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proteasome inhibition suppresses Th17 cell generation and ameliorates autoimmune development in experimental Sjögren’s syndrome

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Cellular & Molecular Immunology 2017年第11期14卷 924-934页

作者： Fan Xiao Xiang Lin Jie Tian Xiaohui Wang Qian Chen Ke Rui Jie Ma Shengjun Wang Qingwen Wang Xiaoqi Wang Dongzhou Liu Lingyun Sun Liwei Lu Department of Pathology and Shenzhen Institute of Research and Innovation The University of Hong KongHong KongChina Department of Immunology Jiangsu University Medical SchoolZhenjiangJiangsu 212013 China Department of Rheumatology and Immunology Peking University Shenzhen HospitalShenzhenGuangdong 518036China Department of Rheumatology Shenzhen People's HospitalShenzhenGuangdong 518020China Department of Rheumatology and Immunology The Affiliated Drum Tower Hospital of Nanjing University Medical SchoolNanjingJiangsu 210008China

Immunoproteasome activation in immune cells is involved in the modulation of immune *** evidence indicates that proteasome inhibitors show beneficial effects in treating autoimmune diseases,but it remains unclear whether proteasome inhibition is an effective approach for suppressing autoimmune development in Sjögren’s syndrome(SS).Our previous work has demonstrated a critical role for Th17 cells in the development of experimental SS(ESS)in *** this study,we detected high levels of low-molecular-weight protein 7(LMP7),a key subunit of the immunoproteasome,in Th17 cells from ESS ***,treatment with bortezomib(BTZ),a proteasome inhibitor,markedly suppressed Th17 differentiation in both murine and human naive T cells in ***,ESS mice treated with BTZ displayed significantly higher saliva flow rates and a reduction in tissue destruction in the salivary glands compared with vehicle-treated ESS ***,BTZ-treated ESS mice showed markedly decreased Th17 cells,germinal center B cells and plasma cells in the peripheral lymphoid *** addition,adoptively transferred wild type naive CD4+T cells rapidly differentiated into Th17 cells and induced salivary dysfunction in IL-17-deficient mice immunized for ESS ***,BTZ treatment profoundly suppressed the donor T-cell-derived Th17 response and ameliorated the reduction in salivary secretion in IL-17-deficient recipient *** together,our findings demonstrate that proteasome inhibition can effectively ameliorate ESS by suppressing the Th17 response,which may contribute to the development of a novel therapeutic strategy for the treatment of SS.

关键词： proteasome inhibition Sjögren’s syndrome Th17 cells

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APP and APLP1 are degraded through autophagy in response to proteasome inhibition in neuronal cells

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Protein & Cell 2011年第5期2卷 377-383页

作者： Fangfang Zhou Theo van Laar Huizhe Huang Long Zhang Faculty of Basic Medical Sciences Medical College of Chongqing Medical UniversityChongqing 400016China Leiden University Medical Center Department of Molecular Cell Biology2333 ZA Leidenthe Netherland

Amyloid beta(Aβ)precursor protein(APP)is a key protein in the pathogenesis of Alzheimer’s disease(AD).Both APP and its paralogue APLP1(amyloid beta precursor-like protein 1)have multiple functions in cell adhesion and *** it was thought that autophagy is a novel beta-amyloid peptide(Aβ)-generating pathway activated in ***,the protein proteolysis of APLP1 is still largely *** present study shows that APLP1 is rapidly degraded in neuronal cells in response to stresses,such as proteasome *** of the endoplasmic reticulum(ER)stress by proteasome inhibitors induces autophagy,causing reduction of mature APLP1/*** autophagy or JNK stress kinase rescues the protein expression for both APP and ***,our results suggest that APP/APLP1 is degraded through autophagy and the APLP1 proteolysis is mainly mediated by autophagy-lysosome pathway.

关键词： amyloid beta precursor-like protein 1(APLP1) amyloid precursor protein(APP) proteasome inhibition endoplasmic reticulum stress autophagy neuronal cells

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Role of proteasome inhibition in sensitized transplant candidates

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Chinese Medical Journal 2011年第5期124卷 771-774页

作者： Matthew J. Everly Jason J. Everly Paul I. Terasaki One Lambda Inc Research 2 Division Los Angeles CA 90064 USA

Objective To review this efficacy and safety of bortezomib, a proteasome inhibitor, in the setting of the sensitized transplant candidate. Data sources The data used in this review were from articles published （PubMed） between 2000 to 2010. Additionally abstracts from medical meetings related to transplant were also used. Study selection Articles were selected if they were trial results or case studies for the use of bortezomib in the sensitized patient *** The early data using bortezomib as a part of desensitization regimens has shown success. Although one cycle （4 doses） of bortezomib seems to have affect on many patients, it also seems likely that to provide complete desensitization multiple cycles will be required. Regarding safety, bortezomib has been shown to have minimal side effects. The most common side effects reported are those of thrombocytopenia and anemia. These side effects are dose related and self limiting upon discontinuation of the *** Bortezomib with plasmapheresis is a promising new alternative to desensitization protocols that use either high dose intravenous immune globulin （IVIG） or low dose IVIG and plasmapheresis. The efficacy on antibody reduction looks to be batter that that of the IVIG based regimens without significant addition toxicity. The results of ongoing prospective trials are positive and their complete results are greatly anticipated.

关键词： proteasome inhibition bortezomib desensitization plasma cell alloantibodies human leukocyte antigen transplantation

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Therapeutic proteasome inhibition in experimental acute pancreatitis

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World Journal of Gastroenterology 2007年第33期13卷 4452-4457页

作者： Tamás Letoha Liliána Z Fehér László Pecze Csaba Somlai Ilona Varga József Kaszaki Gábor Tóth Csaba Vizler László Tiszlavicz Tamás Takács Department of Medical Chemistry University of Szeged H-6720 Szeged Hungary Institute of Biochemistry Biological Research Center of the HungarianAcademy of Sciences H-6726 Szeged Hungary Department of Genetics and Molecular Biology University of Szeged H-6726 Szeged Hungary Institute of Surgical Research University of Szeged H-6720 Szeged Hungary Department of Pathology University of Szeged H-6720 Szeged Hungary First Department of Medicine University of Szeged H-6720 Szeged Hungary

AIM： To establish the therapeutic potential of proteasome inhibition, we examined the therapeutic effects of MG132 （Z-Leu-Leu-Leu-aldehyde） in an experimental model of acute pancreatitis. METHODS： Pancreatitis was induced in rats by two hourly intraperitoneal （ip） injections of cholecystokinin octapeptide （CCK; 2×100μg/kg） and the proteasome inhibitor MG132 （10 mg/kg ip） was administered 30 min after the second CCK injection. Animals were sacrificed 4 h after the first injection of CCK. RESULTS： Administering the proteasome inhibitor MG132 （at a dose of 10 mg/kg, ip） 90 min after the onset of pancreatic inflammation induced the expression of cell-protective 72 kDa heat shock protein （HSP72） and decreased DNA-binding of nuclear factor-κB （NF-κB）. Furthermore MG132 treatment resulted in milder inflammatory response and cellular damage, as revealed by improved laboratory and histological parameters of pancreatitis and associated oxidative stress. CONCLUSION： Our findings suggest that proteasome inhibition might be beneficial not only for the prevention, but also for the therapy of acute pancreatitis.

关键词： Acute pancreatitis Cholecystokinin octapeptide proteasome inhibition Nuclear factor-κB Heat shock proteins

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Epigenetics of proteasome inhibition in the liver of rats fed ethanol chronically

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World Journal of Gastroenterology 2009年第6期15卷 705-712页

作者： Joan Oliva Jennifer Dedes Samuel W French Fawzia Bardag-Gorce Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center TorranceCA 90502 United States

AIM： TO examine the effects of ethanol-induced proteasome inhibition, and the effects of proteasome inhibition in the regulation of epigenetic mechanisms.METHODS： Rats were fed ethanol for 1 mo using the Tsukamoto-French model and were compared to rats given the proteasome inhibitor PS-341 （Bortezomib, Velcade^TM） by intraperitoneal injection. Microarray analysis and real time PCR were performed and proteasome activity assays and Western blot analysis were performed using isolated nuclei.RESULTS： Chronic ethanol feeding caused a significant inhibition of the ubiquitin proteasome pathway in the nucleus, which led to changes in the turnover of transcriptional factors, histone-modifying enzymes, and, therefore, affected epigenetic mechanisms. Chronic ethanol feeding was related to an increase in histone acetylation, and it is hypothesized that the proteasome proteolytic activity regulated histone modifications by controlling the stability of histone modifying enzymes, and, therefore, regulated the chromatin structure, allowing easy access to chromatin by RNA polymerase, and, thus, proper gene expression. proteasome inhibition by PS-341 increased histone acetylation similar to chronic ethanol feeding. In addition, proteasome inhibition caused dramatic changes in hepatic remethylation reactions as there was a significant decrease in the enzymes responsible for the regeneration of S-adenosylmethionine, and, in particular, a significant decrease in the betaine-homocysteine methyltransferase enzyme. This suggested that hypomethylation was associated with proteasome inhibition, as indicated by the decrease in histone methylation.CONCLUSION： The role of proteasome inhibition in regulating epigenetic mechanisms, and its link to liver injury in alcoholic liver disease, is thus a promising approach to study liver injury due to chronic ethanol consumption.

关键词： Alcohol liver injury Betaine Epigenetic mechanisms Homocysteine methyltransferase proteasome inhibition S-adenosylmethionine

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Nuclear effects of ethanol-induced proteasome inhibition in liver cells

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World Journal of Gastroenterology 2009年第10期15卷 1163-1167页

作者： Fawzia Bardag-Gorce Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center 1124 W. Carson St. Torrance CA 90502 United States

Alcohol ingestion causes alteration in several cellular mechanisms, and leads to inflammation, apoptosis, immunological response defects, and fibrosis. These phenomena are associated with significant changes in the epigenetic mechanisms, and subsequently, to liver cell memory. The ubiquitin-proteasome pathway is one of the vital pathways in the cell that becomes dysfunctionial as a result of chronic ethanol consumption. inhibition of the proteasome activity in the nucleus causes changes in the turnover of transcriptional factors, histone modifying enzymes, and therefore, affects epigenetic mechanisms. Alcohol consumption has been associated with an increase in histone acetylation and a decrease in histone methylation, which leads to gene expression changes. DNA and histone modifications that result from ethanol-induced proteasome inhibition are key players in regulating gene expression, especially genes involved in the cell cycle, immunological responses, and metabolism of ethanol. The present review highlights the consequences of ethanol-induced proteasome inhibition in the nucleus of liver cells that are chronically exposed to ethanol.

关键词： Alcohol liver injury proteasome inhibition Epigenetic mechanisms

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