and negatively regulate autoreactive responses. Tofacitinib, a Janus kinase inhibitor developed by Pfizer for treatment of rheumatoid arthritis, is probable to be a promising candidate for inducing tolDCs. The aims of this study were to evaluate the effectiveness of tolDCs induced by tofacitinib in a myelin oligodendrocyte glycoprotein- (MOG-) specific experimental autoimmune encephalomyelitis (EAE) model and to investigate their effects on Th17/Treg balance in the animal model of multiple sclerosis (MS). Our results revealed that tofacitinib-treated DCs maintained a steady semimature phenotype with a low level of proinflammatory cytokines and costimulatory molecules. DCs treated by tofacitinib also induced antigen-specific T cells hyporesponsiveness in a concentration-dependent manner. Upon intravenous injection into EAE mice, MOG pulsed tolDCs significantly dampened disease activity, and adoptive cell therapy (ACT) disturbed Th17/Treg balance with a remarkable decrease of Th1/Th17 cells and an increase in regulatory T cells (Tregs). Overall, DCs modified by tofacitinib exhibited a typical tolerogenic phenotype, and the antigen-specific tolDCs may represent a new avenue of research for the development of future clinical treatments for MS.

Published
2016

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