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Seyrek K, Espe J, Reiss E, Lavrik IN. The Crosstalk of Apoptotic and Non-Apoptotic Signaling in CD95 System. Cells 2024; 13:1814. [PMID: 39513921 PMCID: PMC11545656 DOI: 10.3390/cells13211814] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2024] [Revised: 10/24/2024] [Accepted: 11/01/2024] [Indexed: 11/16/2024] Open
Abstract
The mechanisms of CD95 (Fas/APO-1)-mediated extrinsic apoptotic pathway in cancer cells have been extensively studied. The majority of human cells express CD95, but not all these cells can induce extrinsic apoptosis. Accumulating evidence has shown that CD95 is a multifunctional protein, and its stimulation can also elicit non-apoptotic or even survival signals. It has become clear that under certain cellular contexts, due to the various checkpoints, CD95 activation can trigger both apoptotic and non-apoptotic signals. The crosstalk of death and survival signals may occur at different levels of signal transduction. The strength of the CD95 stimulation, initial levels of anti-apoptotic proteins, and posttranslational modifications of the core DISC components have been proposed to be the most important factors in the life/death decisions at CD95. Successful therapeutic targeting of CD95 signaling pathways will require a better understanding of the crosstalk between CD95-induced apoptotic and cell survival pathways. In this review, in order to gain a systematic understanding of the crosstalk between CD95-mediated apoptosis and non-apoptotic signaling, we will discuss these issues in a step-by-step way.
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Affiliation(s)
| | | | | | - Inna N. Lavrik
- Translational Inflammation Research, Medical Faculty, Otto von Guericke University Magdeburg, 39106 Magdeburg, Germany; (K.S.); (J.E.); (E.R.)
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Xiao B, Li X, Feng XY, Gong S, Li ZB, Zhang J, Yuan HJ, Tan JH. Restraint stress of male mice induces apoptosis in spermatozoa and spermatogenic cells: role of the FasL/Fas system†. Biol Reprod 2020; 101:235-247. [PMID: 31066896 DOI: 10.1093/biolre/ioz057] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2018] [Revised: 12/28/2018] [Accepted: 04/05/2019] [Indexed: 12/23/2022] Open
Abstract
The mechanisms by which psychological stress impairs semen quality are largely unknown. By using a restraint-stressed mouse model, we studied the role of the FasL/Fas system in psychological stress-induced apoptosis of spermatozoa and spermatogenic cells. Male mice were restrained for 48 h before examination for sperm fertilizing potential and for apoptosis and FasL/Fas expression in spermatozoa, spermatogenetic cells/seminiferous tubules, and caudae epididymides. The results showed that the male restraint reduced motility, fertilization rates, and mitochondrial membrane potential while increasing apoptosis and Fas expression in spermatozoa. Restraint also facilitated apoptosis and FasL/Fas expression in spermatogenic cells/seminiferous tubules and caudae epididymides. The restraint-induced apoptosis in spermatozoa and spermatogenic cells was significantly ameliorated in gld mice that harbor a loss-of-function mutation in FasL. However, incubation with FasL did not affect sperm motility and apoptosis, while incubation with tumor necrosis factor (TNF)-α did. The epididymis of the gld mice produced significantly less TNF-α and TNF-related apoptosis-inducing ligand (TRAIL) than that of wild-type mice did after male restraint. Thus, the results confirmed that the FasL/Fas system played an important role in the psychological stress-induced apoptosis of spermatozoa and spermatogenic cells and that FasL triggered sperm apoptosis in epididymis dependently through promoting TNF-α and TRAIL secretion.
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Affiliation(s)
- Bin Xiao
- Shandong Provincial Key Laboratory of Animal Biotechnology and Disease Control and Prevention, College of Animal Science and Veterinary Medicine, Shandong Agricultural University, Tai'an City, P. R. China
| | - Xiao Li
- Shandong Provincial Key Laboratory of Animal Biotechnology and Disease Control and Prevention, College of Animal Science and Veterinary Medicine, Shandong Agricultural University, Tai'an City, P. R. China
| | - Xiu-Yun Feng
- Shandong Provincial Key Laboratory of Animal Biotechnology and Disease Control and Prevention, College of Animal Science and Veterinary Medicine, Shandong Agricultural University, Tai'an City, P. R. China
| | - Shuai Gong
- Shandong Provincial Key Laboratory of Animal Biotechnology and Disease Control and Prevention, College of Animal Science and Veterinary Medicine, Shandong Agricultural University, Tai'an City, P. R. China
| | - Zhi-Bin Li
- Shandong Provincial Key Laboratory of Animal Biotechnology and Disease Control and Prevention, College of Animal Science and Veterinary Medicine, Shandong Agricultural University, Tai'an City, P. R. China
| | - Jie Zhang
- Shandong Provincial Key Laboratory of Animal Biotechnology and Disease Control and Prevention, College of Animal Science and Veterinary Medicine, Shandong Agricultural University, Tai'an City, P. R. China
| | - Hong-Jie Yuan
- Shandong Provincial Key Laboratory of Animal Biotechnology and Disease Control and Prevention, College of Animal Science and Veterinary Medicine, Shandong Agricultural University, Tai'an City, P. R. China
| | - Jing-He Tan
- Shandong Provincial Key Laboratory of Animal Biotechnology and Disease Control and Prevention, College of Animal Science and Veterinary Medicine, Shandong Agricultural University, Tai'an City, P. R. China
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Kong QQ, Wang J, Xiao B, Lin FH, Zhu J, Sun GY, Luo MJ, Tan JH. Cumulus cell-released tumor necrosis factor (TNF)-α promotes post-ovulatory aging of mouse oocytes. Aging (Albany NY) 2019; 10:1745-1757. [PMID: 30048240 PMCID: PMC6075436 DOI: 10.18632/aging.101507] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2018] [Accepted: 07/20/2018] [Indexed: 12/05/2022]
Abstract
Although previous studies indicated that cumulus cells (CCs) accelerate oocyte aging by releasing soluble factors, the factors have yet to be characterized. While demonstrating that CCs promoted oocyte aging by releasing soluble Fas ligand (sFasL), our recent study suggested that CCs might secrete other factors to mediate oocyte aging as well. This study tested whether CCs accelerate oocyte aging by secreting tumor necrosis factor (TNF)-α. The results showed that mouse CCs undergoing apoptosis released soluble TNF-α (sTNF-α) during in vitro aging. While ethanol activation rates were higher, the maturation-promoting factor (MPF) activity was lower significantly after culture of cumulus-denuded oocytes (DOs) in medium conditioned with CCs for 36 h than in medium conditioned for 24 h. Aging mouse oocytes expressed TNF-receptor 1. The CCs released equal amounts of sTNF-α and sFasL during aging in vitro, and the TNF-α-knockdown CCs secreted less sFasL than the control CCs did. Treatment of DOs in vitro with sTNF-α significantly accelerated their aging. The aging-promoting effect of sTNF-α was significantly reduced in TNF-α-knocked-down CCs and in CCs from the TNF-α-knockout mice. It is concluded that mouse CCs accelerate oocyte aging by secreting sTNF-α as well as sFasL.
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Affiliation(s)
- Qiao-Qiao Kong
- Shandong Provincial Key Laboratory of Animal Biotechnology and Disease Control and Prevention, College of Animal Science and Veterinary Medicine, Shandong Agricultural University, Tai'an City 271018, P. R. China
| | - Jia Wang
- Shandong Provincial Key Laboratory of Animal Biotechnology and Disease Control and Prevention, College of Animal Science and Veterinary Medicine, Shandong Agricultural University, Tai'an City 271018, P. R. China
| | - Bin Xiao
- Shandong Provincial Key Laboratory of Animal Biotechnology and Disease Control and Prevention, College of Animal Science and Veterinary Medicine, Shandong Agricultural University, Tai'an City 271018, P. R. China
| | - Fei-Hu Lin
- Shandong Provincial Key Laboratory of Animal Biotechnology and Disease Control and Prevention, College of Animal Science and Veterinary Medicine, Shandong Agricultural University, Tai'an City 271018, P. R. China
| | - Jiang Zhu
- Shandong Provincial Key Laboratory of Animal Biotechnology and Disease Control and Prevention, College of Animal Science and Veterinary Medicine, Shandong Agricultural University, Tai'an City 271018, P. R. China
| | - Guang-Yi Sun
- Shandong Provincial Key Laboratory of Animal Biotechnology and Disease Control and Prevention, College of Animal Science and Veterinary Medicine, Shandong Agricultural University, Tai'an City 271018, P. R. China
| | - Ming-Jiu Luo
- Shandong Provincial Key Laboratory of Animal Biotechnology and Disease Control and Prevention, College of Animal Science and Veterinary Medicine, Shandong Agricultural University, Tai'an City 271018, P. R. China
| | - Jing-He Tan
- Shandong Provincial Key Laboratory of Animal Biotechnology and Disease Control and Prevention, College of Animal Science and Veterinary Medicine, Shandong Agricultural University, Tai'an City 271018, P. R. China
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Ito H, Kurokawa H, Suzuki H, Indo HP, Majima HJ, Matsui H. 5-Aminolevulinic acid induced apoptosis via oxidative stress in normal gastric epithelial cells. J Clin Biochem Nutr 2019; 65:83-90. [PMID: 31592061 DOI: 10.3164/jcbn.18-46] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2018] [Accepted: 01/04/2019] [Indexed: 12/13/2022] Open
Abstract
5-Aminolevulinic acid, a precursor of heme, is utilized in a variety of applications including cancer treatment, surgery, and plant nutrition. However, 5-aminolevulinic acid itself induces oxidative stress and subsequent lipid peroxidation. Reactive oxygen species are factors in oxidative stress, not only causing cellular injury but also inducing several signal transduction pathways. Especially in cancer cells, a significant amount of signalling activation and subsequent activation of protein is caused by the enhancement of reactive oxygen species production. Reactive oxygen species levels in normal cells are low and an oxidative condition is harmful; hence, administration of 5-aminolevulinic acid to normal cells may induce oxidative stress, resulting in cell death. In this study, we investigated the effect of 5-aminolevulinic acid on normal and cancer cells with regard to oxidative stress. We used the rat normal gastric cell line RGM and its cancer-like mutant cell line RGK. 5-Aminolevulinic acid treatment of RGM cells enhanced reactive oxygen species generation and induced apoptosis associated with p53, whereas RGK cells were unaffected. In addition, RGM cell viability was recovered by application of N-acetyl-l-cysteine or p53 inhibitor. These results suggest that 5-aminolevulinic acid causes oxidative stress in normal gastric cells and induces apoptosis via the p53-dependent pathway.
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Affiliation(s)
- Hiromu Ito
- Graduate School of Medical and Dental Sciences, Kagoshima University, 8-35-1 Sakuragaoka, Kagoshima, Kagoshima 890-8544, Japan
| | - Hiromi Kurokawa
- Department of Gastroenterology, Faculty of Medicine, University of Tsukuba, 1-1-1 Tennoh-dai, Tsukuba, Ibaraki 305-8575, Japan
| | - Hideo Suzuki
- Department of Gastroenterology, Faculty of Medicine, University of Tsukuba, 1-1-1 Tennoh-dai, Tsukuba, Ibaraki 305-8575, Japan
| | - Hiroko P Indo
- Graduate School of Medical and Dental Sciences, Kagoshima University, 8-35-1 Sakuragaoka, Kagoshima, Kagoshima 890-8544, Japan
| | - Hideyuki J Majima
- Graduate School of Medical and Dental Sciences, Kagoshima University, 8-35-1 Sakuragaoka, Kagoshima, Kagoshima 890-8544, Japan
| | - Hirofumi Matsui
- Department of Gastroenterology, Faculty of Medicine, University of Tsukuba, 1-1-1 Tennoh-dai, Tsukuba, Ibaraki 305-8575, Japan
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Li C, Yang B, Pan P, Ma Q, Wu Y, Zhang Z, Guo X, Ye J, Gui Y. MicroRNA-130a inhibits spermatogenesis by directly targeting androgen receptor in mouse Sertoli cells. Mol Reprod Dev 2018; 85:768-777. [PMID: 30191667 DOI: 10.1002/mrd.23058] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2018] [Accepted: 09/04/2018] [Indexed: 12/18/2022]
Abstract
MicroRNAs (miRNAs) have been shown to play a key role in spermatogenesis. However, whether the miRNAs influence androgen/androgen receptor (AR) signaling during spermatogenesis remains unclear. Using a bioinformatic approach, a potential miRNA, miR-130a, which could bind to Ar-3'untranslated region directly was identified. The expression pattern of miR-130a was further characterized by quantitative real-time polymerase chain reaction. It was found that miR-130a was abundant in testis and its expression level was negatively correlated with age. Overexpression of miR-130a could inhibit AR expression both in vitro and in vivo. Moreover, the mice with an intratesticular injection of miR-130a showed defects in spermatogenesis and increased germ cell apoptosis. Taken together, these results suggest that miR-130a could negatively regulate AR expression in mouse Sertoli cell, which further cause defects in spermatogenesis.
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Affiliation(s)
- Cailing Li
- Guangdong and Shenzhen Key Laboratory of Male Reproductive Medicine and Genetics, Institute of Urology, Peking University Shenzhen Hospital, Shenzhen PKU-HKUST Medical Center, Shenzhen, China
| | - Bo Yang
- Guangdong and Shenzhen Key Laboratory of Male Reproductive Medicine and Genetics, Institute of Urology, Peking University Shenzhen Hospital, Shenzhen PKU-HKUST Medical Center, Shenzhen, China
| | - Peng Pan
- Reproductive Medicine Center, Jinling Hospital affiliated of Nanjing University, Nanjing, China
| | - Qian Ma
- Guangdong and Shenzhen Key Laboratory of Male Reproductive Medicine and Genetics, Institute of Urology, Peking University Shenzhen Hospital, Shenzhen PKU-HKUST Medical Center, Shenzhen, China
| | - Yong Wu
- Reproductive Center, Jingzhou Central Hospital affiliated of The Second Clinical Medical College, Yangze University, Jingzhou, China
| | - Zeng Zhang
- Guangdong and Shenzhen Key Laboratory of Male Reproductive Medicine and Genetics, Institute of Urology, Peking University Shenzhen Hospital, Shenzhen PKU-HKUST Medical Center, Shenzhen, China
| | - Xin Guo
- Guangdong and Shenzhen Key Laboratory of Male Reproductive Medicine and Genetics, Institute of Urology, Peking University Shenzhen Hospital, Shenzhen PKU-HKUST Medical Center, Shenzhen, China
| | - Jing Ye
- Guangdong and Shenzhen Key Laboratory of Male Reproductive Medicine and Genetics, Institute of Urology, Peking University Shenzhen Hospital, Shenzhen PKU-HKUST Medical Center, Shenzhen, China
| | - Yaoting Gui
- Guangdong and Shenzhen Key Laboratory of Male Reproductive Medicine and Genetics, Institute of Urology, Peking University Shenzhen Hospital, Shenzhen PKU-HKUST Medical Center, Shenzhen, China
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Szymanski L, Cios A, Lewicki S, Szymanski P, Stankiewicz W. Fas/FasL pathway and cytokines in keratinocytes in atopic dermatitis - Manipulation by the electromagnetic field. PLoS One 2018; 13:e0205103. [PMID: 30286163 PMCID: PMC6171903 DOI: 10.1371/journal.pone.0205103] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2018] [Accepted: 08/05/2018] [Indexed: 01/16/2023] Open
Abstract
BACKGROUND Atopic dermatitis (AD) is one of the most frequent skin diseases. Changes of the keratinocytes functionality play a major role in the development of AD. For example, activation of the Fas (CD95)/FasL (CD178) pathway in AD does not lead to extensive apoptosis in skin. Binding of the Fas receptor to its protein ligand-FasL, which are present on the (AD)-modified keratinocytes, should result in the sequential induction of cell death, but there is no evidence of extensive apoptosis of these cells. This suggests that non-apoptotic mechanism of Fas/FasL pathway is commonly encountered, although not examined in the case of AD, phenomenon. An electromagnetic field, which was used to influence cultured cells in this study, can modulate proliferation, apoptosis, differentiation, and metabolism in various cells. OBJECTIVE Here, we evaluate the possibility to manipulate the immune activation of AD keratinocytes and their response to the electromagnetic field, which was not tested before. METHODS Keratinocytes isolated from the skin of healthy subjects (n = 20) and patients with atopic dermatitis (n = 20) as well as HaCaT and PCS-200-010 cell were exposed to the 900 MHz electromagnetic field for 60 minutes. Cytometric analysis of viability, Fas/FasL, p-ERK, p-p38 and p-JNK expression and Luminex analysis of cytokine concentration were performed in two-time points: 4 and 24 hours after the exposition. RESULTS This research has shown upregulated Fas, FasL, p-ERK, p-p38, and p-JNK expression along with increased cytokine secretion (IL-1β, IL-4, IL-8, IL-10, IL-12p70, IL-13, IL-17A, IL-31 and TNFα) by keratinocytes derived from the skin of patients with the AD when compared with healthy control. Exposure of keratinocyte cultures obtained from AD patients to EMF resulted in a decrease of 1β, IL-4, IL-10, IL-12, I L-13, IL-17, IL-31 and TNFα levels. Keratinocytes derived from the skin of AD patients are characterized by elevated Fas and FasL expression when compared to healthy control. CONCLUSION Apoptotic and nonapoptotic activation of the Fas/FasL-dependent signaling pathway may play a significant role in the pathogenesis of AD, by adjusting the local cytokine and chemokine environment at the site of inflammation. Moreover, the electromagnetic field exhibits strong immunomodulatory effects on AD-modified keratinocytes.
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Affiliation(s)
- Lukasz Szymanski
- Department of Microwave Safety, Military Institute of Hygiene and Epidemiology, Warsaw, Poland
| | - Aleksandra Cios
- Department of Microwave Safety, Military Institute of Hygiene and Epidemiology, Warsaw, Poland
| | - Sławomir Lewicki
- Department of Regenerative Medicine and Cell Biology, Military Institute of Hygiene and Epidemiology, Warsaw, Poland
| | - Pawel Szymanski
- Department of Microwave Safety, Military Institute of Hygiene and Epidemiology, Warsaw, Poland
| | - Wanda Stankiewicz
- Department of Microwave Safety, Military Institute of Hygiene and Epidemiology, Warsaw, Poland
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Zou H, Su R, Ruan J, Shao H, Qian K, Ye J, Yao Y, Nair V, Qin A. Double-stranded RNA induces chicken T-cell lymphoma apoptosis by TRIF and NF-κB. Sci Rep 2017; 7:7547. [PMID: 28790362 PMCID: PMC5548913 DOI: 10.1038/s41598-017-07919-w] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2016] [Accepted: 05/10/2017] [Indexed: 12/20/2022] Open
Abstract
Toll-like receptor-3 (TLR3), a member of the pathogen recognition receptor family, has been reported to activate immune response and to exhibit pro-apoptotic activity against some tumor cells. However it is unclear whether TLR3 has same function against chicken lymphoma. In this paper we investigated the effect of TLR3 activation on a Marek’s disease lymphoma-derived chicken cell line, MDCC-MSB1. The TLR3 agonist poly (I:C) activated TLR3 pathway and inhibited tumor cells proliferation through caspase-dependent apoptosis. Using pharmacological approaches, we found that an interferon-independent mechanism involving Toll-IL-1-receptor domain-containing adapter-inducing IFN-α (TRIF) and nuclear factor κB (NF-κB) causes the apoptosis of MDCC-MSB1 cells. This is the first report about the function of TLR3 in chicken T-cell lymphoma, especially in signal pathway. The mechanisms underlying TLR3-mediated apoptosis may contribute to the development of new drug to treat lymphomas and oncovirus infections.
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Affiliation(s)
- Haitao Zou
- Ministry of Education Key Lab for Avian Preventive Medicine, Yangzhou University, No. 12 East Wenhui Road, Yangzhou, Jiangsu, 225009, P. R. China.,Jiangsu Co-innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, No. 12 East Wenhui Road, Yangzhou, Jiangsu, 225009, P. R. China
| | - Ruixue Su
- Ministry of Education Key Lab for Avian Preventive Medicine, Yangzhou University, No. 12 East Wenhui Road, Yangzhou, Jiangsu, 225009, P. R. China.,Jiangsu Co-innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, No. 12 East Wenhui Road, Yangzhou, Jiangsu, 225009, P. R. China
| | - Jing Ruan
- Ministry of Education Key Lab for Avian Preventive Medicine, Yangzhou University, No. 12 East Wenhui Road, Yangzhou, Jiangsu, 225009, P. R. China.,Jiangsu Co-innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, No. 12 East Wenhui Road, Yangzhou, Jiangsu, 225009, P. R. China
| | - Hongxia Shao
- Ministry of Education Key Lab for Avian Preventive Medicine, Yangzhou University, No. 12 East Wenhui Road, Yangzhou, Jiangsu, 225009, P. R. China.,Jiangsu Co-innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, No. 12 East Wenhui Road, Yangzhou, Jiangsu, 225009, P. R. China.,Jiangsu Key Lab of Zoonosis, No. 12 East Wenhui Road, Yangzhou, Jiangsu, 225009, P. R. China
| | - Kun Qian
- Ministry of Education Key Lab for Avian Preventive Medicine, Yangzhou University, No. 12 East Wenhui Road, Yangzhou, Jiangsu, 225009, P. R. China.,Jiangsu Co-innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, No. 12 East Wenhui Road, Yangzhou, Jiangsu, 225009, P. R. China.,Jiangsu Key Lab of Zoonosis, No. 12 East Wenhui Road, Yangzhou, Jiangsu, 225009, P. R. China.,UK-China Centre of Excellence for Research on Avian Diseases, 169 Huanghe 2nd Road, Binzhou, Shandong, P. R. China
| | - Jianqiang Ye
- Ministry of Education Key Lab for Avian Preventive Medicine, Yangzhou University, No. 12 East Wenhui Road, Yangzhou, Jiangsu, 225009, P. R. China.,Jiangsu Co-innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, No. 12 East Wenhui Road, Yangzhou, Jiangsu, 225009, P. R. China.,Jiangsu Key Lab of Zoonosis, No. 12 East Wenhui Road, Yangzhou, Jiangsu, 225009, P. R. China
| | - Yongxiu Yao
- The Pirbright Institute, Ash road, Pirbright, Working, Surrey, GU24 0NF, United Kingdom.,UK-China Centre of Excellence for Research on Avian Diseases, 169 Huanghe 2nd Road, Binzhou, Shandong, P. R. China
| | - Venugopal Nair
- The Pirbright Institute, Ash road, Pirbright, Working, Surrey, GU24 0NF, United Kingdom.,UK-China Centre of Excellence for Research on Avian Diseases, 169 Huanghe 2nd Road, Binzhou, Shandong, P. R. China
| | - Aijian Qin
- Ministry of Education Key Lab for Avian Preventive Medicine, Yangzhou University, No. 12 East Wenhui Road, Yangzhou, Jiangsu, 225009, P. R. China. .,Jiangsu Co-innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, No. 12 East Wenhui Road, Yangzhou, Jiangsu, 225009, P. R. China. .,Jiangsu Key Lab of Zoonosis, No. 12 East Wenhui Road, Yangzhou, Jiangsu, 225009, P. R. China. .,UK-China Centre of Excellence for Research on Avian Diseases, 169 Huanghe 2nd Road, Binzhou, Shandong, P. R. China.
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Yiğit U, Kırzıoğlu FY, Uğuz AC, Nazıroğlu M, Özmen Ö. Is caffeic acid phenethyl ester more protective than doxycycline in experimental periodontitis? Arch Oral Biol 2017; 81:61-68. [PMID: 28482239 DOI: 10.1016/j.archoralbio.2017.04.017] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2016] [Revised: 03/09/2017] [Accepted: 04/17/2017] [Indexed: 12/14/2022]
Abstract
BACKGROUND AND OBJECTIVES Host modulation therapies (anti-inflammatory drugs, bone-stimulating agents, anti-proteinase etc.) target the inhibition or stabilization of tissue breakdown. The aim of the present study was to evaluate the effects of caffeic acid phenethyl ester (CAPE) and/or low dose doxycycline (LDD) administrations on alveolar bone loss (ABL), serum cytokines and gingival apoptosis, as well as the levels of oxidants and anti-oxidants in rats with ligature-induced periodontitis. MATERIAL AND METHODS The animals were randomly divided into five groups: Group C (periodontally healthy), Group PC (Periodontitis+CAPE), Group PD (Periodontitis+LDD), Group PCD (Periodontitis+CAPE+LDD), Group P (Periodontitis). Experimental periodontitis was induced for 14days. Levels of ABL, and the serum cytokines, interleukin (IL)-1 β, IL-6, tumor necrosis factor-α (TNF-α) and IL-10 were assessed as were the levels of the oxidants and anti-oxidants, malondialdehyde (MDA), glutathione (GSH) and glutathione peroxidase (GSH-Px), and levels of gingival apoptosis. RESULTS The lowest ABL levels was evident in the PC group, among the experimental groups. There was also less inflammatory infiltration in the PC group than the PD group. IL-1β, IL-6, and IL-10 were lower in the PC group and higher in the P group in comparison to the levels in the other experiment groups. TNF-α levels in the PD group were higher than levels in the PC and PCD groups. The PC and PCD groups did not differ from the C group in regard to MDA levels. The highest GSH-Px level was found in the PC group. Gingival apoptosis in the PC group was not only lower than the PD and PCD groups, but also lower than in the C group. CONCLUSION The present study suggests that CAPE has more anti-inflammatory, anti-oxidant and anti-apoptotic effects than LDD, with no additive benefits of a CAPE+LDD combination being evident in rats with periodontitis.
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Affiliation(s)
- Umut Yiğit
- Uşak University, Faculty of Dentistry, Department of Periodontology, Uşak, Turkey.
| | - Fatma Yeşim Kırzıoğlu
- Süleyman Demirel University, Faculty of Dentistry, Department of Periodontology, Isparta, Turkey
| | - Abdülhadi Cihangir Uğuz
- Süleyman Demirel University, Faculty of Medicine, Department of Biophysics, Isparta, Turkey; Süleyman Demirel University, Neuroscience Research Center, Isparta, Turkey
| | - Mustafa Nazıroğlu
- Süleyman Demirel University, Faculty of Medicine, Department of Biophysics, Isparta, Turkey; Süleyman Demirel University, Neuroscience Research Center, Isparta, Turkey
| | - Özlem Özmen
- Mehmet Akif Ersoy University, Faculty of Veterinary Medicine, Department of Pathology, Burdur, Turkey
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9
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Toll-like receptor agonists induce apoptosis in mouse B-cell lymphoma cells by altering NF-κB activation. Cell Mol Immunol 2013; 10:360-72. [PMID: 23727784 DOI: 10.1038/cmi.2013.14] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2012] [Revised: 03/14/2013] [Accepted: 03/18/2013] [Indexed: 12/13/2022] Open
Abstract
Toll-like receptor 9 (TLR9) recognizes microbial DNA containing unmethylated cytosyl guanosyl (CpG) sequences, induces innate immune responses, and facilitates antigen-specific adaptive immunity. Recent studies report that in addition to stimulating innate immunity, TLR9 ligands induce apoptosis of TLR9 expressing cancer cells. To understand the mechanism of TLR9-induced apoptosis, we compared the effects of CpG containing oligodeoxynucleotides (CpG ODN) on a mouse B-cell lymphoma line, CH27, with those on mouse splenic B cells. CpG ODN inhibited constitutive proliferation and induced apoptosis in the CH27 B-cell lymphoma line. In contrast, CpG ODN-treated primary B cells were stimulated to proliferate and were rescued from spontaneous apoptosis. The induction of apoptosis required the ODNs to contain the CpG motif and the expression of TLR9 in lymphoma B cells. A decrease in Bcl-xl expression and an increase in Fas and Fas ligand expression accompanied lymphoma B-cell apoptosis. Treatment with the Fas ligand-neutralizing antibody inhibited CpG ODN-induced apoptosis. CpG ODN triggered a transient NF-κB activation in the B-cell lymphoma cell line, which constitutively expresses a high level of c-Myc, while CpG ODN induced sustained increases in NF-κB activation and c-Myc expression in primary B cells. Furthermore, an NF-κB inhibitor inhibited the proliferation of the CH27 B-cell lymphoma line. Our data suggest that the differential responses of lymphoma and primary B cells to CpG ODN are the result of differences in NF-κB activation. The impaired NF-κB activation in the CpG ODN-treated B-cell lymphoma cell line alters the balance between NF-κB and c-Myc, which induces Fas/Fas ligand-dependent apoptosis.
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Chen L. Okadaic acid induces apoptosis through the PKR, NF-κB and caspase pathway in human osteoblastic osteosarcoma MG63 cells. Toxicol In Vitro 2011; 25:1796-802. [PMID: 21964477 DOI: 10.1016/j.tiv.2011.09.014] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2011] [Revised: 09/05/2011] [Accepted: 09/18/2011] [Indexed: 11/24/2022]
Abstract
Okadaic acid (OA) is the major component of diarrheic shellfish poisoning toxins and a potent inhibitor of protein phosphatase 1 and 2A. However, the underlying regulatory mechanisms involved in OA-induced cell death are not well understood. In the present study, we examined the effects of OA on apoptosis of MG63 cells by characterizing apoptotic morphological changes of the cells and DNA fragmentation. The roles of double-stranded RNA-dependent protein kinase (PKR), nuclear factor-κB (NF-κB) and caspase in OA-mediated apoptosis in MG63 cells were also examined. Results showed that OA induced cytotoxicity and apoptosis in MG63 cells at IC50 of 75 nM. A functional PKR pathway is required to induce apoptosis in response to OA treatment. Blockade of NF-κB by ammonium pyrrolidinedithiocarbamate (PDTC) resulted in down-regulation of apoptosis. The caspase-3 and caspase-8 inhibitors blocked apoptosis in MG63 cells. In conclusion, our results imply that OA can induce MG63 cell apoptosis through the PKR, NF-κB and caspase pathway.
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Affiliation(s)
- Ling Chen
- Department of Histology and Oral Histology, Institute of Health Biosciences, University of Tokushima Graduate School, Kuramoto, Tokushima 770-8504, Japan.
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11
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Iyer AKV, Azad N, Talbot S, Stehlik C, Lu B, Wang L, Rojanasakul Y. Antioxidant c-FLIP inhibits Fas ligand-induced NF-kappaB activation in a phosphatidylinositol 3-kinase/Akt-dependent manner. THE JOURNAL OF IMMUNOLOGY 2011; 187:3256-66. [PMID: 21856935 DOI: 10.4049/jimmunol.1002915] [Citation(s) in RCA: 27] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Fas ligand (FasL) belongs to the TNF family of death ligands, and its binding to the FasR leads to activation of several downstream signaling pathways and proteins, including NF-κB and PI3K/Akt. However, it is not known whether cross-talk exists between NF-κB and PI3K/Akt in the context of FasL signaling. We demonstrate using both human renal epithelial 293T cells and Jurkat T-lymphocyte cells that although FasL activates both Akt and NF-κB, Akt inhibits FasL-dependent NF-κB activity in a reactive oxygen species-dependent manner. Cellular FLICE-inhibitory protein (c-FLIP), an antioxidant and an important component of the death-inducing signaling complex, also represses NF-κB upstream of the regulatory IκB kinase-γ protein subunit in the NF-κB signaling pathway, and positive cross-talk exists between Akt and c-FLIP in the context of inhibition of FasL-induced NF-κB activity. The presence of two death effector domains of c-FLIP and S-nitrosylation of its caspase-like domain were found to be important for mediating c-FLIP-dependent downregulation of NF-κB activity. Taken together, our study reveals a novel link between NF-κB and PI3K/Akt and establishes c-FLIP as an important regulator of FasL-mediated cell death.
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12
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Langlois RA, Legge KL. Plasmacytoid dendritic cells enhance mortality during lethal influenza infections by eliminating virus-specific CD8 T cells. JOURNAL OF IMMUNOLOGY (BALTIMORE, MD. : 1950) 2010; 184:4440-6. [PMID: 20220091 PMCID: PMC2851488 DOI: 10.4049/jimmunol.0902984] [Citation(s) in RCA: 47] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Previous studies have shown that the reduction in CD8 T cell immunity observed during high-dose influenza A virus (IAV) infection is mediated via lymph node (LN) dendritic cells (DCs) that express Fas ligand (FasL) and drive FasL-Fas (DC-T)-induced apoptosis. However, the specific DC subset(s) within the LN and the additional factors required for DC-mediated elimination of IAV-specific CD8 T cells remain unknown. In this paper, we demonstrate that plasmacytoid DCs (pDCs), which downregulate FasL during sublethal, but not lethal, IAV infection, accumulate to greater numbers within the LNs of lethal dose-infected mice. Further our findings show that pDCs from lethal, but not sublethal, dose IAV infections drive elimination of Fas(+) CD8 T cells and that this elimination occurs only in the absence of TCR recognition of IAV peptide-MHC class I complexes. Together, these results suggest that pDCs play a heretofore unknown deleterious role during lethal dose IAV infections by limiting the CD8 T cell response.
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Affiliation(s)
- Ryan A. Langlois
- Department of Pathology and Interdisciplinary Graduate Program in Immunology, University of Iowa, Iowa City, IA 52242, United States
| | - Kevin L. Legge
- Department of Pathology and Interdisciplinary Graduate Program in Immunology, University of Iowa, Iowa City, IA 52242, United States
- Department of Microbiology, University of Iowa, Iowa City, IA 52242, United States
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13
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Lu K, Liang CL, Liliang PC, Yang CH, Cho CL, Weng HC, Tsai YD, Wang KW, Chen HJ. Inhibition of extracellular signal-regulated kinases 1/2 provides neuroprotection in spinal cord ischemia/reperfusion injury in rats: relationship with the nuclear factor-kappaB-regulated anti-apoptotic mechanisms. J Neurochem 2010; 114:237-46. [PMID: 20403072 DOI: 10.1111/j.1471-4159.2010.06747.x] [Citation(s) in RCA: 28] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Abstract
Previously we demonstrated benefits of inhibiting the extracellular signal-regulated kinases 1/2 (ERK1/2) signaling pathway in spinal cord ischemia/reperfusion (I/R) injury. To further identify the underlying mechanisms, we investigated the impact of ERK inhibition on apoptosis and cellular protective mechanisms against cell death. Spinal cord I/R injury induced ERK1/2 phosphorylation, followed by neuronal loss through caspase 3-mediated apoptosis. Pre-treatment with U0126, a specific inhibitor of MAPK/ERK kinases 1/2 (MEK1/2), inhibited ERK1/2 phosphorylation, and significantly attenuated apoptosis and increased neuronal survival. MEK/ERK inhibition also induced I-kappaB phosphorylation and enhanced nuclear factor (NF)-kappaB/DNA binding activity, leading to expression of cellular inhibitors of apoptosis protein 2 (c-IAP2), a known nuclear factor-kappaB (NF-kappaB)-regulated endogenous anti-apoptotic molecule. Pyrrolidine dithiocarbamate, an NF-kappaB inhibitor, by blocking I-kappaB phosphorylation, NF-kappaB activation, and c-IAP2 synthesis, abolished the protective effects of U0126. The MEK/ERK pathway appears to mediate cellular death following I/R injury. The U0126 neuroprotection appears related to NF-kappaB-regulated transcriptional control of c-IAP2. MEK/ERK inhibition at the initial stage of I/R injury may cause changes in c-IAP2 gene expression or c-IAP2/caspase 3 interactions, resulting in long lasting therapeutic effects. Future research should focus on the possible cross-talk between the MEK/ERK pathway and the NF-kappaB transcriptional cascade.
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Affiliation(s)
- Kang Lu
- Department of Neurosurgery, E-Da Hospital, I-Shou University, Kaohsiung 824, Taiwan
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14
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Beraza N, Malato Y, Sander LE, Al-Masaoudi M, Freimuth J, Riethmacher D, Gores GJ, Roskams T, Liedtke C, Trautwein C. Hepatocyte-specific NEMO deletion promotes NK/NKT cell- and TRAIL-dependent liver damage. ACTA ACUST UNITED AC 2009; 206:1727-37. [PMID: 19635861 PMCID: PMC2722179 DOI: 10.1084/jem.20082152] [Citation(s) in RCA: 76] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
Nuclear factor κB (NF-κB) is one of the main transcription factors involved in regulating apoptosis, inflammation, chronic liver disease, and cancer progression. The IKK complex mediates NF-κB activation and deletion of its regulatory subunit NEMO in hepatocytes (NEMOΔhepa) triggers chronic inflammation and spontaneous hepatocellular carcinoma development. We show that NEMOΔhepa mice were resistant to Fas-mediated apoptosis but hypersensitive to tumor necrosis factor–related apoptosis-inducing ligand (TRAIL) as the result of a strong up-regulation of its receptor DR5 on hepatocytes. Additionally, natural killer (NK) cells, the main source of TRAIL, were activated in NEMOΔhepa livers. Interestingly, depletion of the NK1.1+ cells promoted a significant reduction of liver inflammation and an improvement of liver histology in NEMOΔhepa mice. Furthermore, hepatocyte-specific NEMO deletion strongly sensitized the liver to concanavalin A (ConA)–mediated injury. The critical role of the NK cell/TRAIL axis in NEMOΔhepa livers during ConA hepatitis was further confirmed by selective NK cell depletion and adoptive transfer of TRAIL-deficient−/− mononuclear cells. Our results uncover an essential mechanism of NEMO-mediated protection of the liver by preventing NK cell tissue damage via TRAIL/DR5 signaling. As this mechanism is important in human liver diseases, NEMOΔhepa mice are an interesting tool to give insight into liver pathophysiology and to develop future therapeutic strategies.
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Affiliation(s)
- Naiara Beraza
- Department of Internal Medicine III, University Hospital (RWTH) Aachen, Aachen 5205, Germany
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15
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Sun Y, Lee JH, Kim NH, Lee CW, Kim MJ, Kim SH, Huh SO. Lysophosphatidylcholine-induced apoptosis in H19-7 hippocampal progenitor cells is enhanced by the upregulation of Fas Ligand. Biochim Biophys Acta Mol Cell Biol Lipids 2009; 1791:61-8. [DOI: 10.1016/j.bbalip.2008.09.007] [Citation(s) in RCA: 15] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2008] [Revised: 09/18/2008] [Accepted: 09/30/2008] [Indexed: 11/15/2022]
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16
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Fernandez-Solà J, Preedy VR, Lang CH, Gonzalez-Reimers E, Arno M, Lin JCI, Wiseman H, Zhou S, Emery PW, Nakahara T, Hashimoto K, Hirano M, Santolaria-Fernández F, González-Hernández T, Fatjó F, Sacanella E, Estruch R, Nicolás JM, Urbano-Márquez A. Molecular and cellular events in alcohol-induced muscle disease. Alcohol Clin Exp Res 2008; 31:1953-62. [PMID: 18034690 DOI: 10.1111/j.1530-0277.2007.00530.x] [Citation(s) in RCA: 66] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
Alcohol consumption induces a dose-dependent noxious effect on skeletal muscle, leading to progressive functional and structural damage of myocytes, with concomitant reductions in lean body mass. Nearly half of high-dose chronic alcohol consumers develop alcoholic skeletal myopathy. The pathogenic mechanisms that lie between alcohol intake and loss of muscle tissue involve multiple pathways, making the elucidation of the disease somewhat difficult. This review discusses the recent advances in basic and clinical research on the molecular and cellular events involved in the development of alcohol-induced muscle disease. The main areas of recent research interest on this field are as follows: (i) molecular mechanisms in alcohol exposed muscle in the rat model; (ii) gene expression changes in alcohol exposed muscle; (iii) the role of trace elements and oxidative stress in alcoholic myopathy; and (iv) the role of apoptosis and preapoptotic pathways in alcoholic myopathy. These aforementioned areas are crucial in understanding the pathogenesis of this disease. For example, there is overwhelming evidence that both chronic alcohol ingestion and acute alcohol intoxication impair the rate of protein synthesis of myofibrillar proteins, in particular, under both postabsorptive and postprandial conditions. Perturbations in gene expression are contributory factors to the development of alcoholic myopathy, as ethanol-induced alterations are detected in over 400 genes and the protein profile (i.e., the proteome) of muscle is also affected. There is supportive evidence that oxidative damage is involved in the pathogenesis of alcoholic myopathy. Increased lipid peroxidation is related to muscle fibre atrophy, and reduced serum levels of some antioxidants may be related to loss of muscle mass and muscle strength. Finally, ethanol induces skeletal muscle apoptosis and increases both pro- and antiapoptotic regulatory mechanisms.
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17
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Chauhan P, Sodhi A, Tarang S. Cisplatin-treated murine peritoneal macrophages induce apoptosis in L929 cells: role of Fas-Fas ligand and tumor necrosis factor-tumor necrosis factor receptor 1. Anticancer Drugs 2007; 18:187-96. [PMID: 17159605 DOI: 10.1097/cad.0b013e3280104b11] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
Abstract
Cisplatin [cis-diamminedichloroplatinum (II)]-treated murine peritoneal macrophages interact with L929 cells in vitro in a sequential manner, resulting in the formation of contact between the two cells. This interaction leads to the death of L929 cells by the process of apoptosis. The detailed investigations have suggested the involvement of two different pathways in macrophage-mediated L929 cell apoptosis. It is observed that the induction of apoptosis in L929 cells by cisplatin-treated macrophages is contact dependent and is mediated through Fas-Fas ligand and tumor necrosis factor-tumor necrosis factor receptor 1 pathways. This conclusion was based on the Western blot and immunoprecipitation analysis of Fas-Fas ligand, tumor necrosis factor-tumor necrosis factor receptor 1, Fas-associated death domain and tumor necrosis factor receptor-associated death domain. The Fas-Fas ligand interaction between macrophages and L929 cells increased the expression of Fas-associated death domain, and tumor necrosis factor-tumor necrosis factor receptor 1 interaction between macrophages and L929 cells increased the expression of tumor necrosis factor receptor-associated death domain in L929 cells. The induction of apoptosis in L929 cells was investigated by DNA fragmentation, Annexin V staining and Western blot analysis of Bax, Bcl-2, Bid, cytochrome c, poly(ADP ribose) polymerase, CAD, caspase-8 and caspase-3.
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Affiliation(s)
- Puja Chauhan
- School of Biotechnology, Banaras Hindu University, Varanasi 221005, India
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18
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Ariel A, Li PL, Wang W, Tang WX, Fredman G, Hong S, Gotlinger KH, Serhan CN. The Docosatriene Protectin D1 Is Produced by TH2 Skewing and Promotes Human T Cell Apoptosis via Lipid Raft Clustering. J Biol Chem 2005; 280:43079-86. [PMID: 16216871 DOI: 10.1074/jbc.m509796200] [Citation(s) in RCA: 186] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/03/2023] Open
Abstract
Docosahexaenoic acid, a major omega-3 fatty acid in human brain, synapses, retina, and other neural tissues, displays beneficial actions in neuronal development, cancer, and inflammatory diseases by mechanisms that remain to be elucidated. In this study we found, using lipid mediator informatics employing liquid chromatography-tandem mass spectrometry, that (10,17S)-docosatriene/neuroprotectin D1, now termed protectin D1 (PD1), is generated from docosahexaenoic acid by T helper type 2-skewed peripheral blood mononuclear cells in a lipoxygenase-dependent manner. PD1 blocked T cell migration in vivo, inhibited tumor necrosis factor alpha and interferon-gamma secretion, and promoted apoptosis mediated by raft clustering. These results demonstrated novel anti-inflammatory roles for PD1 in regulating events associated with inflammation and resolution.
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Affiliation(s)
- Amiram Ariel
- Center for Experimental Therapeutics and Reperfusion Injury, Department of Anesthesiology, Perioperative and Pain Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts 02115, USA
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19
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Fan W, Ha T, Li Y, Ozment-Skelton T, Williams DL, Kelley J, Browder IW, Li C. Overexpression of TLR2 and TLR4 susceptibility to serum deprivation-induced apoptosis in CHO cells. Biochem Biophys Res Commun 2005; 337:840-8. [PMID: 16213463 DOI: 10.1016/j.bbrc.2005.09.123] [Citation(s) in RCA: 18] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2005] [Accepted: 09/20/2005] [Indexed: 12/22/2022]
Abstract
We examined the effect of overexpression of TLR2 and TLR4 on apoptosis. TLR2 and TLR4 transfected CHO cells were subjected to serum deprivation for 0, 24, and 48 h. CHO cells served as control. The survival was 80.4% and 66.8% in CHO cells, 73.8% and 47.6% in TLR2/CHO, and 70.5% and 53.0% in TLR4/CHO, respectively. Flow cytometry examination suggested that apoptotic cells were 7.17% and 32.91% in control CHO cells, 29.0% and 64.6% in TLR2/CHO, and 41.4% and 64.6% in TLR4/CHO, respectively. The levels of FasL and caspase-8 activity in TLR2/CHO and TLR4/CHO cells were significantly higher than that of CHO cells. Transfection of dominant negative FADD into TLR2/CHO and TLR4/CHO cells significantly reduced apoptosis. Our results suggest that overexpression of TLR2 and TLR4 in CHO cells sensitizes the cells to serum deprivation-induced apoptosis and that the mechanisms are involved in the death receptor-mediated signaling pathway.
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Affiliation(s)
- Wei Fan
- Department of Surgery, James H. Quillen College of Medicine, East Tennessee State University, Johnson City, TN 37614, USA
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20
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Chanvorachote P, Nimmannit U, Wang L, Stehlik C, Lu B, Azad N, Rojanasakul Y. Nitric oxide negatively regulates Fas CD95-induced apoptosis through inhibition of ubiquitin-proteasome-mediated degradation of FLICE inhibitory protein. J Biol Chem 2005; 280:42044-50. [PMID: 16246840 DOI: 10.1074/jbc.m510080200] [Citation(s) in RCA: 82] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/18/2023] Open
Abstract
Stimulation of cell surface Fas (CD95) results in recruitment of cytoplasmic proteins and activation of caspase-8, which in turn activates downstream effector caspases leading to programmed cell death. Nitric oxide (NO) plays a key role in the regulation of apoptosis, but its role in Fas-induced cell death and the underlying mechanism are largely unknown. Here we show that stimulation of the Fas receptor by its ligand (FasL) results in rapid generation of NO and concomitant decrease in cellular FLICE inhibitory protein (FLIP) expression without significant effect on Fas and Fas-associated death domain (FADD) adapter protein levels. FLIP down-regulation as well as caspase-8 activation and apoptosis induced by FasL were all inhibited by the NO-liberating agent sodium nitroprusside and dipropylenetriamine NONOate, whereas the NO synthase inhibitor aminoguanidine and NO scavenger 2-(4-carboxyphenyl)-4,4,5,5-tetramethyl-imidazoline-1-oxyl-3-oxide (PTIO) had opposite effects, indicating an anti-apoptotic role of NO in the Fas signaling process. FasL-induced down-regulation of FLIP is mediated by a ubiquitin-proteasome pathway that is negatively regulated by NO. S-nitrosylation of FLIP is an important mechanism rendering FLIP resistant to ubiquitination and proteasomal degradation by FasL. Deletion analysis shows that the caspase-like domain of FLIP is a key target for S-nitrosylation by NO, and mutations of its cysteine 254 and cysteine 259 residues completely inhibit S-nitrosylation, leading to increased ubiquitination and proteasomal degradation of FLIP. These findings indicate a novel pathway for NO regulation of FLIP that provides a key mechanism for apoptosis regulation and a potential new target for intervention in death receptor-associated diseases.
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Affiliation(s)
- Pithi Chanvorachote
- Department of Pharmaceutical Sciences and Mary Babb Randolph Cancer Center, West Virginia University, Morgantown, West Virginia 26506, USA
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21
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Peng Y, Gallagher SF, Haines K, Baksh K, Murr MM. Nuclear factor-kappaB mediates Kupffer cell apoptosis through transcriptional activation of Fas/FasL. J Surg Res 2005; 130:58-65. [PMID: 16154149 DOI: 10.1016/j.jss.2005.07.030] [Citation(s) in RCA: 33] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2005] [Revised: 07/06/2005] [Accepted: 07/23/2005] [Indexed: 01/06/2023]
Abstract
INTRODUCTION Nuclear factor (NF)-kappaB is a key transcriptional factor for cell survival, inflammation, and stress response. We demonstrated that Kupffer cell-derived FasL plays a central role in pancreatitis-induced hepatocyte injury. The aim of this study was to determine the role of NF-kappaB in regulating death ligand/receptor pathway in Kupffer cells during conditions that mimic acute pancreatitis. MATERIALS AND METHODS Tissue cultures of rat Kupffer cells were treated with elastase (1 U/L) to mimic pancreatitis before and after infection with AdIkappaB to block activation of NF-kappaB. Tumor necrosis factor (enzyme-linked immunoassay), Fas/FasL, and caspase-3 (Western), tumor necrosis factor and Fas/FasL mRNA (reverse-transcription polymerase chain reaction), and NF-kappaB DNA binding (electrophoretic mobility shift assay) were determined. Apoptosis was measured by terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick-end labeling (TUNEL) and DNA fragmentation. Gels were quantified by densitometry. Data (n=3) are mean+/-SEM; student's t test was used for statistical analysis. RESULTS AdIkappaB infection up-regulated mutated IkappaBalpha that maintained its binding properties to NF-kappaB. Promoter-reporter assay demonstrated that FasL gene promoter was regulated by NF-kappaB. Infection with AdIkappaB attenuated the elastase-induced up-regulation of Fas/FasL (all P<0.01 versus elastase) and NF-kappaB DNA binding but did not affect elastase-induced up-regulation of TNF. AdIkappaB attenuated elastase-induced cleavage of caspase-3, DNA fragmentation and TUNEL staining (all P<0.01 versus elastase). CONCLUSIONS Inhibition of NF-kappaB DNA binding down-regulates Fas/FasL and attenuates elastase-induced apoptosis; however, it has no effect on TNF production, suggesting that regulation of Fas/FasL and TNF may occur via different pathways. The ability of Kupffer cells to autoregulate their stress response by up-regulating their death ligand/receptor and apoptosis warrants further investigation.
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Affiliation(s)
- Yanhua Peng
- Department of Surgery, James A. Haley Veterans Affairs Medical Center, and University of South Florida Health Sciences Center, Tampa, Florida 33601, USA
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22
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Berasain C, García-Trevijano ER, Castillo J, Erroba E, Santamaría M, Lee DC, Prieto J, Avila MA. Novel Role for Amphiregulin in Protection from Liver Injury. J Biol Chem 2005; 280:19012-20. [PMID: 15753092 DOI: 10.1074/jbc.m413344200] [Citation(s) in RCA: 103] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022] Open
Abstract
Clinically, the Fas and Fas ligand system plays a central role in the development of hepatocyte apoptosis, a process contributing to a broad spectrum of liver diseases. Therefore, the development of therapies aimed at the inhibition of hepatocyte apoptosis is a major issue. Activation of the epidermal growth factor receptor has been shown to convey survival signals to the hepatocyte. To learn about the endogenous response of epidermal growth factor receptor ligands during Fas-mediated liver injury we investigated the expression of epidermal growth factor, transforming growth factor alpha, heparin-binding epidermal growth factor-like growth factor, betacellulin, epiregulin, and amphiregulin in the liver of mice challenged with Fas-agonist antibody. Amphiregulin expression, barely detectable in healthy liver, was significantly up-regulated. Amphiregulin administration abrogated Fas-mediated liver injury in mice and showed direct anti-apoptotic effects in primary hepatocytes. Amphiregulin activated the Akt and signal transducer and activator of transcription-3 survival pathways, and up-regulated Bcl-xL expression. Amphiregulin knock-out mice showed signs of chronic liver damage in the absence of any noxious treatment, and died faster than wild type mice in response to lethal doses of Fas-agonist antibody. In contrast, these mice were more resistant against sublethal liver damage, supporting the hypothesis that chronic liver injury can precondition hepatocytes inducing resistance to subsequent cell death. These results show that amphiregulin is a protective factor induced in response to liver damage and that it may be therapeutic in liver diseases.
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Affiliation(s)
- Carmen Berasain
- Division of Hepatology and Gene Therapy, Centro de Investigación Médica Aplicada, Facultad de Medicina, Universidad de Navarra, Pío XII, 55, 31008 Pamplona, Spain
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23
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Neff TA, Guo RF, Neff SB, Sarma JV, Speyer CL, Gao H, Bernacki KD, Huber-Lang M, McGuire S, Hoesel LM, Riedemann NC, Beck-Schimmer B, Zetoune FS, Ward PA. Relationship of acute lung inflammatory injury to Fas/FasL system. THE AMERICAN JOURNAL OF PATHOLOGY 2005; 166:685-94. [PMID: 15743781 PMCID: PMC1602343 DOI: 10.1016/s0002-9440(10)62290-0] [Citation(s) in RCA: 60] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Accepted: 12/02/2004] [Indexed: 11/21/2022]
Abstract
There is mounting evidence that apoptosis plays a significant role in tissue damage during acute lung injury. To evaluate the role of the apoptosis mediators Fas and FasL in acute lung injury, Fas (lpr)- or FasL (gld)-deficient and wild-type mice were challenged with intrapulmonary deposition of IgG immune complexes. Lung injury parameters ((125)I-albumin leak, accumulation of myeloperoxidase, and wet lung weights) were measured and found to be consistently reduced in both lpr and gld mice. In wild-type mice, lung injury was associated with a marked increase in Fas protein in lung. Inflamed lungs of wild-type mice showed striking evidence of activated caspase-3, which was much diminished in inflamed lungs from lpr mice. Intratracheal administration of a monoclonal Fas-activating antibody (Jo2) in wild-type mice induced MIP-2 and KC production in bronchoalveolar lavage fluids, and a murine alveolar macrophage cell line (MH-S) showed significantly increased MIP-2 production after incubation with this antibody. Bronchoalveolar lavage fluid content of MIP-2 and KC was substantially reduced in lpr mice after lung injury when compared to levels in wild-type mice. These data suggest that the Fas/FasL system regulates the acute lung inflammatory response by positively affecting CXC-chemokine production, ultimately leading to enhanced neutrophil influx and tissue damage.
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Affiliation(s)
- Thomas A Neff
- Department of Pathology, The University of Michigan Medical School, 1301 Catherine Rd., Ann Arbor, MI 48109-0602, USA
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24
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Rasoulpour RJ, Boekelheide K. NF-κB Is Activated in the Rat Testis Following Exposure to Mono-(2-Ethylhexyl) Phthalate. Biol Reprod 2005; 72:479-86. [PMID: 15496515 DOI: 10.1095/biolreprod.104.034363] [Citation(s) in RCA: 41] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/01/2022] Open
Abstract
The process of spermatogenesis requires a delicate balance of proapoptotic and antiapoptotic signaling to maintain optimal sperm output. A major transcription factor known to regulate numerous apoptosis-related genes is NF-kappaB. Here we show that mono-(2-ethylhexyl) phthalate (MEHP, 1 g/kg) induces translocation of NF-kappaB subunits (p65, p50, and c-Rel) to germ cell nuclei in young rats (Postnatal Day 28) as early as 1 h after exposure. Immunohistochemistry of rat testes exposed to MEHP showed increased p50 and c-Rel presence in spermatocytes and spermatogonia. In addition, there was increased p65 nuclear positivity in Sertoli cells and germ cells after MEHP, while Rel-B localization was unchanged. These alterations correlated with increased nuclear NF-kappaB-binding activity after MEHP exposure, as shown by electrophoretic mobility shift assays of whole-testis nuclear protein extracts. The increased activity of this transcription factor was associated with a transient protection of the seminiferous epithelium manifested as a decreased number of germ cell apoptotic nuclei measured by TUNEL assay 6 h after MEHP exposure. These results suggest that NF-kappaB is involved in the testicular response to MEHP-induced injury.
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Affiliation(s)
- Reza J Rasoulpour
- Department of Pathology and Laboratory Medicine, Brown University, Providence, Rhode Island 02912, USA
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25
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Hutter R, Valdiviezo C, Sauter BV, Savontaus M, Chereshnev I, Carrick FE, Bauriedel G, Lüderitz B, Fallon JT, Fuster V, Badimon JJ. Caspase-3 and Tissue Factor Expression in Lipid-Rich Plaque Macrophages. Circulation 2004; 109:2001-8. [PMID: 15078795 DOI: 10.1161/01.cir.0000125526.91945.ae] [Citation(s) in RCA: 88] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
BACKGROUND Macrophages associated with arterial wall lipid deposition contribute to inflammatory processes. Tissue factor (TF) has been implicated in the thrombogenicity of atherosclerotic plaques. Intimal cells undergoing apoptosis have been postulated as a source for TF. However, there is only limited knowledge of cell type, plaque component, and conditions associated with TF expression and apoptosis. We examined the hypothesis that macrophages exposed to conditions of lipid-rich plaque undergo apoptosis and express TF. METHODS AND RESULTS In human carotid (n=15) and coronary (n=6) atherosclerotic plaques, TF and caspase-3 mRNA and protein expression (evaluated by in situ hybridization and immunohistochemistry) were increased significantly in lipid-rich compared with fibrous plaque components (P<0.01) and correlated with high macrophage content (P<0.05). Double-labeling studies demonstrated colocalization of TF and active caspase-3. In hyperlipidemic mice, expression of TF and active caspase-3 was observed simultaneously and colocalized in neointimal macrophages after arterial injury. In neointima of normolipidemic animals, TF and active caspase-3 were absent after arterial injury. In monocytes cultured in the presence of oxidized LDL, strong induction and colocalization of TF and active caspase-3 were found compared with baseline (P<0.05). Both antigens were significantly decreased after cotreatment with a caspase inhibitor (P<0.05) and were absent in untreated control cells. CONCLUSIONS The expression of TF as the primary cell-associated activator of the coagulation pathway proves to be closely related to macrophages undergoing apoptosis in conditions of lipid-rich plaque, pointing to a key role of lipid content and inflammatory cell viability in determining plaque thrombogenicity.
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Affiliation(s)
- Randolph Hutter
- Cardiovascular Institute/Cardiovascular Biology Research Laboratory, Mount Sinai School of Medicine, New York, NY, USA
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Kampa M, Alexaki VI, Notas G, Nifli AP, Nistikaki A, Hatzoglou A, Bakogeorgou E, Kouimtzoglou E, Blekas G, Boskou D, Gravanis A, Castanas E. Antiproliferative and apoptotic effects of selective phenolic acids on T47D human breast cancer cells: potential mechanisms of action. Breast Cancer Res 2003; 6:R63-74. [PMID: 14979919 PMCID: PMC400651 DOI: 10.1186/bcr752] [Citation(s) in RCA: 252] [Impact Index Per Article: 11.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2003] [Revised: 11/18/2003] [Accepted: 11/21/2003] [Indexed: 02/05/2023] Open
Abstract
INTRODUCTION The oncoprotective role of food-derived polyphenol antioxidants has been described but the implicated mechanisms are not yet clear. In addition to polyphenols, phenolic acids, found at high concentrations in a number of plants, possess antioxidant action. The main phenolic acids found in foods are derivatives of 4-hydroxybenzoic acid and 4-hydroxycinnamic acid. METHODS This work concentrates on the antiproliferative action of caffeic acid, syringic acid, sinapic acid, protocatechuic acid, ferulic acid and 3,4-dihydroxy-phenylacetic acid (PAA) on T47D human breast cancer cells, testing their antioxidant activity and a number of possible mechanisms involved (interaction with membrane and intracellular receptors, nitric oxide production). RESULTS The tested compounds showed a time-dependent and dose-dependent inhibitory effect on cell growth with the following potency: caffeic acid > ferulic acid = protocatechuic acid = PAA > sinapic acid = syringic acid. Caffeic acid and PAA were chosen for further analysis. The antioxidative activity of these phenolic acids in T47D cells does not coincide with their inhibitory effect on tumoral proliferation. No interaction was found with steroid and adrenergic receptors. PAA induced an inhibition of nitric oxide synthase, while caffeic acid competes for binding and results in an inhibition of aryl hydrocarbon receptor-induced CYP1A1 enzyme. Both agents induce apoptosis via the Fas/FasL system. CONCLUSIONS Phenolic acids exert a direct antiproliferative action, evident at low concentrations, comparable with those found in biological fluids after ingestion of foods rich in phenolic acids. Furthermore, the direct interaction with the aryl hydrocarbon receptor, the nitric oxide synthase inhibition and their pro-apoptotic effect provide some insights into their biological mode of action.
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Affiliation(s)
- Marilena Kampa
- Laboratory of Experimental Endocrinology, University of Crete, Heraklion, Greece
| | | | - George Notas
- Laboratory of Gastroenterology, University of Crete, Heraklion, Greece
| | | | - Anastassia Nistikaki
- Laboratory of Experimental Endocrinology, University of Crete, Heraklion, Greece
| | - Anastassia Hatzoglou
- Laboratory of Experimental Endocrinology, University of Crete, Heraklion, Greece
| | | | | | - George Blekas
- Laboratory of Food Chemistry and Technology, Department of Chemistry, Aristotle University of Thessaloniki, Greece
| | - Dimitrios Boskou
- Laboratory of Food Chemistry and Technology, Department of Chemistry, Aristotle University of Thessaloniki, Greece
| | - Achille Gravanis
- Laboratory of Pharmacology, University of Crete, Heraklion, Greece
| | - Elias Castanas
- Laboratory of Experimental Endocrinology, University of Crete, Heraklion, Greece
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Wang XZ, Chen XC, Chen YX, Zhang LJ, Li D, Chen FL, Chen ZX, Chen HY, Tao QM. Overexpression of HBxAg in hepatocellular carcinoma and its relationship with Fas/FasL system. World J Gastroenterol 2003; 9:2671-5. [PMID: 14669310 PMCID: PMC4612029 DOI: 10.3748/wjg.v9.i12.2671] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To study the expression and serum level of HBxAg, Fas and FasL in tissues of HCC patients, and to assess the relationship between HBxAg and Fas/FasL system.
METHODS: Tissues from 50 patients with HCC were tested for the expression of HBxAg, Fas and FasL by S-P immunohistochemistry. Serum levels of sFas/sFasL and HBsAg/HBeAg were measured by ELISA assay. HBV X gene was detected by PCR in serum and confirmed by automatic sequencing. Fifty cases of liver cirrhosis and 30 normal controls were involved in serum analysis.
RESULTS: The expression of HBxAg, Fas and FasL in carcinoma tissues was 96%, 84% and 98%, respectively. Staining of HBxAg, Fas and FasL was observed predominately in cytoplasms, no significant difference was found in intensity between HBxAg, Fas and FasL (P > 0.05). HBxAg, Fas and FasL might express in the same area of carcinoma tissues and this co-expression could be found in most patients with HCC. The mean levels of sFas in serum from HCC, cirrhosis and normal controls were 762.29 ± 391.56 μg·L-1, 835.36 ± 407.33 μg·L-1 and 238.27 ± 135.29 μg·L-1. The mean levels of sFasL in serum from HCC, cirrhosis and normal controls were 156.36 ± 9.61 μg·L-1, 173.63 ± 18.74 μg·L-1 and 121.96 ± 7.83 μg·L-1. Statistical analysis showed that both sFas and sFasL in HCC and cirrhosis patients were significantly higher than those in normal controls (P < 0.01). Serum HBV X gene was found in 32% of HCC patients and 46% of cirrhotic patients. There was no significant relationship between serum level of sFas/sFasL and serum X gene detection (P > 0.05). Eight percent of HCC patients with negative HBsAg and HBeAg in serum might have X gene in serum and HBxAg expression in carcinoma tissues.
CONCLUSION: Our data suggest that HBxAg and Fas/FasL system plays an important role in the development of human HCC. Expression of HBxAg can leads to expression of Fas/ FasL system which and reverse apoptosis of hepatocellular carcinoma induced by FasL.
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Affiliation(s)
- Xiao-Zhong Wang
- Department of Gastroenterology, Affiliated Union Hospital, Fujian Medical University, Fuzhou 350001, Fujian Province, China.
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Dan N, Kanai T, Totsuka T, Iiyama R, Yamazaki M, Sawada T, Miyata T, Yagita H, Okumura K, Watanabe M. Ameliorating effect of anti-Fas ligand MAb on wasting disease in murine model of chronic colitis. Am J Physiol Gastrointest Liver Physiol 2003; 285:G754-60. [PMID: 12969829 DOI: 10.1152/ajpgi.00071.2003] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
Fas/Fas ligand (FasL) interaction has been implicated in the pathogenesis of various diseases. To clarify the involvement of Fas/FasL in the pathogenesis of intestinal inflammation, we investigated the preventive and therapeutic effects of neutralizing anti-FasL monoclonal antibody (MAb) on the development of chronic colitis induced by adaptive transfer of CD4+CD45RBhigh T cells to SCID mice. Administration of anti-FasL MAb from 1 day after T cell transfer (prevention study) resulted in a significant improvement of clinical manifestations such as wasting and diarrhea. However, histological examination showed that mucosal inflammation in the colon, such as infiltration of T cells and macrophages, was not improved by the anti-FasL MAb treatment. In vitro studies showed that anti-FasL MAb did not inhibit IFN-gamma production by anti-CD3/CD28-stimulated lamina propria CD4+ T cells but suppressed TNF-alpha and IL-1beta production by lamina propria mononuclear cells. Therapeutic administration of anti-FasL MAb from 3 wk after T cell transfer also improved ongoing wasting disease but not intestinal inflammation. These results suggest that the Fas/FasL interaction plays a critical role in regulating systemic wasting disease but not local intestinal inflammation.
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Affiliation(s)
- N Dan
- Dept. of Gastroenterology and Hepatology, Graduate School of Medicine, Tokyo Medical and Dental University, Tokyo, Japan
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Park DR, Thomsen AR, Frevert CW, Pham U, Skerrett SJ, Kiener PA, Liles WC. Fas (CD95) induces proinflammatory cytokine responses by human monocytes and monocyte-derived macrophages. JOURNAL OF IMMUNOLOGY (BALTIMORE, MD. : 1950) 2003; 170:6209-16. [PMID: 12794152 DOI: 10.4049/jimmunol.170.12.6209] [Citation(s) in RCA: 134] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/10/2023]
Abstract
Fas (CD95, APO-1) is regarded as the prototypical cell death receptor of the TNFR superfamily. Fas-induced apoptosis is generally considered to be a noninflammatory process, contributing to the silent resolution of immune and inflammatory responses. However, accumulating evidence indicates that Fas may also induce cellular activation signals. We hypothesized that Fas could activate proinflammatory cytokine responses by normal human monocytes and macrophages. Monocytes were isolated by negative immunoselection from the PBMC fraction of venous blood from healthy volunteers, and monocyte-derived macrophages were cultivated in vitro. Both monocytes and monocyte-derived macrophages released TNF-alpha and IL-8 following Fas ligation, and conditioned medium from Fas-activated monocytes and macrophages induced the directed migration of neutrophils in a chemotaxis assay. Fas-induced monocyte cytokine responses were associated with monocyte apoptosis, nuclear translocation of NF-kappaB, and cytokine gene expression and were blocked by caspase inhibition but not by inhibition of IL-1beta signaling. In contrast, Fas-induced macrophage cytokine responses occurred in the absence of apoptosis and were caspase independent, indicating maturation-dependent differences in the Fas signaling pathways that lead to proinflammatory cytokine induction. Rather than contributing to the resolution of inflammation, Fas ligation on circulating monocytes and tissue macrophages may induce proinflammatory cytokine responses that can initiate acute inflammatory responses and tissue injury.
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Affiliation(s)
- David R Park
- Division of Pulmonary and Critical Care Medicine, Department of Medicine, University of Washington School of Medicine, Seattle, WA 98104, USA.
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Zhao WX, Zhao J, Liang CL, Zhao B, Pang RQ, Pan XH. Effect of caffeic acid phenethyl ester on proliferation and apoptosis of hepatic stellate cells in vitro. World J Gastroenterol 2003; 9:1278-81. [PMID: 12800240 PMCID: PMC4611800 DOI: 10.3748/wjg.v9.i6.1278] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/07/2002] [Revised: 01/04/2003] [Accepted: 01/08/2003] [Indexed: 02/06/2023] Open
Abstract
AIM To investigate the role of nuclear factor-kappaB (NF-kappaB) inhibitor caffeic acid phenethy1 ester (CAPE) in the proliferation, collagen synthesis and apoptosis of hepatic stellate cells (HSCs) of rats. METHODS The HSCs from rats were isolated and cultured in Dulbecco's Modified Eagle's Medium (DMEM) and treated with CAPE. The proliferation and collagen synthesis of HSCs were determined by (3)H-TdR and (3)H-proline incorporation respectively, and the expression of type I, III procollagen genes was further explored by in situ hybridization. Apoptosis cell indices (AIs) were examined using terminal deoxynucleotidyl transferase- mediated DIG-dUTP nick end labeling (TUNEL). RESULTS In activated HSC in culture, CAPE significantly inhibited (3)H-TdR and (3)H-proline incorporation by HSCs at concentrations of 5 micromol/L and 10 micromol/L respectively. CAPE also reduced the type I procollagen gene expression (P<0.05) at higher concentration. Apoptosis of HSC was induced by CAPE and the AIs were time-and dose-dependently increased from 2.82+/-0.73 % to 7.66+/-1.25 % at 12 h (P<0.01) and from 3.15+/-0.88 % to 10.61+/-2.88 % at 24 h (P<0.01). CONCLUSION CAPE inhibits proliferation and collagen synthesis of HSC at lower concentration and induces HSC apoptosis at higher concentration.
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Affiliation(s)
- Wen-Xing Zhao
- Medical Laboratory of Kunming General Hospital, Chengdu Command, 212 Daguan Road, Kunming 650032, Yunnan Province, China.
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