Both intrinsic and extrinsic apoptotic pathways are involved in Toll-like receptor 4 (TLR4)-induced cell death in monocytic THP-1 cells |
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| Affiliation: | 1. Medical Research Center, Changsha Central Hospital, Changsha, China;2. Department of Pathology, Affiliated Tianyou Hospital, Wuhan University of Science and Technology, Wuhan, China;3. Department of Laboratory Medicine, XinXiang Medical University, XinXiang, China;4. Department of Urology, Renmin Hospital of Wuhan University, Wuhan, China;5. Tuberculosis Research Center, Changsha Central Hospital, Changsha, China;1. Department of Toxicology, School of public health, Zhejiang University School of Medicine, Hangzhou 310058, China;2. Institute of Immunology, Zhejiang University School of Medicine, Hangzhou 310058, China;3. State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Disease, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China;4. The Children’s Hospital, Zhejiang University School of Medicine, Hangzhou 31000, China;5. Department of Clinical Medicine, Zhejiang University City College School of Medicine, Hangzhou 310000, China;6. Blood center of Zhejiang Province, Hangzhou 310000, China;1. Department of Paediatrics, Foundation IRCCS Policlinico San Matteo, University of Pavia, Pavia, Italy;2. Department of Maternal and Children’s Health, Obstetrics and Gynecology Unit, Foundation IRCCS Policlinico San Matteo, University of Pavia, Pavia, Italy;3. Department of Electrical, Computer and Biomedical Engineering, University of Pavia, Italy;4. Department of Maternal and Children’s Health, Neonatal Intensive Care Unit, Foundation IRCCS Policlinico San Matteo, University of Pavia, Pavia, Italy;1. Environmental and Experimental Pathology, Paulista University (UNIP), Rua Dr. Bacelar 1212, 4th Floor, 04026-002, São Paulo, SP, Brazil;2. Microbiology, Immunology and Parasitology Department, Federal University, Rua Sena Madureira 1500, 04021-001, São Paulo, SP, Brazil;3. Physiopathology Department, Butantan Institute, Rua Vital Brasil 1500, 05503-900, São Paulo, SP, Brazil;1. Biozentrum, University of Basel, Klingelbergstrasse 50, CH-4056 Basel, Switzerland;2. Division of Infectious Diseases and Hospital Epidemiology, University Hospital of Zurich, Ramistrasse 100, CH-8091 Zurich, Switzerland;3. Department of Medicine, Cantonal Hospital of Winterthur, Brauerstrasse 15, CH-8401 Winterthur, Switzerland;1. Department of Microbiology, Immunology, and Molecular Genetics, University of Kentucky College of Medicine, 800 Rose Street Rm MS409, Lexington, KY 40536, USA;2. Department of Pharmacy Practice and Science, University of Kentucky College of Pharmacy, 789 S. Limestone Street Suite 292, Lexington, KY 40536, USA;3. Department of Internal Medicine, University of Kentucky College of Medicine, 900 S. Limestone Street Suite 303, Lexington, KY 40536, USA |
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| Abstract: | ![]()
Our previous study showed that TLR3 induces apoptosis via both death receptors and mitochondial in human endothelial cells. We report here that the activation of TLR4 induced dose- and time-dependent cell death in moncytic THP-1 cells. LPS treatment of THP-1 cells induced the activation of both caspase 8 and 9, suggesting the involvement of intrinsic and extrinsic apoptosis pathways. TNFα was induced by TLR4 activation at both mRNA and protein levels, but its neutralization did not down-regulated TLR4-induced cell death. TLR4 activation also induced the up-regulation of TRAIL and its receptors DR4 and DR5, and the neutralization of TRAIL ameliorated TLR4 induced apoptosis, suggesting the involvement of TRAIL and its receptors DR4 and DR5 in LPS-induced cell death. Meanwhile, LPS treatment down-regulated the expression of FLICE inhibitory protein (FLIP), a suppressor of death receptor-induced cell death. In addition, TLR4 activation down-regulated the anti-apoptotic protein bcl-2, and up-regulated the pro-apoptotic proteins Noxa and Puma, suggesting that mitochondrial apoptotic pathway was also involved in LPS-induced cell death. Furthermore, we found that TAP63α might confer to the activation of intrinsic and extrinsic apoptotic pathways. The treatment of THP-1 cells with LPS induced the translocation of TAP63α from cytoplasm to nucleus. Taken together, our study suggested that both death receptors and mitochondial were involved in TLR4-induced cell death, and TAP63α may be a target for the prevention of LPS-induced cell death. |
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| Keywords: | TLR4 Cell death Monocyte Death receptor Mitochondrial TAp63α |
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