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Guerrache A, Micheau O. TNF-Related Apoptosis-Inducing Ligand: Non-Apoptotic Signalling. Cells 2024; 13:521. [PMID: 38534365 PMCID: PMC10968836 DOI: 10.3390/cells13060521] [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: 02/07/2024] [Revised: 03/01/2024] [Accepted: 03/14/2024] [Indexed: 03/28/2024] Open
Abstract
TNF-related apoptosis-inducing ligand (TRAIL or Apo2 or TNFSF10) belongs to the TNF superfamily. When bound to its agonistic receptors, TRAIL can induce apoptosis in tumour cells, while sparing healthy cells. Over the last three decades, this tumour selectivity has prompted many studies aiming at evaluating the anti-tumoral potential of TRAIL or its derivatives. Although most of these attempts have failed, so far, novel formulations are still being evaluated. However, emerging evidence indicates that TRAIL can also trigger a non-canonical signal transduction pathway that is likely to be detrimental for its use in oncology. Likewise, an increasing number of studies suggest that in some circumstances TRAIL can induce, via Death receptor 5 (DR5), tumour cell motility, potentially leading to and contributing to tumour metastasis. While the pro-apoptotic signal transduction machinery of TRAIL is well known from a mechanistic point of view, that of the non-canonical pathway is less understood. In this study, we the current state of knowledge of TRAIL non-canonical signalling.
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Affiliation(s)
- Abderrahmane Guerrache
- Université de Bourgogne, 21000 Dijon, France
- INSERM Research Center U1231, «Equipe DesCarTes», 21000 Dijon, France
| | - Olivier Micheau
- Université de Bourgogne, 21000 Dijon, France
- INSERM Research Center U1231, «Equipe DesCarTes», 21000 Dijon, France
- Laboratoire d’Excellence LipSTIC, 21000 Dijon, France
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2
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Qian G, Guo J, Vallega KA, Hu C, Chen Z, Deng Y, Wang Q, Fan S, Ramalingam SS, Owonikoko TK, Wei W, Sun SY. Membrane-Associated RING-CH 8 Functions as a Novel PD-L1 E3 Ligase to Mediate PD-L1 Degradation Induced by EGFR Inhibitors. Mol Cancer Res 2021; 19:1622-1634. [PMID: 34183449 PMCID: PMC8492505 DOI: 10.1158/1541-7786.mcr-21-0147] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2021] [Revised: 05/21/2021] [Accepted: 06/17/2021] [Indexed: 11/16/2022]
Abstract
Expression of programmed death-ligand 1 (PD-L1) on cancer cells is a critical mechanism contributing to immunosuppression and immune escape. PD-L1 expression may also affect therapeutic outcomes of epidermal growth factor receptor (EGFR)-targeted therapy (e.g., with osimertinib/AZD9291) against EGFR-mutant non-small cell lung cancers (NSCLC) and can even be altered during the treatment albeit with largely undefined mechanisms. This study primarily focuses on elucidating the mechanism by which osimertinib induces PD-L1 degradation in addition to validating osimertinib's effect on decreasing PD-L1 expression in EGFR-mutant NSCLC cells and tumors. Osimertinib and other EGFR inhibitors effectively decreased PD-L1 levels primarily in EGFR-mutant NSCLCs and xenografted tumors. Osimertinib not only decreased PD-L1 mRNA expression, but also prompted proteasomal degradation of PD-L1 protein, indicating both transcriptional and posttranslational mechanisms accounting for osimertinib-induced reduction of PD-L1. Knockdown of β-TrCP or inhibition of GSK3 failed to prevent PD-L1 reduction induced by osimertinib. Rather, knockdown of membrane-associated RING-CH 8 (MARCH8) that encodes a membrane-bound E3 ubiquitin ligase rescued osimertinib-induced PD-L1 reduction. Furthermore, manipulation of MARCH8 expression accordingly altered PD-L1 degradation rate. Critically, MARCH8 interacted with PD-L1 through its N-terminal region and also ubiquitinated PD-L1 in cells. Collectively, these results strongly suggest that MARCH8 is a previously undiscovered E3 ubiquitin ligase responsible for PD-L1 degradation including osimertinib-induced PD-L1 degradation, establishing a novel connection between MARCH8 and PD-L1 regulation. IMPLICATIONS: This study has demonstrated a previously undiscovered function of MARCH8 in mediating PD-L1 degradation induced by EGFR inhibitors in EGFR-mutant NSCLC cells, establishing a novel connection between MARCH8 and PD-L1 regulation.
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Affiliation(s)
- Guoqing Qian
- Department of Hematology and Medical Oncology, Emory University School of Medicine and Winship Cancer Institute, Atlanta, Georgia
| | - Jianping Guo
- Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts
| | - Karin A Vallega
- Department of Hematology and Medical Oncology, Emory University School of Medicine and Winship Cancer Institute, Atlanta, Georgia
| | - Changjiang Hu
- Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts
| | - Zhen Chen
- Department of Hematology and Medical Oncology, Emory University School of Medicine and Winship Cancer Institute, Atlanta, Georgia
| | - Yunfu Deng
- Department of Hematology and Medical Oncology, Emory University School of Medicine and Winship Cancer Institute, Atlanta, Georgia
| | - Qiming Wang
- Department of Internal Medicine, The Affiliated Cancer Hospital of Zhengzhou University, Henan Cancer Hospital, Zhengzhou, Henan, China
| | - Songqing Fan
- Department of Pathology, The Second Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Suresh S Ramalingam
- Department of Hematology and Medical Oncology, Emory University School of Medicine and Winship Cancer Institute, Atlanta, Georgia
| | - Taofeek K Owonikoko
- Department of Hematology and Medical Oncology, Emory University School of Medicine and Winship Cancer Institute, Atlanta, Georgia
| | - Wenyi Wei
- Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts
| | - Shi-Yong Sun
- Department of Hematology and Medical Oncology, Emory University School of Medicine and Winship Cancer Institute, Atlanta, Georgia.
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3
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Moore DK, Loxton AG. Regulatory B lymphocytes: development and modulation of the host immune response during disease. Immunotherapy 2019; 11:691-704. [DOI: 10.2217/imt-2018-0185] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
The role of B lymphocytes (B cells) in immunogenic responses has become increasingly important over the past decade, focusing on a new B-cell subtype: regulatory B-cells (Bregs). These Bregs have been shown to possess potent immunosuppressive activities and have identified as key players in disease control and immune tolerance. In this review, the occurrence of Breg type in various conditions, along with evidence supporting discovered functions and proposed purposes will be explored. An example of such regulatory functions includes the induction or suppression of various T lymphocyte phenotypes in response to a particular stimulus. Should Bregs prove effective in mediating immune responses, and correlate with favorable disease outcome, they may serve as a novel therapeutic to combat disease and prevent infection. However, the induction, function and stability of these cells remain unclear and further investigation is needed to better understand their role and therapeutic efficacy.
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Affiliation(s)
- Dannielle K Moore
- DST-NRF Centre of Excellence for Biomedical Tuberculosis Research, Stellenbosch University, Cape Town, South Africa, 8000
- South African Medical Research Council Centre for Tuberculosis Research, Stellenbosch University, Cape Town, South Africa, 8000
- Faculty of Medicine & Health Sciences, Division of Molecular Biology & Human Genetics, Stellenbosch University, Cape Town, South Africa, 8000
| | - Andre G Loxton
- DST-NRF Centre of Excellence for Biomedical Tuberculosis Research, Stellenbosch University, Cape Town, South Africa, 8000
- South African Medical Research Council Centre for Tuberculosis Research, Stellenbosch University, Cape Town, South Africa, 8000
- Faculty of Medicine & Health Sciences, Division of Molecular Biology & Human Genetics, Stellenbosch University, Cape Town, South Africa, 8000
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Importance of TRAIL Molecular Anatomy in Receptor Oligomerization and Signaling. Implications for Cancer Therapy. Cancers (Basel) 2019; 11:cancers11040444. [PMID: 30934872 PMCID: PMC6521207 DOI: 10.3390/cancers11040444] [Citation(s) in RCA: 46] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2019] [Revised: 03/25/2019] [Accepted: 03/26/2019] [Indexed: 12/12/2022] Open
Abstract
(TNF)-related apoptosis-inducing ligand (TRAIL) is able to activate the extrinsic apoptotic pathway upon binding to DR4/TRAIL-R1 and/or DR5/TRAIL-R2 receptors. Structural data indicate that TRAIL functions as a trimer that can engage three receptor molecules simultaneously, resulting in receptor trimerization and leading to conformational changes in TRAIL receptors. However, receptor conformational changes induced by the binding of TRAIL depend on the molecular form of this death ligand, and not always properly trigger the apoptotic cascade. In fact, TRAIL exhibits a much stronger pro-apoptotic activity when is found as a transmembrane protein than when it occurs as a soluble form and this enhanced biological activity is directly linked to its ability to cluster TRAIL receptors in supra-molecular structures. In this regard, cells involved in tumor immunosurveillance, such as activated human T cells, secrete endogenous TRAIL as a transmembrane protein associated with lipid microvesicles called exosomes upon T-cell reactivation. Consequently, it seems clear that a proper oligomerization of TRAIL receptors, which leads to a strong apoptotic signaling, is crucial for inducing apoptosis in cancer cells upon TRAIL treatment. In this review, the current knowledge of oligomerization status of TRAIL receptors is discussed as well as the implications for cancer treatment when using TRAIL-based therapies.
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Anel A, Gallego-Lleyda A, de Miguel D, Naval J, Martínez-Lostao L. Role of Exosomes in the Regulation of T-cell Mediated Immune Responses and in Autoimmune Disease. Cells 2019; 8:cells8020154. [PMID: 30759880 PMCID: PMC6406439 DOI: 10.3390/cells8020154] [Citation(s) in RCA: 118] [Impact Index Per Article: 19.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/27/2018] [Revised: 01/24/2019] [Accepted: 02/11/2019] [Indexed: 01/01/2023] Open
Abstract
: T-cell mediated immune responses should be regulated to avoid the development of autoimmune or chronic inflammatory diseases. Several mechanisms have been described to regulate this process, namely death of overactivated T cells by cytokine deprivation, suppression by T regulatory cells (Treg), induction of expression of immune checkpoint molecules such as CTLA-4 and PD-1, or activation-induced cell death (AICD). In addition, activated T cells release membrane microvesicles called exosomes during these regulatory processes. In this review, we revise the role of exosome secretion in the different pathways of immune regulation described to date and its importance in the prevention or development of autoimmune disease. The expression of membrane-bound death ligands on the surface of exosomes during AICD or the more recently described transfer of miRNA or even DNA inside T-cell exosomes is a molecular mechanism that will be analyzed.
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Affiliation(s)
- Alberto Anel
- Immunity, Cancer & Stem Cells Group, Department of Biochemistry and Molecular and Cell Biology, Faculty of Sciences, Campus San Francisco Sq., University of Zaragoza and Aragón Health Research Institute (IIS Aragón), E-50009 Zaragoza, Spain.
| | - Ana Gallego-Lleyda
- Department of Biochemistry and Molecular and Cell Biology, Faculty of Sciences, Campus San Francisco Sq., University of Zaragoza and Aragón Health Research Institute (IIS Aragón), E-50009 Zaragoza, Spain.
| | - Diego de Miguel
- Centre for Cell Death, Cancer and Inflammation (CCCI), UCL Cancer Institute, University College London, Gower St, Bloomsbury, WC1E 6BT London, UK.
| | - Javier Naval
- Immunity, Cancer & Stem Cells Group, Department of Biochemistry and Molecular and Cell Biology, Faculty of Sciences, Campus San Francisco Sq., University of Zaragoza and Aragón Health Research Institute (IIS Aragón), E-50009 Zaragoza, Spain.
| | - Luis Martínez-Lostao
- Immunology Department, Lozano Blesa Clinical Hospital, and Aragón Health Research Institute (IIS Aragón), E-50009 Zaragoza, Spain.
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Oh YT, Qian G, Deng J, Sun SY. Monocyte chemotactic protein-induced protein-1 enhances DR5 degradation and negatively regulates DR5 activation-induced apoptosis through its deubiquitinase function. Oncogene 2018; 37:3415-3425. [PMID: 29551769 DOI: 10.1038/s41388-018-0200-9] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2017] [Revised: 12/20/2017] [Accepted: 02/09/2018] [Indexed: 11/10/2022]
Abstract
Monocyte chemotactic protein-induced protein-1 (MCPIP1; also called Regnase-1) encoded by the ZC3H12A gene critically regulates inflammatory responses and immune homeostasis primarily by RNase-dependent and -independent mechanisms. However, the relationship of MCPIP1 with apoptosis and cancer and the underlying mechanisms are largely unclear. The current study has demonstrated a previously uncovered connection between MCPIP1 and the negative regulation of death receptor 5 (DR5; also known as TRAIL-R2 or killer/DR5), a cell surface receptor for tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), which is produced endogenously by various immune cells such as T cells. Our findings have revealed that MCPIP1 decreases both total cellular and cell surface DR5, primarily through modulating DUB-mediated protein autophagic/lysosomal degradation. Suppression of MCPIP1 by gene knockdown induces the formation of death-induced signaling complex (DISC) and enhances TRAIL or DR5 activation-induced apoptosis in cancer cells. Moreover, we demonstrated an inverse correlation between MCPIP1 expression and DR5 expression/cell sensitivity to DR5 activation-induced apoptosis in cancer cells. Our findings warrant future investigation of the roles of negative regulation of DR5 by MCPIP1 in cancer and in T-cell immunity.
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Affiliation(s)
- You-Take Oh
- Department of Hematology and Medical Oncology, Winship Cancer Institute, Emory University School of Medicine, Atlanta, GA, USA
| | - Guoqing Qian
- Department of Hematology and Medical Oncology, Winship Cancer Institute, Emory University School of Medicine, Atlanta, GA, USA
| | - Jiusheng Deng
- Department of Hematology and Medical Oncology, Winship Cancer Institute, Emory University School of Medicine, Atlanta, GA, USA
| | - Shi-Yong Sun
- Department of Hematology and Medical Oncology, Winship Cancer Institute, Emory University School of Medicine, Atlanta, GA, USA.
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Beyer K, Stollhof L, Poetschke C, von Bernstorff W, Partecke LI, Diedrich S, Maier S, Bröker BM, Heidecke CD. TNF-related apoptosis-inducing ligand deficiency enhances survival in murine colon ascendens stent peritonitis. J Inflamm Res 2016; 9:103-13. [PMID: 27366100 PMCID: PMC4914030 DOI: 10.2147/jir.s99887] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023] Open
Abstract
Background Apart from inducing apoptosis in tumor cells, tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) influences inflammatory reactions. Murine colon ascendens stent peritonitis (CASP) represents a model of diffuse peritonitis. Recently, it has been demonstrated that administration of exogenous TRAIL not only induces apoptosis in neutrophils but also enhances survival in this model. The aim of this study was to examine the impact of genetic TRAIL deficiency on the course of CASP. Methods Peritonitis was induced in 6- to 8-week-old female TRAIL−/− mice as well as in wild-type mice. The sepsis severity score and survival of mice were monitored. Bacterial loads in blood as well as in the lymphoid organs were examined. Additionally, the number of apoptotic cells within the lymphoid organs was determined. Results As early as 8 hours postinduction of CASP, TRAIL−/− mice were significantly more affected by sepsis than wild-type mice, as measured by the sepsis severity score. However, during the further course of sepsis, TRAIL deficiency led to significantly decreased sepsis severity scores, resulting in an enhanced overall survival in TRAIL−/− mice. The better survival of TRAIL−/− mice was accompanied by a decreased bacterial load within the blood. In marked contrast, the number of apoptotic cells within the lymphoid organs was highly increased in TRAIL−/− mice 20 hours after induction of CASP. Conclusion Hence, exogenous and endogenous TRAIL is protective during the early phase of sepsis, while endogenous TRAIL appears to be detrimental in the later course of this disease.
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Affiliation(s)
- Katharina Beyer
- Department of General, Visceral, Thoracic, and Vascular Surgery, University of Greifswald, Greifswald, Germany
| | - Laura Stollhof
- Department of General, Visceral, Thoracic, and Vascular Surgery, University of Greifswald, Greifswald, Germany
| | | | - Wolfram von Bernstorff
- Department of General, Visceral, Thoracic, and Vascular Surgery, University of Greifswald, Greifswald, Germany
| | - Lars Ivo Partecke
- Department of General, Visceral, Thoracic, and Vascular Surgery, University of Greifswald, Greifswald, Germany
| | - Stephan Diedrich
- Department of General, Visceral, Thoracic, and Vascular Surgery, University of Greifswald, Greifswald, Germany
| | - Stefan Maier
- Department of General, Visceral, Thoracic, and Vascular Surgery, University of Greifswald, Greifswald, Germany
| | - Barbara M Bröker
- Institute of Immunology, University of Greifswald, Greifswald, Germany
| | - Claus-Dieter Heidecke
- Department of General, Visceral, Thoracic, and Vascular Surgery, University of Greifswald, Greifswald, Germany
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8
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Edgunlu T, Solak Tekin N, Ozel Turkcu Ü, Karakaş-Çelik S, Urhan-Kucuk M, Tekin L. Evaluation of serum trail level and DR4 gene variants as biomarkers for vitiligo patients. J Eur Acad Dermatol Venereol 2015; 30:e97-e98. [PMID: 26404509 DOI: 10.1111/jdv.13340] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
Affiliation(s)
- T Edgunlu
- School of Health Sciences, Mugla Sitki Kocman University, Mugla, Turkey.
| | - N Solak Tekin
- Department of Dermatology, Faculty of Medicine, Bulent Ecevit University, Zonguldak, Turkey
| | - Ü Ozel Turkcu
- Medical Biochemistry, Faculty of Medicine, Mugla Sitki Kocman University, Mugla, Turkey
| | - S Karakaş-Çelik
- Department of Medical Genetic, Faculty of Medicine, Bulent Ecevit University, Zonguldak, Turkey
| | - M Urhan-Kucuk
- Department of Medical Biology, Faculty of Medicine, Mustafa Kemal University, Hatay, Turkey
| | - L Tekin
- Department of Pathology, Faculty of Medicine, Mugla Sitki Kocman University, Mugla, Turkey
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9
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Martinez-Lostao L, de Miguel D, Al-Wasaby S, Gallego-Lleyda A, Anel A. Death ligands and granulysin: mechanisms of tumor cell death induction and therapeutic opportunities. Immunotherapy 2015; 7:883-2. [PMID: 26314314 DOI: 10.2217/imt.15.56] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/28/2022] Open
Abstract
The immune system plays a key role in cancer immune surveillance to control tumor development. The final goal is recognizing and killing transformed cells and consequently the elimination of the tumor. The main effector cell types exerting cytotoxicity against tumors are natural killer (NK) cells and cytotoxic T lymphocytes (CTLs). Although the mechanism of activation of NK cells and CTLs are quite different, both cell types share common antitumor effector mechanisms of cytotoxicity which lead to induction of cell death of tumor cells by apoptosis. Among these mechanisms are the death ligand- and granulysin-mediated cell deaths. In this review, we summarize the main concepts of these effector cytotoxic mechanisms against cancer cells, how NK cells and CTLs use them to control tumor development and the therapeutic approaches currently developed based on these molecules.
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Affiliation(s)
- Luis Martinez-Lostao
- Departamento de Bioquímica, Biología Molecular y Celular, Facultad de Ciencias, Universidad de Zaragoza, C/Pedro Cerbuna 12, Zaragoza, 50009, Spain.,Instituto de Nanociencia de Aragón, Zaragoza Spain
| | - Diego de Miguel
- Departamento de Bioquímica, Biología Molecular y Celular, Facultad de Ciencias, Universidad de Zaragoza, C/Pedro Cerbuna 12, Zaragoza, 50009, Spain
| | - Sameer Al-Wasaby
- Departamento de Bioquímica, Biología Molecular y Celular, Facultad de Ciencias, Universidad de Zaragoza, C/Pedro Cerbuna 12, Zaragoza, 50009, Spain
| | - Ana Gallego-Lleyda
- Departamento de Bioquímica, Biología Molecular y Celular, Facultad de Ciencias, Universidad de Zaragoza, C/Pedro Cerbuna 12, Zaragoza, 50009, Spain
| | - Alberto Anel
- Departamento de Bioquímica, Biología Molecular y Celular, Facultad de Ciencias, Universidad de Zaragoza, C/Pedro Cerbuna 12, Zaragoza, 50009, Spain
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10
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Audo R, Daien C, Papon L, Lukas C, Vittecoq O, Hahne M, Combe B, Morel J. Osteoprotegerin and tumor necrosis factor-related apoptosis-inducing ligand as prognostic factors in rheumatoid arthritis: results from the ESPOIR cohort. Arthritis Res Ther 2015. [PMID: 26220665 PMCID: PMC4518710 DOI: 10.1186/s13075-015-0705-3] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/02/2022] Open
Abstract
Introduction We previously reported that low ratio of osteoprotegerin (OPG) to tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) was associated with Disease Activity Score in 28 joints (DAS28) remission at 6 months in patients with early rheumatoid arthritis (RA). Here, we aimed to evaluate the value of baseline OPG/TRAIL ratio in predicting clinical and radiological outcomes in patients with early RA in the ESPOIR cohort. Methods OPG and TRAIL serum concentrations were assessed in the ESPOIR cohort patients. Patients with definite RA were included in this study. Patients were excluded if they had high erosion score at baseline (>90th percentile) or received biological therapy during the first 2 years of follow-up. Data were analyzed by univariate analysis and multivariate logistic regression to predict 1-year DAS28 remission and 2-year radiographic disease progression. Results On univariate analysis of 399 patients, OPG/TRAIL ratio at baseline was significantly lower in patients with than without remission at 1 year (p = 0.015). On multivariate logistic regression including age, gender, body mass index and DAS28, low OPG/TRAIL ratio was independently associated with remission at 1 year (odds ratio 1.68 [95 % confidence interval 1.01–2.79]). On univariate analysis, high OPG/TRAIL ratio at baseline was associated with rapid progression of erosion at 2 years (p = 0.041), and on multivariate logistic regression including age, anti-citrullinated protein antibody positivity and C-reactive protein level, OPG/TRAIL ratio independently predicted rapid progression of erosion at 2 years. Conclusions OPG/TRAIL ratio at baseline was an independent predictor of 1-year remission and 2-year rapid progression of erosion for patients with early rheumatoid arthritis. Thus, OPG/TRAIL ratio could be included in matrix prediction scores to predict rapid radiographic progression. Further confirmation in an independent cohort is warranted.
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Affiliation(s)
- Rachel Audo
- Department of Rheumatology, Lapeyronie Hospital, Montpellier University, 371 avenue doyen Giraud, 34295, Montpellier, France. .,Montpellier University, 163 rue Auguste Broussonnet, 34000, Montpellier, France. .,Institut de Génétique Moléculaire de Montpellier, CNRS-UMR 5535, 1919 Route de Mende, 34293, Montpellier, France.
| | - Claire Daien
- Department of Rheumatology, Lapeyronie Hospital, Montpellier University, 371 avenue doyen Giraud, 34295, Montpellier, France. .,Montpellier University, 163 rue Auguste Broussonnet, 34000, Montpellier, France. .,Institut de Génétique Moléculaire de Montpellier, CNRS-UMR 5535, 1919 Route de Mende, 34293, Montpellier, France.
| | - Laura Papon
- Montpellier University, 163 rue Auguste Broussonnet, 34000, Montpellier, France. .,Institut de Génétique Moléculaire de Montpellier, CNRS-UMR 5535, 1919 Route de Mende, 34293, Montpellier, France.
| | - Cédric Lukas
- Department of Rheumatology, Lapeyronie Hospital, Montpellier University, 371 avenue doyen Giraud, 34295, Montpellier, France. .,Montpellier University, 163 rue Auguste Broussonnet, 34000, Montpellier, France.
| | - Olivier Vittecoq
- Department of Rheumatology and CIC/CRB 1404, Rouen University Hospital, Inserm U 905, Institute for Research and Innovation in Biomedicine, 1, rue de Germont, 76031 Rouen, France.
| | - Michael Hahne
- Montpellier University, 163 rue Auguste Broussonnet, 34000, Montpellier, France. .,Institut de Génétique Moléculaire de Montpellier, CNRS-UMR 5535, 1919 Route de Mende, 34293, Montpellier, France. .,Academic Medical Center, University of Amsterdam, Meibergdreef 9, 1105 AZ, Amsterdam, The Netherlands.
| | - Bernard Combe
- Department of Rheumatology, Lapeyronie Hospital, Montpellier University, 371 avenue doyen Giraud, 34295, Montpellier, France. .,Montpellier University, 163 rue Auguste Broussonnet, 34000, Montpellier, France. .,Institut de Génétique Moléculaire de Montpellier, CNRS-UMR 5535, 1919 Route de Mende, 34293, Montpellier, France.
| | - Jacques Morel
- Department of Rheumatology, Lapeyronie Hospital, Montpellier University, 371 avenue doyen Giraud, 34295, Montpellier, France. .,Montpellier University, 163 rue Auguste Broussonnet, 34000, Montpellier, France. .,Institut de Génétique Moléculaire de Montpellier, CNRS-UMR 5535, 1919 Route de Mende, 34293, Montpellier, France.
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11
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RIP1 modulates death receptor mediated apoptosis and autophagy in macrophages. Mol Oncol 2014; 9:806-17. [PMID: 25583602 DOI: 10.1016/j.molonc.2014.12.004] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2014] [Revised: 12/01/2014] [Accepted: 12/11/2014] [Indexed: 12/12/2022] Open
Abstract
Macrophages are responsible for defending against diverse pathogens and play a crucial role in the innate immune system. Macrophage's lifespan is determined by homeostatic balance between survival and apoptosis. Here we report that tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) triggers both apoptosis and autophagy in human U937 cells. Inhibition of autophagy facilitates TRAIL-induced apoptosis, suggesting that autophagy of macrophages protects against TRAIL-induced apoptosis. TRAIL treatment influences the expression of death receptors, indicating that TRAIL-induced apoptosis and autophagy are mediated by death receptors. RIP1 ubiquitination and expression regulate apoptosis and autophagy. Furthermore, expression and bioactivity of the p43/41-caspase-8 variant are critical to TRAIL-induced autophagy and apoptosis. Knockdown of RIP1 suppresses autophagy in macrophage. These data demonstrate that RIP1 is essential for the regulation of death receptor mediated autophagy and apoptosis. The results in this study contribute to understanding the regulation of autophagy and apoptosis in macrophages, and shed lights on death receptor-targeted therapy for cancer, inflammation and autoimmune diseases.
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12
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Stolp J, Turka LA, Wood KJ. B cells with immune-regulating function in transplantation. Nat Rev Nephrol 2014; 10:389-97. [PMID: 24846332 DOI: 10.1038/nrneph.2014.80] [Citation(s) in RCA: 46] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
In transplantation, the contribution of B cells to the rejection or acceptance of the allograft is a topic of major interest. The presence of donor-specific antibodies in transplant recipients is often associated with decreased graft function and rejection, clearly indicating a pathogenetic role of B cells in transplantation. However, data from studies in humans and rodents suggest that under certain conditions, B cells have the capacity to control or regulate the immune response to a transplanted organ. Although a great deal of attention has been focused on B cells in human and murine models of autoimmunity, our understanding of the role of these cells in transplantation is limited at present. Indeed, results in this setting are controversial and seem to depend on the model system used or the clinical situation studied. Here, we review the current understanding of the various phenotypes and roles that have been associated with immune-regulating B cells. We also discuss the mechanisms employed by subsets of these regulatory B cells to control the immune response in transplant recipients and in animal models of transplantation.
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Affiliation(s)
- Jessica Stolp
- Transplantation Research Immunology Group, Nuffield Department of Surgical Sciences, University of Oxford John Radcliffe Hospital, Oxford OX3 9DU, UK
| | - Laurence A Turka
- Transplantation Biology Research Centre, Massachusetts General Hospital, Room 5102, Charlestown, MA 02129, USA
| | - Kathryn J Wood
- Transplantation Research Immunology Group, Nuffield Department of Surgical Sciences, University of Oxford John Radcliffe Hospital, Oxford OX3 9DU, UK
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Edgünlü TG, Ozge A, Yalın OÖ, Kul S, Erdal ME. A Study of the Impact of Death Receptor 4 (DR4) Gene Polymorphisms in Alzheimer's Disease. Balkan Med J 2013; 30:268-72. [PMID: 25207117 DOI: 10.5152/balkanmedj.2013.7455] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2012] [Accepted: 04/07/2013] [Indexed: 11/22/2022] Open
Abstract
BACKGROUND Excessive apoptosis is believed to play a role in many degenerative and non-degenerative neurological diseases including Alzheimer's disease (AD). Much recent data suggest that apoptotic mechanisms may represent the missing link between Aβ deposition and proteolysis of tau protein. However, there is emerging evidence that apoptotic mechanisms may play a role in Alzheimer's Disease pathogenesis in the absence of overt apoptosis. TNF-related apoptosis inducing ligand receptor 1 (Death Receptor 4, DR4) might impair the apoptotic signal transduction and lead to dysregulation of the homeostasis between cell survival and cell death. AIMS The aim of our study was to further investigate the relationship between genetic variants of DR4 and Alzheimer's Disease. STUDY DESIGN Case control study. METHODS Sixty-eight patients with AD were included in the study. The control group comprised 72 subjects without signs of neurodegenerative diseases, as evidenced by the examination.DNA was extracted from whole blood using the salting-out procedure. Genotypes were identified by restriction fragment length polymorphism analysis of polymerase chain reaction (PCR-RFLP) products. RESULTS We observed significant differences in the genotypic distribution of the rs6557634 polymorphism in AD patients compared with controls (p<0.05); our data suggest that the GA genotype in rs6557634 could be protective against AD (p<0.05). However, there were no significant differences between AD patients and control groups in terms of the DR4 rs20575 polymorphism (p>0.05) and the DR4 rs20576 polymorphism (p>0.05). According to haplotype analysis of the DR4 gene for rs6557634, rs20575 and rs20576 polymorphisms, GCA and GCC haplotypes might be a risk factor for AD. Also, we have shown that ACA, GGC and GGA haplotypes might be protective factors against AD. CONCLUSION The present results indicate for the first time the possible contribution of the DR4 gene rs6557634, rs20575, rs20576 polymorphisms in Alzheimer's Disease, which may influence susceptibility to Alzheimer's Disease.
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Affiliation(s)
| | - Aynur Ozge
- Department of Neurology, Mersin University School of Medicine, Mersin, Turkey
| | - Osman Özgür Yalın
- Department of Neurology, Mersin University School of Medicine, Mersin, Turkey
| | - Seval Kul
- Department of Biostatistics, Gaziantep University School of Medicine, Gaziantep, Turkey
| | - Mehmet Emin Erdal
- Department of Medical Biology and Genetics, Mersin University School of Medicine, Mersin, Turkey
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Yang M, Rui K, Wang S, Lu L. Regulatory B cells in autoimmune diseases. Cell Mol Immunol 2013; 10:122-32. [PMID: 23292280 PMCID: PMC4003045 DOI: 10.1038/cmi.2012.60] [Citation(s) in RCA: 150] [Impact Index Per Article: 12.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2012] [Accepted: 11/06/2012] [Indexed: 12/11/2022] Open
Abstract
B cells are generally considered to be positive regulators of the immune response because of their capability to produce antibodies, including autoantibodies. The production of antibodies facilitates optimal CD4(+) T-cell activation because B cells serve as antigen-presenting cells and exert other modulatory functions in immune responses. However, certain B cells can also negatively regulate the immune response by producing regulatory cytokines and directly interacting with pathogenic T cells via cell-to-cell contact. These types of B cells are defined as regulatory B (Breg) cells. The regulatory function of Breg cells has been demonstrated in mouse models of inflammation, cancer, transplantation, and particularly in autoimmunity. In this review, we focus on the recent advances that lead to the understanding of the development and function of Breg cells and the implications of B cells in human autoimmune diseases.
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Affiliation(s)
- Min Yang
- Department of Pathology and Center for Infection and Immunology, The University of Hong Kong, Hong Kong, China
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15
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Abstract
Rheumatoid arthritis (RA) is the most common inflammatory disease of the musculoskeletal system primarily affecting the joints. It is characterized by massive synovial hyperplasia and subsequent destruction of articular cartilage and bone. Although various aspects in the pathogenesis of RA remain unclear, genetic, environmental and of course immunological factors have been involved. Defects in apoptosis seem to play a role in both initiation and perpetuation of RA. Apo2 ligand/ tumor necrosis factor (TNF) related apoptosis-inducing ligand (Apo2L/TRAIL) is a cytokine that belongs to the TNF superfamily capable of inducing apoptosis on tumor cells through activation of the extrinsic pathway. Besides this function, like other members of the TNF superfamily, Apo2L/TRAIL has been shown to exert important functions in the regulation of the immune system. Concerning pathological conditions, the Apo2L/TRAIL signaling pathway plays an important role in the response to infections, in immune surveillance against tumors and in autoimmune diseases such as RA. Furthermore, its implication in suppression of autoimmunity suggests that Apo2L/TRAIL has potential as therapeutic agent not only in cancer but also in autoimmune diseases. In fact, Apo2L/TRAIL-based therapies have been shown effective in various animal models of RA. This review summarizes the current knowledge on the biology of Apo2L/TRAIL and its role in RA.
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Targeting the Apo2L/TRAIL system for the therapy of autoimmune diseases and cancer. Biochem Pharmacol 2012; 83:1475-83. [DOI: 10.1016/j.bcp.2011.12.036] [Citation(s) in RCA: 39] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2011] [Revised: 12/22/2011] [Accepted: 12/22/2011] [Indexed: 01/07/2023]
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17
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Liu L, Su Z, Xin S, Cheng J, Li J, Xu L, Wei Q. The Calcineurin B Subunit (CnB) Is a New Ligand of Integrin αM That Mediates CnB-Induced Apo2L/TRAIL Expression in Macrophages. THE JOURNAL OF IMMUNOLOGY 2011; 188:238-47. [DOI: 10.4049/jimmunol.1102029] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
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18
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Audo R, Calmon-Hamaty F, Baeten D, Bruyer A, Combe B, Hahne M, Morel J. Mechanisms and clinical relevance of TRAIL-triggered responses in the synovial fibroblasts of patients with rheumatoid arthritis. ACTA ACUST UNITED AC 2011; 63:904-13. [PMID: 21305500 DOI: 10.1002/art.30181] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/03/2023]
Abstract
OBJECTIVE Results of studies in mice suggest a protective role for TRAIL in arthritis. The aim of this study was to investigate the role of TRAIL in patients with rheumatoid arthritis (RA). METHODS In the present study, we compared RA fibroblast-like synoviocytes (FLS) that were resistant or sensitive to TRAIL-induced apoptosis and the expression of TRAIL receptors in these cells, and also investigated the clinical features of the patients from whom the FLS were derived. Furthermore, we evaluated the levels of TRAIL and its soluble decoy receptor osteoprotegerin (OPG) in patients with RA, patients with osteoarthritis (OA), and patients with spondylarthritis (SpA). RESULTS Sensitivity to TRAIL-induced apoptosis varied in FLS from different patients, and the severity of disease in patients with RA was inversely correlated with the susceptibility of their FLS to TRAIL-induced apoptosis. TRAIL-sensitive cells expressed significantly lower levels of TRAILR-1, and silencing of TRAILR-1 increased TRAIL-induced apoptosis in RA FLS. TRAIL levels were elevated in the arthritic joints of patients with established RA, and TRAIL levels in the synovial fluid of these patients were elevated compared with levels in the synovial fluid of patients with OA or SpA. At baseline, a low OPG-to-TRAIL ratio in the sera of patients with early RA was associated with a better evolution of disease activity, but high serum levels of TRAIL at followup were associated with joint damage. CONCLUSION These findings suggest that TRAIL has a dual role in RA, and that the resistance of RA FLS to TRAIL-induced apoptosis is associated with a disease-promoting activity of TRAIL in RA.
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Affiliation(s)
- Rachel Audo
- Institut de Génétique Moléculaire de Montpellier, Université Montpellier I, Montpellier, France
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Martinez-Lostao L, García-Alvarez F, Basáñez G, Alegre-Aguarón E, Desportes P, Larrad L, Naval J, Martínez-Lorenzo MJ, Anel A. Liposome-bound APO2L/TRAIL is an effective treatment in a rabbit model of rheumatoid arthritis. ACTA ACUST UNITED AC 2010; 62:2272-82. [PMID: 20506326 DOI: 10.1002/art.27501] [Citation(s) in RCA: 71] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
Abstract
OBJECTIVE We previously observed that T lymphocytes present in synovial fluid (SF) from patients with rheumatoid arthritis (RA) were sensitive to APO2L/TRAIL. In addition, there was a drastic decrease in the amount of bioactive APO2L/TRAIL associated with exosomes in SF from RA patients. This study was undertaken to evaluate the effectiveness of bioactive APO2L/TRAIL conjugated with artificial lipid vesicles resembling natural exosomes as a treatment in a rabbit model of antigen-induced arthritis (AIA). METHODS We used a novel Ni(2+)-(N-5-amino-1-carboxypentyl)-iminodiacetic acid)-containing liposomal system. APO2L/TRAIL bound to liposomes was intraarticularly injected into the knees of animals with AIA. One week after treatment, rabbits were killed, and arthritic synovial tissue was analyzed. RESULTS Tethering APO2L/TRAIL to the liposome membrane increased its bioactivity and resulted in more effective treatment of AIA compared with soluble, unconjugated APO2L/TRAIL, with substantially reduced synovial hyperplasia and inflammation in rabbit knee joints. The results of biophysical studies suggested that the increased bioactivity of APO2L/TRAIL associated with liposomes was due to the increase in the local concentration of the recombinant protein, augmenting its receptor crosslinking potential, and not to conformational changes in the protein. In spite of this increase in bioactivity, the treatment lacked systemic toxicity and was not hepatotoxic. CONCLUSION Our findings indicate that binding APO2L/TRAIL to the liposome membrane increases its bioactivity and results in effective treatment of AIA.
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Affiliation(s)
- Luis Martinez-Lostao
- Departamento de Bioquímica, Biología Molecular y Celular, Facultad de Ciencias, Universidad de Zaragoza, C/Pedro Cerbuna 12, Zaragoza 50009, Spain.
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20
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Yan X, Xu L, Qi J, Liang X, Ma C, Guo C, Zhang L, Sun W, Zhang J, Wei X, Gao L. sTRAIL levels and TRAIL gene polymorphisms in Chinese patients with fatty liver disease. Immunogenetics 2009; 61:551-6. [PMID: 19629467 DOI: 10.1007/s00251-009-0389-4] [Citation(s) in RCA: 31] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2009] [Accepted: 07/10/2009] [Indexed: 01/12/2023]
Abstract
Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) is a member of the TNF superfamily, and has been identified as a novel mediator of fatty liver disease (FLD). The aim of our study was to further investigate the relationship between TRAIL and FLD. We found that soluble TRAIL (sTRAIL) concentrations in non-alcoholic FLD (NAFLD) patients were significantly higher than those of controls, and that sTRAIL levels positively correlated with triglyceride concentrations in NAFLD patients. Our results also indicated that the AA/TT genotypes of TRAIL at 1525/1595 engendered a lower risk of FLD attack and a less severe form of steatosis for NAFLD patients in Chinese population. This study provides a means to test for susceptibility to FLD and may assist in the diagnosis of FLD. In addition, we found that 1525G/A and 1595C/T sites were in complete linkage disequilibrium in Chinese population. This might indicate a haplotype with high genetic frequency of TRAIL.
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Affiliation(s)
- Xiaohua Yan
- Department of Immunology, Shandong University School of Medicine, 44# Wenhua Xi Road, Jinan, 250012, People's Republic of China
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Maret M, Ruffié C, Létuvé S, Phelep A, Thibaudeau O, Marchal J, Pretolani M, Druilhe A. A role for Bid in eosinophil apoptosis and in allergic airway reaction. THE JOURNAL OF IMMUNOLOGY 2009; 182:5740-7. [PMID: 19380821 DOI: 10.4049/jimmunol.0800864] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/19/2022]
Abstract
Bid, a proapoptotic member of Bcl-2 family, is involved in Fas receptor signaling. Fas activation promotes human eosinophil cell death and is believed to accelerate the resolution of pulmonary Th2-driven allergic reaction in mice. We hypothesized that Bid would regulate eosinophil apoptosis and Ag-induced airway inflammation, particularly eosinophilia. C57BL/6 Bid(-/-) and wild-type mice were immunized and repeatedly challenged with OVA, and bronchoalveolar lavage (BAL) fluid, lung, and spleen were collected 4-240 h after the final challenge. Cultured BAL eosinophils from Bid-deficient mice showed resistance to Fas-mediated apoptotic DNA fragmentation, phosphatidylserine exposure, mitochondria depolarization, and caspase-3 activity. In addition, OVA-challenged Bid(-/-) mice had higher BAL eosinophilia and a lower proportion of BAL apoptotic eosinophils than Bid(+/+) mice. This was accompanied by augmented BAL levels of the eosinophilotactic cytokine, IL-5, and of the eosinophil-associated mediators, TGF-beta1 and fibronectin. Finally, cultured OVA-stimulated lung mononuclear cells and splenocytes from Bid-deficient mice showed increased release of the Th2-type cytokines, IL-4 and IL-5, but no change in cell number. We conclude that Bid modulates BAL eosinophilia by regulating both eosinophil apoptosis and Th2-type cytokine production.
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Affiliation(s)
- Marielle Maret
- Institut National de la Santé et de la Recherche Médicale Unité 700 and Université Paris Diderot-Paris 7, Paris, France
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22
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TRAIL receptor mediates inflammatory cytokine release in an NF-κB-dependent manner. Cell Res 2009; 19:758-67. [DOI: 10.1038/cr.2009.57] [Citation(s) in RCA: 42] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022] Open
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Lundy SK. Killer B lymphocytes: the evidence and the potential. Inflamm Res 2009; 58:345-57. [PMID: 19262989 DOI: 10.1007/s00011-009-0014-x] [Citation(s) in RCA: 81] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2008] [Accepted: 12/04/2008] [Indexed: 12/12/2022] Open
Abstract
Immune regulation plays a critical role in controlling potentially dangerous inflammation and maintaining health. The Fas ligand/Fas receptor axis has been studied extensively as a mechanism of killing T cells and other cells during infections, autoimmunity, and cancer. FasL expression has been primarily attributed to activated T cells and NK cells. Evidence has emerged that B lymphocytes can express FasL and other death-inducing ligands, and can mediate cell death under many circumstances. Among B cell subsets, the expression of both Fas ligand and IL-10 is highest on the CD5(+) B cell population, suggesting that CD5(+) B cells may have a specialized regulatory function. The relevance of killer B cells to normal immune regulation, disease pathogenesis, and inflammation is discussed.
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Affiliation(s)
- Steven K Lundy
- Division of Rheumatology, Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, MI 48109-2200, USA.
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24
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Razmara M, Hilliard B, Ziarani AK, Murali R, Yellayi S, Ghazanfar M, Chen YH, Tykocinski ML. Fn14-TRAIL, a chimeric intercellular signal exchanger, attenuates experimental autoimmune encephalomyelitis. THE AMERICAN JOURNAL OF PATHOLOGY 2009; 174:460-74. [PMID: 19147815 DOI: 10.2353/ajpath.2009.080462] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/02/2023]
Abstract
Hallmarks of the pathogenesis of autoimmune encephalomyelitis include perivascular infiltration of inflammatory cells into the central nervous system, multifocal demyelination in the brain and spinal cord, and focal neuronal degeneration. Optimal treatment of this complex disease will ultimately call for agents that target the spectrum of underlying pathogenic processes. In the present study, Fn14-TRAIL is introduced as a unique immunotherapeutic fusion protein that is designed to exchange and redirect intercellular signals within inflammatory cell networks, and, in so doing, to impact multiple pathogenic events and yield a net anti-inflammatory effect. In this soluble protein product, a Fn14 receptor component (capable of blocking the pro-inflammatory TWEAK ligand) is fused to a TRAIL ligand (capable of inhibiting activated, pathogenic T cells). Sustained Fn14-TRAIL expression was obtained in vivo using a transposon-based eukaryotic expression vector. Fn14-TRAIL expression effectively prevented chronic, nonremitting, paralytic disease in myelin oligodendrocyte glycoprotein-challenged C57BL/6 mice. Disease suppression in this model was reflected by decreases in the clinical score, disease incidence, nervous tissue inflammation, and Th1, Th2, and Th17 cytokine responses. Significantly, the therapeutic efficacy of Fn14-TRAIL could not be recapitulated simply by administering its component parts (Fn14 and TRAIL) as soluble agents, either alone or in combination. Its functional pleiotropism was manifest in its additional ability to attenuate the enhanced permeability of the blood-brain barrier that typically accompanies autoimmune encephalomyelitis.
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Affiliation(s)
- Marjaneh Razmara
- Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA
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25
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Mooij P, Balla-Jhagjhoorsingh SS, Koopman G, Beenhakker N, van Haaften P, Baak I, Nieuwenhuis IG, Kondova I, Wagner R, Wolf H, Gómez CE, Nájera JL, Jiménez V, Esteban M, Heeney JL. Differential CD4+ versus CD8+ T-cell responses elicited by different poxvirus-based human immunodeficiency virus type 1 vaccine candidates provide comparable efficacies in primates. J Virol 2008; 82:2975-88. [PMID: 18184713 PMCID: PMC2258966 DOI: 10.1128/jvi.02216-07] [Citation(s) in RCA: 67] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2007] [Accepted: 12/13/2007] [Indexed: 12/20/2022] Open
Abstract
Poxvirus vectors have proven to be highly effective for boosting immune responses in diverse vaccine settings. Recent reports reveal marked differences in the gene expression of human dendritic cells infected with two leading poxvirus-based human immunodeficiency virus (HIV) vaccine candidates, New York vaccinia virus (NYVAC) and modified vaccinia virus Ankara (MVA). To understand how complex genomic changes in these two vaccine vectors translate into antigen-specific systemic immune responses, we undertook a head-to-head vaccine immunogenicity and efficacy study in the pathogenic HIV type 1 (HIV-1) model of AIDS in Indian rhesus macaques. Differences in the immune responses in outbred animals were not distinguished by enzyme-linked immunospot assays, but differences were distinguished by multiparameter fluorescence-activated cell sorter analysis, revealing a difference between the number of animals with both CD4(+) and CD8(+) T-cell responses to vaccine inserts (MVA) and those that elicit a dominant CD4(+) T-cell response (NYVAC). Remarkably, vector-induced differences in CD4(+)/CD8(+) T-cell immune responses persisted for more than a year after challenge and even accompanied antigenic modulation throughout the control of chronic infection. Importantly, strong preexposure HIV-1/simian immunodeficiency virus-specific CD4(+) T-cell responses did not prove deleterious with respect to accelerated disease progression. In contrast, in this setting, animals with strong vaccine-induced polyfunctional CD4(+) T-cell responses showed efficacies similar to those with stronger CD8(+) T-cell responses.
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Affiliation(s)
- Petra Mooij
- Department of Virology, Biomedical Primate Research Centre (BPRC), P.O. Box 3306, 2280 GH Rijswijk, The Netherlands.
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Mérino D, Lalaoui N, Morizot A, Solary E, Micheau O. TRAIL in cancer therapy: present and future challenges. Expert Opin Ther Targets 2007; 11:1299-314. [PMID: 17907960 PMCID: PMC2976473 DOI: 10.1517/14728222.11.10.1299] [Citation(s) in RCA: 129] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
Since its identification in 1995, TNF-related apoptosis-inducing ligand (TRAIL) has sparked growing interest in oncology due to its reported ability to selectively trigger cancer cell death. In contrast to other members of the TNF superfamily, TRAIL administration in vivo is safe. The relative absence of toxic side effects of this naturally occurring cytokine, in addition to its antitumoural properties, has led to its preclinical evaluation. However, despite intensive investigations, little is known in regards to the mechanisms underlying TRAIL selectivity or efficiency. An appropriate understanding of its physiological relevance, and of the mechanisms controlling cancer cells escape from TRAIL-induced cell death, will be required to optimally use the cytokine in clinics. The present review focuses on recent advances in the understanding of TRAIL signal transduction and discusses the existing and future challenges of TRAIL-based cancer therapy development.
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