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Keshavarz Shahbaz S, Koushki K, Ayati SH, Bland AR, Bezsonov EE, Sahebkar A. Inflammasomes and Colorectal Cancer. Cells 2021; 10:2172. [PMID: 34571825 PMCID: PMC8467678 DOI: 10.3390/cells10092172] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2021] [Revised: 06/22/2021] [Accepted: 07/29/2021] [Indexed: 02/07/2023] Open
Abstract
Inflammasomes are important intracellular multiprotein signaling complexes that modulate the activation of caspase-1 and induce levels of the proinflammatory cytokines interleukin-1β (IL-1β) and IL-18 in response to pathogenic microorganisms and molecules that originated from host proteins. Inflammasomes play contradictory roles in the development of inflammation-induced cancers. Based on several findings, inflammasomes can initiate and promote carcinogenesis. On the contrary, inflammasomes also exhibit anticancer effects by triggering pyroptosis and immunoregulatory functions. Herein, we review extant studies delving into different functions of inflammasomes in colorectal cancer development.
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Affiliation(s)
- Sanaz Keshavarz Shahbaz
- Cellular and Molecular Research Center, Research Institute for Prevention of Non-Communicable Disease, Qazvin University of Medical Science, Qazvin 3419759811, Iran;
| | - Khadijeh Koushki
- Department of Immunology, School of Medicine, Mashhad University of Medical Sciences, Mashhad 9177948564, Iran;
| | - Seyed Hassan Ayati
- Immunobiochemistry Lab, Immunology Research Center, School of Medicine, Mashhad University of Medical Sciences, Mashhad 9177948564, Iran;
| | - Abigail R. Bland
- Department of Pharmacology and Toxicology, School of Biomedical Sciences, University of Otago, Dunedin 9016, New Zealand;
| | - Evgeny E. Bezsonov
- Laboratory of Angiopathology, Institute of General Pathology and Pathophysiology, 8 Baltiiskaya Street, 125315 Moscow, Russia;
| | - Amirhossein Sahebkar
- Biotechnology Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad 9177948564, Iran
- Applied Biomedical Research Center, Mashhad University of Medical Sciences, Mashhad 1313199137, Iran
- School of Medicine, The University of Western Australia, Perth 6009, Australia
- School of Pharmacy, Mashhad University of Medical Sciences, Mashhad 9177948564, Iran
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Association of interleukin-18 gene polymorphisms with Takayasu arteritis in a Chinese Han population. Chin Med J (Engl) 2020; 133:2315-2320. [PMID: 32826615 PMCID: PMC7546839 DOI: 10.1097/cm9.0000000000001047] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/05/2022] Open
Abstract
Background: Interleukin-18 (IL18) gene polymorphisms are related to many inflammatory and autoimmune diseases. However, a correlation analysis between IL18 −607C/A and −137G/C gene polymorphisms and Takayasu arteritis (TA) is lacking. Methods: This study enrolled 200 patients with TA as the case group and 334 region-, age-, and sex-matched healthy subjects as the control group. We genotyped alleles and genotypes at positions −607 and −137 of the IL18 gene and analyzed the distribution frequencies. Mann-Whitney U test, t test, Chi-squared test and Hardy-Weinberg equilibrium were performed. Results: After adjusting for risk factors, the adjusted odds ratios and 95% confidence intervals at position −607C/A were 0.533, 0.391 to 0.880 (P = 0.010); 0.266, 0.586 to 1.002 (P = 0.051); and 0.122, 0.552 to 1.420 (P = 0.613) under the dominant, additive, and recessive models, respectively. For the −137G/C polymorphism, the adjusted odds ratios and 95% confidence intervals were 1.571, 1.068 to 2.311 (P = 0.022); 1.467, 1.086 to 1.980 (P = 0.012); and 1.815, 0.901 to 3.656 (P = 0.095) under the dominant, additive, and recessive models, respectively. Moreover, regardless of the model used, we found no statistical difference in distribution frequency between the active and quiescent states of TA for the −607C/A (P = 0.355, 0.631, and 0.705, respectively) and −137G/C polymorphisms (P = 0.205, 0.385, and 0.208, respectively). Conclusions: The IL18 −607C/A gene polymorphism may decrease the risk of TA, and thus is a protective factor, whereas −137G/C may increase the risk of TA, and thus is a risk factor. However, neither polymorphism was related to activity (active vs. quiescent) of TA.
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Chakravarti D, Hu B, Mao X, Rashid A, Li J, Li J, Liao WT, Whitley EM, Dey P, Hou P, LaBella KA, Chang A, Wang G, Spring DJ, Deng P, Zhao D, Liang X, Lan Z, Lin Y, Sarkar S, Terranova C, Deribe YL, Blutt SE, Okhuysen P, Zhang J, Vilar E, Nielsen OH, Dupont A, Younes M, Patel KR, Shroyer NF, Rai K, Estes MK, Wang YA, Bertuch AA, DePinho RA. Telomere dysfunction activates YAP1 to drive tissue inflammation. Nat Commun 2020; 11:4766. [PMID: 32958778 PMCID: PMC7505960 DOI: 10.1038/s41467-020-18420-w] [Citation(s) in RCA: 41] [Impact Index Per Article: 8.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2020] [Accepted: 08/19/2020] [Indexed: 02/06/2023] Open
Abstract
Germline telomere maintenance defects are associated with an increased incidence of inflammatory diseases in humans, yet whether and how telomere dysfunction causes inflammation are not known. Here, we show that telomere dysfunction drives pATM/c-ABL-mediated activation of the YAP1 transcription factor, up-regulating the major pro-inflammatory factor, pro-IL-18. The colonic microbiome stimulates cytosolic receptors activating caspase-1 which cleaves pro-IL-18 into mature IL-18, leading to recruitment of interferon (IFN)-γ-secreting T cells and intestinal inflammation. Correspondingly, patients with germline telomere maintenance defects exhibit DNA damage (γH2AX) signaling together with elevated YAP1 and IL-18 expression. In mice with telomere dysfunction, telomerase reactivation in the intestinal epithelium or pharmacological inhibition of ATM, YAP1, or caspase-1 as well as antibiotic treatment, dramatically reduces IL-18 and intestinal inflammation. Thus, telomere dysfunction-induced activation of the ATM-YAP1-pro-IL-18 pathway in epithelium is a key instigator of tissue inflammation.
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Affiliation(s)
- Deepavali Chakravarti
- Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA
| | - Baoli Hu
- Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA
- Division of Pediatric Neurosurgery, Children's Hospital of Pittsburgh of UPMC, Pittsburgh, PA, 15224, USA
- Department of Neurological Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA, 15261, USA
| | - Xizeng Mao
- Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA
| | - Asif Rashid
- Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA
| | - Jiexi Li
- Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA
| | - Jun Li
- Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA
| | - Wen-Ting Liao
- Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA
- Department of Pathology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, China
| | - Elizabeth M Whitley
- Department of Veterinary Medicine & Surgery, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA
| | - Prasenjit Dey
- Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA
- Department of Immunology, Roswell Park Comprehensive Cancer Center, Buffalo, NY, 14263, USA
| | - Pingping Hou
- Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA
| | - Kyle A LaBella
- Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA
| | - Andrew Chang
- Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA
| | - Guocan Wang
- Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA
- Department of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA
| | - Denise J Spring
- Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA
| | - Pingna Deng
- Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA
| | - Di Zhao
- Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA
| | - Xin Liang
- Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA
| | - Zhengdao Lan
- Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA
- Division of Neurocritical Care, Department of Neurosurgery, Emory University, Atlanta, GA, 30303, USA
| | - Yiyun Lin
- Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA
| | - Sharmistha Sarkar
- Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA
| | - Christopher Terranova
- Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA
| | - Yonathan Lissanu Deribe
- Department of Thoracic and Cardiovascular Surgery, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA
| | - Sarah E Blutt
- Department of Molecular Virology and Microbiology, Baylor College of Medicine, Houston, TX, 77030, USA
| | - Pablo Okhuysen
- Department of Infectious Diseases, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA
| | - Jianhua Zhang
- Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA
| | - Eduardo Vilar
- Department of Clinical Cancer Prevention, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA
| | - Ole Haagen Nielsen
- Department of Gastroenterology, Herlev Hospital, University of Copenhagen, Herlev, DK-2730, Denmark
| | - Andrew Dupont
- Division of Gastroenterology, Hepatology and Nutrition, Department of Internal Medicine, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, TX, 77030, USA
| | - Mamoun Younes
- Department of Pathology and Laboratory Medicine, University of Texas Health Science Center at Houston, McGovern Medical School and Memorial Hermann Hospital-TMC, Houston, TX, 77030, USA
| | - Kalyani R Patel
- Department of Pathology, Texas Children's Hospital, Houston, TX, 77030, USA
| | - Noah F Shroyer
- Department of Medicine, Section of Gastroenterology and Hepatology, Baylor College of Medicine, Houston, TX, 77030, USA
| | - Kunal Rai
- Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA
| | - Mary K Estes
- Department of Molecular Virology and Microbiology, Baylor College of Medicine, Houston, TX, 77030, USA
| | - Y Alan Wang
- Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA
| | - Alison A Bertuch
- Division of Hematology/Oncology, Department of Pediatrics, Baylor College of Medicine, Houston, TX, 77030, USA
- Department of Molecular & Human Genetics, Baylor College of Medicine, Houston, TX, 77030, USA
| | - Ronald A DePinho
- Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA.
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Cristina Lopes do Carmo M, Mateus Martins I, Elisa Ramos Magalhães A, Roberto Maróstica Júnior M, Alves Macedo J. Passion fruit (Passiflora edulis) leaf aqueous extract ameliorates intestinal epithelial barrier dysfunction and reverts inflammatory parameters in Caco-2 cells monolayer. Food Res Int 2020; 133:109162. [PMID: 32466926 DOI: 10.1016/j.foodres.2020.109162] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2019] [Revised: 03/02/2020] [Accepted: 03/15/2020] [Indexed: 12/15/2022]
Abstract
The aqueous extract of Passiflora edulis leaves is rich in bioactive polyphenolics, with antioxidant and anti-inflammatory properties. In this study, the recovery of barrier dysfunction and the anti-inflammatory effect of P. edulis leaf aqueous extract (PELE) were evaluated using a Caco-2 monolayer model challenged with IL-1β and LPS. After inflammatory stimuli, it was observed a 28% reduction in transepithelial electrical resistance (TER) and 78% increase of LY permeability. After 48-h treatment with PELE (10 mg mL-1), the monolayer showed 35% increase in TER after inflammatory decreases, and 67% lower LY paracellular permeability, showing a recovery of the monolayer integrity. The treatment also suppressed IL-8 production in 65%. Our results suggest that PELE is a potent source of antioxidants that may promote a protective effect by repairing the intestinal epithelial integrity.
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Affiliation(s)
- Mônica Cristina Lopes do Carmo
- Food and Nutrition Department, Faculty of Food Engineering, State University of Campinas - UNICAMP, Rua Monteiro Lobato, 80, Cidade Universitária Zeferino Vaz, CP 6121, CEP 13083-862, Campinas, SP, Brazil.
| | - Isabela Mateus Martins
- Food and Nutrition Department, Faculty of Food Engineering, State University of Campinas - UNICAMP, Rua Monteiro Lobato, 80, Cidade Universitária Zeferino Vaz, CP 6121, CEP 13083-862, Campinas, SP, Brazil
| | - Ana Elisa Ramos Magalhães
- Food and Nutrition Department, Faculty of Food Engineering, State University of Campinas - UNICAMP, Rua Monteiro Lobato, 80, Cidade Universitária Zeferino Vaz, CP 6121, CEP 13083-862, Campinas, SP, Brazil
| | - Mário Roberto Maróstica Júnior
- Food and Nutrition Department, Faculty of Food Engineering, State University of Campinas - UNICAMP, Rua Monteiro Lobato, 80, Cidade Universitária Zeferino Vaz, CP 6121, CEP 13083-862, Campinas, SP, Brazil
| | - Juliana Alves Macedo
- Food and Nutrition Department, Faculty of Food Engineering, State University of Campinas - UNICAMP, Rua Monteiro Lobato, 80, Cidade Universitária Zeferino Vaz, CP 6121, CEP 13083-862, Campinas, SP, Brazil
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Nanini HF, Bernardazzi C, Castro F, de Souza HSP. Damage-associated molecular patterns in inflammatory bowel disease: From biomarkers to therapeutic targets. World J Gastroenterol 2018; 24:4622-4634. [PMID: 30416310 PMCID: PMC6224468 DOI: 10.3748/wjg.v24.i41.4622] [Citation(s) in RCA: 33] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/05/2018] [Revised: 10/08/2018] [Accepted: 10/16/2018] [Indexed: 02/06/2023] Open
Abstract
The chronic inflammatory process underlying inflammatory bowel disease (IBD), comprising Crohn's disease and ulcerative colitis, derives from the interplay of several components in a genetically susceptible host. These components include environmental elements and gut microbiota a dysbiosis. For decades, immune abnormalities have been investigated as critically important in IBD pathogenesis, and attempts to develop effective therapies have predominantly targeted the immune system. Nevertheless, immune events represent only one of the constituents contributing to IBD pathogenesis within the context of the complex cellular and molecular network underlying chronic intestinal inflammation. These factors need to be appreciated within the milieu of non-immune components. Damage-associated molecular patterns (DAMPs), which are essentially endogenous stress proteins expressed or released as a result of cell or tissue damage, have been shown to act as direct pro-inflammatory mediators. Excessive or persistent signalling mediated by such molecules can underlie several chronic inflammatory disorders, including IBD. The release of endogenous DAMPs amplifies the inflammatory response driven by immune and non-immune cells and promotes epigenetic reprogramming in IBD. The effects determine pathologic changes, which may sustain chronic intestinal inflammation and also underlie specific disease phenotypes. In addition to highlighting the potential use of DAMPs such as calprotectin as biomarkers, research on DAMPs may reveal novel mechanistic associations in IBD pathogenesis and is expected to uncover putative therapeutic targets.
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Affiliation(s)
- Hayandra Ferreira Nanini
- Serviço de Gastroenterologia e Laboratório Multidisciplinar de Pesquisa, Departamento de Clínica Médica, Hospital Universitário Clementino Fraga Filho, Universidade Federal do Rio de Janeiro, Rio de Janeiro, RJ 21941-913, Brazil
| | - Claudio Bernardazzi
- Serviço de Gastroenterologia e Laboratório Multidisciplinar de Pesquisa, Departamento de Clínica Médica, Hospital Universitário Clementino Fraga Filho, Universidade Federal do Rio de Janeiro, Rio de Janeiro, RJ 21941-913, Brazil
| | - Fernando Castro
- Serviço de Gastroenterologia e Laboratório Multidisciplinar de Pesquisa, Departamento de Clínica Médica, Hospital Universitário Clementino Fraga Filho, Universidade Federal do Rio de Janeiro, Rio de Janeiro, RJ 21941-913, Brazil
| | - Heitor Siffert Pereira de Souza
- Serviço de Gastroenterologia e Laboratório Multidisciplinar de Pesquisa, Departamento de Clínica Médica, Hospital Universitário Clementino Fraga Filho, Universidade Federal do Rio de Janeiro, Rio de Janeiro, RJ 21941-913, Brazil
- D’Or Institute for Research and Education (IDOR), Rua Diniz Cordeiro 30, Botafogo, Rio de Janeiro, RJ 22281-100, Brazil
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6
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NLRP3 inflammasome in colitis and colitis-associated colorectal cancer. Mamm Genome 2018; 29:817-830. [DOI: 10.1007/s00335-018-9783-2] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2018] [Accepted: 09/04/2018] [Indexed: 12/21/2022]
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Inflammasomes in the Gut Mucosal Homeostasis. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2017; 1024:133-151. [PMID: 28921468 DOI: 10.1007/978-981-10-5987-2_6] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
Inflammasomes are critical checkpoints in inflammation. The activation of inflammasome can cause a series of inflammatory responses including maturation of interleukin (IL)-1β and IL-18 and a specialized form of cell death called pyroptosis. Since its identification in the early 2000s, inflammasomes have been implicated to play multifaceted roles in varied pathological and physiological conditions, especially in the mucosal compartments including the gut. Maintaining gut mucosal homeostasis has always been a remarkable challenge for the host due to both the vast mucosal surface that is exposed to the outside and the enormous amount of local microbiota. To accomplish this challenge, the host mounts a constant dynamic low-grade inflammatory response (physiological inflammation) in coping with insults of microbes in the intestine. This book chapter aims to summarize the current knowledge of how inflammasomes contribute to gut mucosal homeostasis.
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Cholecalciterol cholesterol emulsion ameliorates experimental colitis via down-regulating the pyroptosis signaling pathway. Exp Mol Pathol 2016; 100:386-92. [PMID: 26970278 DOI: 10.1016/j.yexmp.2016.03.003] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2015] [Revised: 03/03/2016] [Accepted: 03/07/2016] [Indexed: 12/13/2022]
Abstract
The therapeutic effect of 1,25(OH)2 vitamin D3 and its analog (paricalcitol) on experimental colitis in animals has been heavily demonstrated. However, the response to Cholecalciterol Cholesterol Emulsion (CCE), a precursor of 1,25(OH)2 vitamin D3, has not yet been reported. Whether pyroptosis is involved in colitic deterioration also remains unclear. Therefore, we adopted molecular biology and histology approaches to examine mechanisms by which CCE was able to regulate experimental colitis in the animal model induced by 2,4,6-trinitrobenzenesulfonic acid (TNBS). Our data revealed that mice displayed a remarkable reduction in colonic histological scores, colonic inflammation and colonic histological damage. In addition, there was an overall improvement in general status (change in body weight, food and water intake, mental status, activity) and a 30% increase in survival rate due to the downregulation of pyroptosis following treatment with CCE. In conclusion, our data have provided evidence that CCE can attenuate the damage of experimental colitis by suppressing pyroptosis signaling.
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Hu Y, Yoshida K, Cologne JB, Maki M, Morishita Y, Sasaki K, Hayashi I, Ohishi W, Hida A, Kyoizumi S, Kusunoki Y, Tokunaga K, Nakachi K, Hayashi T. CD14 and IL18 gene polymorphisms associated with colorectal cancer subsite risks among atomic bomb survivors. Hum Genome Var 2015; 2:15035. [PMID: 27081544 PMCID: PMC4785571 DOI: 10.1038/hgv.2015.35] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2015] [Revised: 08/10/2015] [Accepted: 08/11/2015] [Indexed: 01/09/2023] Open
Abstract
Colorectal cancer (CRC) is a common malignancy worldwide, and chronic inflammation is a risk factor for CRC. In this study, we carried out a cohort study among the Japanese atomic bomb (A-bomb) survivor population to investigate any association between immune- and inflammation-related gene polymorphisms and CRC. We examined the effects of six single-nucleotide polymorphisms of CD14 and IL18 on relative risks (RRs) of CRC. Results showed that RRs of CRC, overall and by anatomic subsite, significantly increased with increasing radiation dose. The CD14–911A/A genotype showed statistically significant higher risks for all CRC and distal CRC compared with the other two genotypes. In addition, the IL18–137 G/G genotype showed statistically significant higher risks for proximal colon cancer compared with the other two genotypes. In phenotype–genotype analyses, the CD14–911A/A genotype presented significantly higher levels of membrane and soluble CD14 compared with the other two genotypes, and the IL18–137 G/G genotype tended to be lower levels of plasma interleukin (IL)-18 compared with the other two genotypes. These results suggest the potential involvement of a CD14-mediated inflammatory response in the development of distal CRC and an IL18-mediated inflammatory response in the development of proximal colon cancer among A-bomb survivors.
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Affiliation(s)
- Yiqun Hu
- Department of Radiobiology/Molecular Epidemiology, Radiation Effects Research Foundation , Hiroshima, Japan
| | - Kengo Yoshida
- Department of Radiobiology/Molecular Epidemiology, Radiation Effects Research Foundation , Hiroshima, Japan
| | - John B Cologne
- Department of Statistics, Radiation Effects Research Foundation , Hiroshima, Japan
| | - Mayumi Maki
- Department of Radiobiology/Molecular Epidemiology, Radiation Effects Research Foundation , Hiroshima, Japan
| | - Yukari Morishita
- Department of Radiobiology/Molecular Epidemiology, Radiation Effects Research Foundation , Hiroshima, Japan
| | - Keiko Sasaki
- Department of Radiobiology/Molecular Epidemiology, Radiation Effects Research Foundation , Hiroshima, Japan
| | - Ikue Hayashi
- Central Research Laboratory, Hiroshima University Faculty of Dentistry , Hiroshima, Japan
| | - Waka Ohishi
- Clinical Studies, Radiation Effects Research Foundation , Hiroshima, Japan
| | - Ayumi Hida
- Department of Clinical Studies, Radiation Effects Research Foundation , Nagasaki, Japan
| | - Seishi Kyoizumi
- Department of Radiobiology/Molecular Epidemiology, Radiation Effects Research Foundation , Hiroshima, Japan
| | - Yoichiro Kusunoki
- Department of Radiobiology/Molecular Epidemiology, Radiation Effects Research Foundation , Hiroshima, Japan
| | - Katsushi Tokunaga
- Department of Human Genetics, Graduate School of Medicine, University of Tokyo , Tokyo, Japan
| | - Kei Nakachi
- Department of Radiobiology/Molecular Epidemiology, Radiation Effects Research Foundation , Hiroshima, Japan
| | - Tomonori Hayashi
- Department of Radiobiology/Molecular Epidemiology, Radiation Effects Research Foundation , Hiroshima, Japan
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Kanai T, Mikami Y, Hayashi A. A breakthrough in probiotics: Clostridium butyricum regulates gut homeostasis and anti-inflammatory response in inflammatory bowel disease. J Gastroenterol 2015; 50:928-39. [PMID: 25940150 DOI: 10.1007/s00535-015-1084-x] [Citation(s) in RCA: 107] [Impact Index Per Article: 10.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/10/2015] [Accepted: 04/18/2015] [Indexed: 02/04/2023]
Abstract
Intestinal immune homeostasis is regulated by gut microbiota, including beneficial and pathogenic microorganisms. Imbalance in gut bacterial constituents provokes host proinflammatory responses causing diseases such as inflammatory bowel disease (IBD). The development of next-generation sequencing technology allows the identification of microbiota alterations in IBD. Several studies have shown reduced diversity in the gut microbiota of patients with IBD. Advances in gnotobiotic technology have made possible analysis of the role of specific bacterial strains in immune cells in the intestine. Using these techniques, we have shown that Clostridium butyricum as a probiotic induces interleukin-10-producing macrophages in inflamed mucosa via the Toll-like receptor 2/myeloid differentiation primary response gene 88 pathway to prevent acute experimental colitis. In this review, we focus on the new approaches for the role of specific bacterial strains in immunological responses, as well as the potential of bacterial therapy for IBD treatments.
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Affiliation(s)
- Takanori Kanai
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Keio University School of Medicine, Tokyo, 160-8582, Japan,
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11
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Saavedra PHV, Demon D, Van Gorp H, Lamkanfi M. Protective and detrimental roles of inflammasomes in disease. Semin Immunopathol 2015; 37:313-22. [PMID: 25895577 DOI: 10.1007/s00281-015-0485-5] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2015] [Accepted: 03/23/2015] [Indexed: 10/23/2022]
Abstract
Over recent years, inflammasomes have emerged as key regulators of immune and inflammatory responses. They induce programmed cell death and direct the release of danger signals and the inflammatory cytokines interleukin (IL)-1β and IL-18. The concerted actions of inflammasomes are of utmost importance for responding adequately to harmful environmental agents and infections. However, deregulated inflammasome signaling is increasingly linked to a diversity of human pathologies, including rheumatoid arthritis, inflammatory bowel disease, and rare, hereditary periodic fever syndromes. In this review, we discuss recent insight in the protective and detrimental roles of inflammasomes in selected infectious, autoinflammatory and autoimmune diseases, and cover clinically approved therapies that interfere with inflammasome signaling. These findings highlight the importance of fine-balancing the Ying and Yang activities of inflammasomes for sustained homeostasis and suggest that further understanding of inflammasome mechanisms may offer new cures for human diseases.
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Affiliation(s)
- Pedro H V Saavedra
- Department of Medical Protein Research, VIB, Albert Baertsoenkaai 3, B-9000, Ghent, Belgium
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12
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Schmitz S, Werling D, Allenspach K. Effects of ex-vivo and in-vivo treatment with probiotics on the inflammasome in dogs with chronic enteropathy. PLoS One 2015; 10:e0120779. [PMID: 25799280 PMCID: PMC4370582 DOI: 10.1371/journal.pone.0120779] [Citation(s) in RCA: 32] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2014] [Accepted: 01/27/2015] [Indexed: 01/15/2023] Open
Abstract
Inflammasomes coordinate the maturation of IL-1β and IL-18 in response to danger signals. They are vital for maintenance of intestinal homeostasis and have been linked to chronic intestinal inflammation in humans. Probiotics have been advocated as treatment in intestinal inflammation. So far, no study has investigated the role of the inflammasome in canine chronic enteropathy (CE). In this study the intestinal expression of inflammasome components was assessed in CE dogs compared to controls, when treated with probiotic Enterococcus faecium (EF) ex-vivo and in-vivo. RNA extraction from endoscopic biopsies and reverse-transcriptase quantitative PCR was performed for NLRP3, casp-1, IL-1β and IL-18. Immunohistochemistry was performed to investigate protein expression in tissues. Gene expression of casp-1 and NLRP3 was lower in CE samples than controls. Ex-vivo treatment with EF reduced NLRP3 expression in control samples. Treatment of CE dogs with EF alongside dietary intervention had no effect on gene expression. In contrast, IL-1β protein expression in CE decreased with dietary treatment (but not with probiotics). The results of this study suggest that the inflammasome or its components may be partially involved in the inflammatory process seen in CE, but distinct from intestinal inflammation in humans.
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Affiliation(s)
- Silke Schmitz
- Department of Veterinary Sciences and Services, Royal Veterinary College, University of London, Hawkshead Campus, North Mymms, United Kingdom
- * E-mail:
| | - Dirk Werling
- Department of Pathology and Pathogen Biology, Royal Veterinary College, University of London, Hawkshead Campus, North Mymms, United Kingdom
| | - Karin Allenspach
- Department of Veterinary Sciences and Services, Royal Veterinary College, University of London, Hawkshead Campus, North Mymms, United Kingdom
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Elia PP, Tolentino YFM, Bernardazzi C, de Souza HSP. The role of innate immunity receptors in the pathogenesis of inflammatory bowel disease. Mediators Inflamm 2015; 2015:936193. [PMID: 25821356 PMCID: PMC4364059 DOI: 10.1155/2015/936193] [Citation(s) in RCA: 38] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2014] [Accepted: 12/18/2014] [Indexed: 12/14/2022] Open
Abstract
Innate immunity constitutes the first line of defense, fundamental for the recognition and the initiation of an inflammatory response against microorganisms. The innate immune response relies on the sensing of microbial-associated molecular patterns through specialized structures such as toll-like receptors (TLRs) and the nucleotide oligomerization domain- (NOD-) like receptors (NLRs). In the gut, these tasks are performed by the epithelial barrier and the presence of adaptive and innate immune mechanisms. TLRs and NLRs are distributed throughout the gastrointestinal mucosa, being more expressed in the epithelium, and in lamina propria immune and nonimmune cells. These innate immunity receptors exhibit complementary biological functions, with evidence for pathways overlapping. However, as tolerance is the predominant physiological response in the gastrointestinal mucosa, it appears that the TLRs are relatively downregulated, while NLRs play a critical role in mucosal defense in the gut. Over the past two decades, genetic polymorphisms have been associated with several diseases including inflammatory bowel disease. Special emphasis has been given to the susceptibility to Crohn's disease, in association with abnormalities in the NOD2 and in the NLRP3/inflammasome. Nevertheless, the mechanisms underlying innate immune receptors dysfunction that result in the persistent inflammation in inflammatory bowel disease remain to be clarified.
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Affiliation(s)
- Paula Peruzzi Elia
- Serviço de Gastroenterologia and Laboratório Multidisciplinar de Pesquisa, Hospital Universitario, Universidade Federal do Rio de Janeiro, 21941-913 Rio de Janeiro, RJ, Brazil
| | - Yolanda Faia M. Tolentino
- Serviço de Gastroenterologia and Laboratório Multidisciplinar de Pesquisa, Hospital Universitario, Universidade Federal do Rio de Janeiro, 21941-913 Rio de Janeiro, RJ, Brazil
| | - Claudio Bernardazzi
- Serviço de Gastroenterologia and Laboratório Multidisciplinar de Pesquisa, Hospital Universitario, Universidade Federal do Rio de Janeiro, 21941-913 Rio de Janeiro, RJ, Brazil
| | - Heitor Siffert Pereira de Souza
- Serviço de Gastroenterologia and Laboratório Multidisciplinar de Pesquisa, Hospital Universitario, Universidade Federal do Rio de Janeiro, 21941-913 Rio de Janeiro, RJ, Brazil
- D'Or Institute for Research and Education (IDOR), Rua Diniz Cordeiro 30, Botafogo, 22281-100 Rio de Janeiro, RJ, Brazil
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14
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Magni S, Buoli Comani G, Elli L, Vanessi S, Ballarini E, Nicolini G, Rusconi M, Castoldi M, Meneveri R, Muckenthaler MU, Bardella MT, Barisani D. miRNAs affect the expression of innate and adaptive immunity proteins in celiac disease. Am J Gastroenterol 2014; 109:1662-1674. [PMID: 25070052 DOI: 10.1038/ajg.2014.203] [Citation(s) in RCA: 44] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/26/2014] [Accepted: 06/17/2014] [Indexed: 12/11/2022]
Abstract
OBJECTIVES microRNAs (miRNAs) are short RNAs that regulate gene expression in various processes, including immune response. Altered immune response is a pivotal event in the pathogenesis of celiac disease (CD), and miRNAs could have a role in modulating both innate and adaptive response to gluten in celiac patients. METHODS We compared miRNA profiles in duodenal biopsies of controls and CD patients by miRNA array. Differentially expressed miRNAs were validated in controls, Marsh 3A-B, and Marsh 3C patients by quantitative PCR (qPCR). Target gene expression was assessed by qPCR, western blotting, and immunohistochemistry, and the effect of gliadin was evaluated by in vitro stimulation experiments on duodenal biopsies. RESULTS Seven miRNAs were identified as significantly downregulated in the duodenum of adult CD patients as compared with controls. qPCR validated the decreased expression of miR-192-5p, miR-31-5p, miR-338-3p, and miR-197, in particular in patients with more severe histological lesions (Marsh 3C). In silico analysis of possible miRNA targets identified several genes involved in innate and adaptive immunity. Among these, chemokine C-X-C motif ligand 2 (CXCL2) and NOD2 showed significantly increased mRNA and protein level in Marsh 3C patients and a significant inverse correlation with the regulatory miR-192-5p. In addition, forkhead box P3 (FOXP3), Run-related transcription factor 1, and interleukin-18 (targets of miR-31-5p, miR-338-3p, and miR-197, respectively) showed upregulation in CD patients. Furthermore, alterations in CXCL2 and NOD2, FOXP3, miR-192-5p, and miR-31-5p expression were triggered by gliadin exposure in CD patients. CONCLUSIONS miRNA expression is significantly altered in duodenal mucosa of CD patients, and this alteration can increase the expression of molecules involved in immune response.
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Affiliation(s)
- Serena Magni
- Department of Health Sciences, School of Medicine, University of Milano-Bicocca, Monza, Italy
| | - Gaia Buoli Comani
- Department of Health Sciences, School of Medicine, University of Milano-Bicocca, Monza, Italy
| | - Luca Elli
- Center for the Prevention and Diagnosis of Celiac Disease and UOC Gastroenterologia ed Endoscopia, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Dipartimento di Fisiopatologia Medico-Chirurgica e dei Trapianti, Università degli Studi di Milano, Milan, Italy
| | - Samanta Vanessi
- Department of Health Sciences, School of Medicine, University of Milano-Bicocca, Monza, Italy
| | - Elisa Ballarini
- Experimental Neurology Unit, Department of Surgery and Translational Medicine, School of Medicine, University of Milano-Bicocca, Monza, Italy
| | - Gabriella Nicolini
- Experimental Neurology Unit, Department of Surgery and Translational Medicine, School of Medicine, University of Milano-Bicocca, Monza, Italy
| | - Michela Rusconi
- Department of Health Sciences, School of Medicine, University of Milano-Bicocca, Monza, Italy
| | - Mirco Castoldi
- 1] Department of Pediatric Oncology, Hematology and Immunology, University Hospital of Heidelberg, Heidelberg, Germany [2] Clinic for Gastroenterology, Hepatology and Infectious Diseases, Heinrich-Heine University Düsseldorf, Düsseldorf, Germany
| | - Raffaella Meneveri
- Department of Health Sciences, School of Medicine, University of Milano-Bicocca, Monza, Italy
| | - Martina U Muckenthaler
- Department of Pediatric Oncology, Hematology and Immunology, University Hospital of Heidelberg, Heidelberg, Germany
| | - Maria Teresa Bardella
- Center for the Prevention and Diagnosis of Celiac Disease and UOC Gastroenterologia ed Endoscopia, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Dipartimento di Fisiopatologia Medico-Chirurgica e dei Trapianti, Università degli Studi di Milano, Milan, Italy
| | - Donatella Barisani
- 1] Department of Health Sciences, School of Medicine, University of Milano-Bicocca, Monza, Italy [2] International Research Center for Hepato-Biliary-Pancreatic Diseases-IRCHD, University of Milano-Bicocca, Monza, Italy
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15
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Characteristics of Japanese inflammatory bowel disease susceptibility loci. J Gastroenterol 2014; 49:1217-30. [PMID: 23942620 DOI: 10.1007/s00535-013-0866-2] [Citation(s) in RCA: 33] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/04/2013] [Accepted: 07/29/2013] [Indexed: 02/04/2023]
Abstract
BACKGROUND There are substantial differences in inflammatory bowel disease (IBD) genetics depending on the populations examined. We aimed to identify Japanese population-specific or true culprit susceptibility genes through a meta-analysis of past genetic studies of Japanese IBD. METHODS For this study, we reviewed 2,703 articles. The review process consisted of three screening stages: we initially searched for relevant studies and then relevant single nucleotide polymorphisms (SNPs). Finally, we adjusted them for the meta-analysis. To maximize our chances of analysis, we introduced proxy SNPs during the first stage. To minimize publication bias, no significant SNPs and solitary SNPs without pairs were combined to be reconsidered during the third stage. Additionally, two SNPs were newly genotyped. Finally, we conducted a meta-analysis of 37 published studies in 50 SNPs located at 22 loci corresponding to the total number of 4,853 Crohn's disease (CD), 5,612 ulcerative colitis (UC) patients, and 14,239 healthy controls. RESULTS We confirmed that the NKX2-3 polymorphism is associated with common susceptibility to IBD and that HLA-DRB1*0450 alleles increase susceptibility to CD but reduce risk for UC while HLA-DRB1*1502 alleles increase susceptibility to UC but reduce CD risk. Moreover, we found individual disease risk loci: TNFSF15 and TNFα to CD and HLA-B*5201, and NFKBIL1 to UC. The genetic risk of HLA was substantially high (odds ratios ranged from 1.54 to 2.69) while that of common susceptibility loci to IBD was modest (odds ratio ranged from 1.13 to 1.24). CONCLUSIONS Results indicate that Japanese IBD susceptibility loci identified by the meta-analysis are closely associated with the HLA regions.
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16
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Corridoni D, Arseneau KO, Cifone MG, Cominelli F. The dual role of nod-like receptors in mucosal innate immunity and chronic intestinal inflammation. Front Immunol 2014; 5:317. [PMID: 25071778 PMCID: PMC4090755 DOI: 10.3389/fimmu.2014.00317] [Citation(s) in RCA: 47] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2014] [Accepted: 06/24/2014] [Indexed: 01/11/2023] Open
Abstract
Nucleotide-binding and oligomerization domain NOD-like receptors (NLRs) are highly conserved cytosolic pattern recognition receptors that play, in combination with toll-like receptors, a critical role in innate immunity and inflammation. These proteins are characterized by a central oligomerization domain termed nucleotide-binding domain, and a protein interaction domain containing leucine-rich repeats. Some NLRs, including NOD1 and NOD2, sense the cytosolic presence of conserved bacterial molecular signatures and drive the activation of mitogen-activated protein kinase and the transcription factor NF-κB. A different set of NLRs induces caspase-1 activation through the assembly of large protein complexes known as inflammasomes. Activation of NLR proteins results in secretion of pro-inflammatory cytokines and subsequent inflammatory responses. The critical role of NLRs in innate immunity is underscored by the fact that polymorphisms within their genes are implicated in the development of several immune-mediated diseases, including inflammatory bowel disease. Over the past few years, the role of NLRs in intestinal homeostasis has been highlighted, however the mechanism by which dysfunction in these proteins leads to aberrant inflammation is still the focus of much investigation. The purpose of this review is to systematically evaluate the function of NLRs in mucosal innate immunity and understand how genetic or functional alterations in these components can lead to the disruption of intestinal homeostasis, and the subsequent development of chronic inflammation.
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Affiliation(s)
- Daniele Corridoni
- Department of Medicine, Case Western Reserve University , Cleveland, OH , USA ; Digestive Health Research Center, Case Western Reserve University , Cleveland, OH , USA
| | - Kristen O Arseneau
- Department of Medicine, Case Western Reserve University , Cleveland, OH , USA ; Digestive Health Research Center, Case Western Reserve University , Cleveland, OH , USA
| | - Maria Grazia Cifone
- Department of Life, Health and Environmental Sciences, University of L'Aquila , L'Aquila , Italy
| | - Fabio Cominelli
- Department of Medicine, Case Western Reserve University , Cleveland, OH , USA ; Digestive Health Research Center, Case Western Reserve University , Cleveland, OH , USA
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17
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Parlato M, Yeretssian G. NOD-like receptors in intestinal homeostasis and epithelial tissue repair. Int J Mol Sci 2014; 15:9594-627. [PMID: 24886810 PMCID: PMC4100112 DOI: 10.3390/ijms15069594] [Citation(s) in RCA: 57] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2014] [Revised: 05/16/2014] [Accepted: 05/20/2014] [Indexed: 12/13/2022] Open
Abstract
The intestinal epithelium constitutes a dynamic physical barrier segregating the luminal content from the underlying mucosal tissue. Following injury, the epithelial integrity is restored by rapid migration of intestinal epithelial cells (IECs) across the denuded area in a process known as wound healing. Hence, through a sequence of events involving restitution, proliferation and differentiation of IECs the gap is resealed and homeostasis reestablished. Relapsing damage followed by healing of the inflamed mucosa is a hallmark of several intestinal disorders including inflammatory bowel diseases (IBD). While several regulatory peptides, growth factors and cytokines stimulate restitution of the epithelial layer after injury, recent evidence in the field underscores the contribution of innate immunity in controlling this process. In particular, nucleotide-binding and oligomerization domain-like receptors (NLRs) play critical roles in sensing the commensal microbiota, maintaining homeostasis, and regulating intestinal inflammation. Here, we review the process of intestinal epithelial tissue repair and we specifically focus on the impact of NLR-mediated signaling mechanisms involved in governing epithelial wound healing during disease.
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Affiliation(s)
- Marianna Parlato
- Department of Medicine, Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
| | - Garabet Yeretssian
- Department of Medicine, Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
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18
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The complex role of inflammasomes in the pathogenesis of Inflammatory Bowel Diseases - lessons learned from experimental models. Cytokine Growth Factor Rev 2014; 25:715-30. [PMID: 24803013 DOI: 10.1016/j.cytogfr.2014.04.003] [Citation(s) in RCA: 53] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2014] [Accepted: 04/04/2014] [Indexed: 02/08/2023]
Abstract
Inflammasomes are a large family of multiprotein complexes recognizing pathogen-associated molecular pattern molecules (PAMPs) and damage-associated molecular patterns (DAMPs). This leads to caspase-1 activation, promoting the secretion of mature IL-1β, IL-18 and under certain conditions even induce pyroptosis. Inflammatory Bowel Diseases (IBD) is associated with alterations in microbiota composition, inappropriate immune responses and genetic predisposition associated to bacterial sensing and autophagy. Besides their acknowledged role in mounting microbial induced host responses, a crucial role in maintenance of intestinal homeostasis was revealed in inflammasome deficient mice. Further, abnormal activation of these functions appears to contribute to the pathology of intestinal inflammation including IBD and colitis-associated cancer. Herein, the current literature implicating the inflammasomes, microbiota and IBD is comprehensively reviewed.
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19
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Wang Y, Tong J, Chang B, Wang BF, Zhang D, Wang BY. Genetic polymorphisms in the IL-18 gene and ulcerative colitis risk: a meta-analysis. DNA Cell Biol 2014; 33:438-47. [PMID: 24621393 DOI: 10.1089/dna.2013.2310] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/30/2023] Open
Abstract
This meta-analysis was performed to evaluate the relationships between genetic polymorphisms in the IL-18 gene and ulcerative colitis (UC) risk. The PubMed, CISCOM, CINAHL, Web of Science, Google Scholar, EBSCO, Cochrane Library, and CBM databases were searched for relevant articles published before November 1st, 2013 without any language restrictions. Meta-analysis was conducted using the STATA 12.0 software. Crude odds ratios (ORs) with their 95% confidence intervals (95% CI) were calculated. Eight case-control studies with a total of 1000 UC cases and 1392 healthy subjects met the inclusion criteria. Six common polymorphisms in the IL-18 gene were evaluated, including rs1946518 A>C, rs187238 G>C, rs917997 G>A, Codon35, rs1946519 C>A, and rs360718 A>C. The results of our meta-analysis suggest that the IL-18 rs1946518 (allele model: OR=1.22, 95% CI: 1.01-1.48, p=0.039; dominant model: OR=1.44, 95% CI: 1.01-2.06, p=0.045; respectively), rs187238 (allele model: OR=1.38, 95% CI: 1.19-1.61, p<0.001; dominant model: OR=1.50, 95% CI: 1.03-2.19, p=0.034; respectively), and rs360718 (allele model: OR=2.18, 95% CI: 1.22-3.90, p=0.008) polymorphisms might be strongly correlated with an increased risk of UC. A subgroup analysis was conducted to investigate the effect of ethnicity on an individual's risk of UC. Our results revealed positive significant correlations between IL-18 genetic polymorphisms and an increased risk of UC among Asians (allele model: OR=1.36, 95% CI: 1.16-1.60, p<0.001; dominant model: OR=1.50, 95% CI: 1.14-1.98, p=0.004; respectively) and Africans (allele model: OR=1.45, 95% CI: 1.03-2.05, p=0.034), but not among Caucasians (all p>0.05). Our findings provide convincing evidence that IL-18 genetic polymorphisms may contribute to susceptibility to UC, especially the rs1946518, rs187238, and rs360718 polymorphisms among Asians and Africans.
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Affiliation(s)
- Ying Wang
- Department of Gastroenterology, The First Hospital of China Medical University , Shenyang, People's Republic of China
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20
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Interleukin 18 gene polymorphism is a risk factor for multiple sclerosis. Mol Biol Rep 2014; 41:1653-8. [DOI: 10.1007/s11033-013-3013-5] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2013] [Accepted: 12/30/2013] [Indexed: 12/13/2022]
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21
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Lopetuso LR, Chowdhry S, Pizarro TT. Opposing Functions of Classic and Novel IL-1 Family Members in Gut Health and Disease. Front Immunol 2013; 4:181. [PMID: 23847622 PMCID: PMC3705591 DOI: 10.3389/fimmu.2013.00181] [Citation(s) in RCA: 117] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2013] [Accepted: 06/24/2013] [Indexed: 12/17/2022] Open
Abstract
In addition to their well-established role(s) in the pathogenesis of gastrointestinal (GI)-related inflammatory disorders, including inflammatory bowel disease (IBD) and inflammation-associated colorectal cancer (CRC), emerging evidence confirms the critical involvement of the interleukin-1 (IL-1) cytokine family and their ligands in the maintenance of normal gut homeostasis. In fact, the paradigm that IBD occurs in two distinct phases is substantiated by the observation that classic IL-1 family members, such as IL-1, the IL-1 receptor antagonist (IL-1Ra), and IL-18, possess dichotomous functions depending on the phase of disease, as well as on their role in initiating vs. sustaining chronic gut inflammation. Another recently characterized IL-1 family member, IL-33, also possesses dual functions in the gut. IL-33 is upregulated in IBD and potently induces Th2 immune responses, while also amplifying Th1-mediated inflammation. Neutralization studies in acute colitis models, however, have yielded controversial results and recent reports suggest a protective role of IL-33 in epithelial regeneration and mucosal wound healing. Finally, although little is currently known regarding the potential contribution of IL-36 family members in GI inflammation/homeostasis, another IL-1 family member, IL-37, is emerging as a potent anti-inflammatory cytokine with the ability to down-regulate colitis. This new body of information has important translational implications for both the prevention and treatment of patients suffering from IBD and inflammation-associated CRC.
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Affiliation(s)
- Loris R Lopetuso
- Department of Pathology, Case Western Reserve University School of Medicine , Cleveland, OH , USA ; Internal Medicine, Gastroenterology Division, Catholic University of Rome , Rome , Italy
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22
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Latiano A, Palmieri O, Pastorelli L, Vecchi M, Pizarro TT, Bossa F, Merla G, Augello B, Latiano T, Corritore G, Settesoldi A, Valvano MR, D'Incà R, Stronati L, Annese V, Andriulli A. Associations between genetic polymorphisms in IL-33, IL1R1 and risk for inflammatory bowel disease. PLoS One 2013; 8:e62144. [PMID: 23634226 PMCID: PMC3636262 DOI: 10.1371/journal.pone.0062144] [Citation(s) in RCA: 80] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2012] [Accepted: 03/18/2013] [Indexed: 02/07/2023] Open
Abstract
BACKGROUND Recent evidence suggests that the IL-33/IL1RL1 axis plays a critical role in several autoimmune and inflammatory disorders; however, its mechanistic role in inflammatory bowel disease (IBD) has not been clearly defined. We investigated the contribution of IL-33 and IL1RL1 polymorphisms to IBD risk, and possible correlations with phenotype in an Italian cohort of adult and pediatric patients. METHODS We evaluated the association of six SNPs in IL-33 and IL1RL1 genes, in 805 Crohn's disease (CD), 816 ulcerative colitis (UC), and 752 controls, using Taqman. IL-33 and IL1RL1 mRNA expression was also analyzed. RESULTS Significant allele and genotype associations with IL-33 rs3939286 were found in CD (P = 0.004; P = 0.035) and UC patients (P = 0.002; P = 0.038). After stratifying the cohort for age at diagnosis, the differences remained significant only in the IBD adult-onset. Significant associations were also obtained in CD patients with two IL1RL1 polymorphisms (rs13015714 and rs2058660, P<0.015). By combining homo- and heterozygous carriers of the rs13015714 risk allele, differences were still significant for both CD adult- and pediatric-onset. Upon genotype-phenotype evaluation, an increased frequency of extensive colitis in adult UC (P = 0.019) and in steroid-responsive pediatric patients (P = 0.024) carrying the IL-33 rs3939286 risk genotype, was observed. mRNA expression of IL-33 and IL1RL1 in inflamed IBD biopsy samples was significantly increased. CONCLUSIONS Common IL-33 and IL1RL1 polymorphisms contribute to the risk of IBD in an Italian cohort of adult and pediatric patients, with some influence on sub-phenotypes.
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Affiliation(s)
- Anna Latiano
- Division of Gastroenterology, IRCCS Casa Sollievo della Sofferenza, San Giovanni Rotondo, Italy.
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23
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Nunes T, de Souza HS. Inflammasome in intestinal inflammation and cancer. Mediators Inflamm 2013; 2013:654963. [PMID: 23606794 PMCID: PMC3625567 DOI: 10.1155/2013/654963] [Citation(s) in RCA: 40] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2013] [Accepted: 03/07/2013] [Indexed: 02/07/2023] Open
Abstract
The activation of specific cytosolic pathogen recognition receptors, the nucleotide-binding-oligomerization-domain- (NOD-) like receptors (NLRs), leads to the assembly of the inflammasome, a multimeric complex platform that activates caspase-1. The caspase-1 pathway leads to the upregulation of important cytokines from the interleukin (IL)-1 family, IL-1β , and IL-18, with subsequent activation of the innate immune response. In this review, we discuss the molecular structure, the mechanisms behind the inflammasome activation, and its possible role in the pathogenesis of inflammatory bowel diseases and intestinal cancer. Here, we show that the available data points towards the importance of the inflammasome in the innate intestinal immune response, being the complex involved in the maintenance of intestinal homeostasis, correct intestinal barrier function and efficient elimination of invading pathogens.
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Affiliation(s)
- Tiago Nunes
- Biofunctionality Unit, ZIEL Research Center for Nutrition and Food Sciences, Technical University of Munich, 85354 Freising-Weihenstephan, Germany
| | - Heitor S. de Souza
- Serviço de Gastroenterologia & Laboratório Multidisciplinar de Pesquisa, Hospital Universitario, Universidade Federal do Rio de Janeiro, 21941-913 Rio de Janeiro, RJ, Brazil
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24
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Elinav E, Henao-Mejia J, Flavell RA. Integrative inflammasome activity in the regulation of intestinal mucosal immune responses. Mucosal Immunol 2013; 6:4-13. [PMID: 23212196 DOI: 10.1038/mi.2012.115] [Citation(s) in RCA: 69] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
The mammalian intestinal tract harbors a vast and diverse ecosystem of microbes that are separated from the sterile host milieu by a single layer of epithelial cells. While this bio-geographical configuration is critical for host biological processes, it imposes a risk for microbial penetration and life-threatening systemic invasion. Inflammasomes are cytosolic multi-protein platforms that sense both microbial and damage-associated molecular patterns and initiate a potent innate immune anti-microbial response. In this review, we will highlight the role of inflammasomes in the orchestration and regulation of the intestinal immune response, focusing on the roles of inflammasomes in maintenance of intestinal homeostasis, enteric infection, auto-inflammation, and tumorigenesis. We highlight the centrality of inflammasome signaling in the complex cross-talk between host mucosal immune arms and the environment, in particular the microflora, with emphasis on the spatial and temporal integration of inflammasome activation with signals from other innate signaling platforms.
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Affiliation(s)
- E Elinav
- Department of Immunobiology, Yale University School of Medicine, New Haven, Connecticut, USA
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25
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von Moltke J, Ayres JS, Kofoed EM, Chavarría-Smith J, Vance RE. Recognition of bacteria by inflammasomes. Annu Rev Immunol 2012; 31:73-106. [PMID: 23215645 DOI: 10.1146/annurev-immunol-032712-095944] [Citation(s) in RCA: 337] [Impact Index Per Article: 25.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Abstract
Inflammasomes are cytosolic multiprotein complexes that assemble in response to a variety of infectious and noxious insults. Inflammasomes play a critical role in the initiation of innate immune responses, primarily by serving as platforms for the activation of inflammatory caspase proteases. One such caspase, CASPASE-1 (CASP1), initiates innate immune responses by cleaving pro-IL-1β and pro-IL-18, leading to their activation and release. CASP1 and another inflammatory caspase termed CASP11 can also initiate a rapid and inflammatory form of cell death termed pyroptosis. Several distinct inflammasomes have been described, each of which contains a unique sensor protein of the NLR (nucleotide-binding domain, leucine-rich repeat-containing) superfamily or the PYHIN (PYRIN and HIN-200 domain-containing) superfamily. Here we describe the surprisingly diverse mechanisms by which NLR/PYHIN proteins sense bacteria and initiate innate immune responses. We conclude that inflammasomes represent a highly adaptable scaffold ideally suited for detecting and initiating rapid innate responses to diverse and rapidly evolving bacteria.
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Affiliation(s)
- Jakob von Moltke
- Department of Molecular & Cell Biology, Division of Immunology and Pathogenesis, University of California, Berkeley, California 94720, USA
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26
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Affiliation(s)
- Mohamed Lamkanfi
- Department of Biochemistry, Ghent University, Ghent 9000, Belgium
- Department of Medical Protein Research, VIB, Ghent 9000, Belgium;
| | - Vishva M. Dixit
- Department of Physiological Chemistry, Genentech, South San Francisco, California 94080;
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Huang CY, Ting WH, Lo FS, Wu YL, Chang TY, Chan HW, Lin WS, Chen WF, Lien YP, Lee YJ. The IL18 gene and Hashimoto thyroiditis in children. Hum Immunol 2012; 74:120-4. [PMID: 23073298 DOI: 10.1016/j.humimm.2012.10.005] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2012] [Revised: 09/13/2012] [Accepted: 10/03/2012] [Indexed: 02/04/2023]
Abstract
Interleukin 18 (IL18) stimulates interferon-γ production in Th1 cells which are prominent in the thyroid of Hashimoto thyroiditis (HT). We investigated the association between the IL18 gene and HT. There were 116 children with HT and 1272 controls. rs187238 and rs1946518 in the promoter region of the IL18 gene were genotyped. Differences in genotype, allele, carrier, and haplotype distributions between patients and controls were compared. A Pc value <0.05 was considered significant. The frequency of the C/G genotype of rs187238 was significantly higher in patients and conferred a risk of HT (OR, 1.96; 95% CI, 1.30-2.95; Pc, 0.0021). So did the frequencies of allele C (OR, 1.73; 95% CI, 1.22-2.44; Pc, 0.0035) and carrier C (OR, 1.96; 95% CI, 1.31-2.92; Pc, 0.0017), however the frequency of the G/G genotype was significantly lower in patients than in controls (OR, 0.51; 95% CI, 0.34-0.76; Pc, 0.0034). There was no association between HT and rs1946518. The CT haplotype was significantly more frequent in patients than in controls and conferred a risk of HT (OR, 1.76; 95% CI, 1.24-2.49; Pc, 0.0049). We concluded that the IL18 gene was associated with HT in children. The rs187238C allele and CT haplotype conferred a risk of HT.
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Affiliation(s)
- Chi-Yu Huang
- Department of Pediatrics, Mackay Memorial Hospital, Taipei, Taiwan
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Kim JM. [Inflammatory bowel diseases and inflammasome]. THE KOREAN JOURNAL OF GASTROENTEROLOGY 2012; 58:300-10. [PMID: 22198227 DOI: 10.4166/kjg.2011.58.6.300] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/25/2022]
Abstract
Inflammatory bowel disease (IBD), the most important entities being ulcerative colitis and Crohn's disease, are chronic, relapsing and remitting inflammatory conditions that result from chronic dysregulation of the mucosal immune system in the intestinal tract. Although the precise pathogenesis of IBD is still incompletely understood, increased levels of proinflammatory cytokines, including interleukin (IL)-1b, IL-18 and tumor necrosis factor-a, are detected in active IBD and correlate with the severity of inflammation, indicating that these cytokines may play a key role in the development of IBD. Recently, the intracellular nucleotide-binding oligomerization domain-like receptor (NLR) family members, including NLRP1, NLRP3, NLRC4 and NLRP6, are emerging as important regulators of intestinal homeostasis. Together, one of those aforementioned molecules or the DNA sensor absent in melanoma 2 (AIM2), apoptosis-associated speck-like protein containing 'a caspase recruitment domain (CARD)' (ASC) and caspase-1 form a large (> 700 kDa) multi-protein complex called the inflammasome. Stimulation with specific microbial and endogenous molecules triggers inflammasome assembly and caspase-1 activation. Activated caspase-1 leads to the secretion of proinflammatory cytokines, including IL-1b and IL-18, and the promotion of pyroptosis, a form of phagocyte cell death induced by bacterial pathogens, in an inflamed tissue. Therefore, inflammasomes are assumed to mediate host defense against microbial pathogens and gut homeostasis, so that their dysregulation might contribute to IBD pathogenesis. This review focuses on recent advances of the role of NLRP3 inflammasome signaling in IBD pathogenesis. Improving knowledge of the inflammasome could provide insights into potential therapeutic targets for patients with IBD.
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Affiliation(s)
- Jung Mogg Kim
- Department of Microbiology, Hanyang University College of Medicine, Seoul, Korea.
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29
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Abstract
Inflammasomes are multi-protein complexes that sense microbial molecules and endogenous danger signals in intracellular compartments. Inflammasome assembly results in caspase-1 activation, which in turn drives maturation and secretion of the pro-inflammatory cytokines interleukin 1β (IL-1β) and IL-18, and induces pyroptosis to eliminate the infectious agent. The importance of inflammasomes in regulating immune responses was recognized with the discovery of polymorphisms in genes encoding inflammasome components and their linkage to aberrant production of IL-1β and IL-18 in autoimmune and hereditary periodic fevers syndromes. We review the current knowledge on the role of inflammasomes in regulating innate and adaptive immune responses with an emphasis on the role of these immune complexes in autoinflammatory disorders and autoimmune diseases such as colitis, type I diabetes, multiple sclerosis and vitiligo.
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Abstract
Colorectal cancer is a major health problem in developed countries. Chronic intestinal inflammation predisposes individuals to the development of colorectal cancer. The intracellular NOD-like receptors (NLRs) have emerged as crucial regulators of intestinal inflammation and colorectal tumorigenesis. Activation of several NLRs leads to the formation of a protein complex called the inflammasome, which then triggers the activation of the cysteine protease caspase-1 and the downstream maturation and secretion of the inflammatory cytokines interleukin-1β and -18. Defective inflammasome signaling in the gut contributes to colitis and colorectal tumorigenesis by increasing the permeability of the epithelial barrier, dysregulating the proliferation of epithelial cells, and inducing oncogenic mediators. In this review, we discuss our current knowledge on how the inflammasome protects against colorectal tumorigenesis.
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Affiliation(s)
- Md Hasan Zaki
- Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN, 38105, USA
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31
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Chen GY, Núñez G. Inflammasomes in intestinal inflammation and cancer. Gastroenterology 2011; 141:1986-99. [PMID: 22005480 PMCID: PMC3442608 DOI: 10.1053/j.gastro.2011.10.002] [Citation(s) in RCA: 125] [Impact Index Per Article: 8.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/03/2011] [Revised: 10/06/2011] [Accepted: 10/12/2011] [Indexed: 02/08/2023]
Abstract
Inflammasomes are multi-protein complexes that mediate activation of caspase-1, which promotes secretion of the proinflammatory cytokines interleukin-1β and interleukin-18 and pyroptosis, a form of phagocyte cell death induced by bacterial pathogens. Members of the Nod-like receptor family (including Nlrp1, Nlrp3, and Nlrc4), the DNA sensor Aim2, the adaptor apoptosis-associated speck-like protein (ASC), and pro-caspase-1 are important components of inflammasomes. Stimulation with specific microbial and endogenous molecules leads to inflammasome assembly and caspase-1 activation. Inflammasomes are believed to mediate host defense against microbial pathogens and tissue homeostasis within the intestine, and their dysregulation might contribute to inflammatory diseases and intestinal cancer. Improving our understanding of inflammasome signaling pathways could provide insights into the pathogenesis of many gastrointestinal disorders and the development of therapeutic targets and approaches to treat diseases such as inflammatory bowel diseases and gastrointestinal cancers.
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Affiliation(s)
- Grace Y. Chen
- Division of Hematology and Oncology, Department of Internal Medicine, and Comprehensive Cancer Center, University of Michigan, Ann Arbor, MI 48109
| | - Gabriel Núñez
- Department of Pathology, and Comprehensive Cancer Center, University of Michigan, MI 48109
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Liu J, Liu J, Zhou Y, Li S, Li Y, Song X, Wang J, Wang L, Ying B. Association Between Promoter Variants of Interleukin-18 and Schizophrenia in a Han Chinese Population. DNA Cell Biol 2011; 30:913-7. [PMID: 21510800 DOI: 10.1089/dna.2011.1221] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/05/2023] Open
Affiliation(s)
- Jinnan Liu
- Department of Laboratory Medicine, West China Hospital, Sichuan University, Chengdu, P.R. China
| | - Jiaming Liu
- Department of Laboratory Medicine, West China Hospital, Sichuan University, Chengdu, P.R. China
| | - Yi Zhou
- Department of Laboratory Medicine, West China Hospital, Sichuan University, Chengdu, P.R. China
| | - Siyue Li
- Department of Laboratory Medicine, West China Hospital, Sichuan University, Chengdu, P.R. China
| | - Yi Li
- Department of Laboratory Medicine, West China Hospital, Sichuan University, Chengdu, P.R. China
| | - Xingbo Song
- Department of Laboratory Medicine, West China Hospital, Sichuan University, Chengdu, P.R. China
| | - Jun Wang
- Department of Laboratory Medicine, West China Hospital, Sichuan University, Chengdu, P.R. China
| | - Lanlan Wang
- Department of Laboratory Medicine, West China Hospital, Sichuan University, Chengdu, P.R. China
| | - Binwu Ying
- Department of Laboratory Medicine, West China Hospital, Sichuan University, Chengdu, P.R. China
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NOD-like receptors and the innate immune system: Coping with danger, damage and death. Cytokine Growth Factor Rev 2011; 22:257-76. [DOI: 10.1016/j.cytogfr.2011.09.003] [Citation(s) in RCA: 155] [Impact Index Per Article: 11.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2011] [Accepted: 09/07/2011] [Indexed: 12/26/2022]
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Zaki MH, Lamkanfi M, Kanneganti TD. The Nlrp3 inflammasome: contributions to intestinal homeostasis. Trends Immunol 2011; 32:171-9. [PMID: 21388882 PMCID: PMC3070791 DOI: 10.1016/j.it.2011.02.002] [Citation(s) in RCA: 232] [Impact Index Per Article: 16.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2010] [Revised: 01/31/2011] [Accepted: 02/01/2011] [Indexed: 01/11/2023]
Abstract
Inflammatory bowel diseases (IBD) such as Crohn's disease and ulcerative colitis constitute a major health problem in developed countries. Moreover, IBD predisposes to the development of colorectal cancer. The intracellular NOD-like receptor Nlrp3 is rapidly emerging as a crucial regulator of intestinal homeostasis. This innate immune receptor mediates assembly of the inflammasome complex in the presence of microbial ligands, triggering caspase-1 activation and secretion of IL-1β and IL-18. Recent studies suggest that defective Nlrp3 inflammasome signaling in the gut contributes to IBD through increased permeability across the epithelial barrier and the induction of detrimental immune responses against invading commensals. Here, we review and discuss recent advances of the role of the Nlrp3 inflammasome in colitis and colon tumorigenesis.
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Affiliation(s)
- Md. Hasan Zaki
- Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN, 38105, USA
| | - Mohamed Lamkanfi
- Department of Biochemistry, Ghent University, VIB, B-9000 Ghent, Belgium
- Department of Medical Protein Research, VIB, B-9000 Ghent, Belgium
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Leonard F, Collnot EM, Lehr CM. A three-dimensional coculture of enterocytes, monocytes and dendritic cells to model inflamed intestinal mucosa in vitro. Mol Pharm 2010; 7:2103-19. [PMID: 20809575 DOI: 10.1021/mp1000795] [Citation(s) in RCA: 158] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
While epithelial cell culture models (e.g., Caco-2 cell line) are widely used to assess the absorption of drug molecules across healthy intestinal mucosa, there are no suitable in vitro models of the intestinal barrier in the state of inflammation. Thus development of novel drugs and formulations for the treatment of inflammatory bowel disease is largely bound to animal models. We here report on the development of a complex in vitro model of the inflamed intestinal mucosa, starting with the selection of suitable enterocyte cell line and proinflammatory stimulus and progressing to the setup and characterization of a three-dimensional coculture of human intestinal epithelial cells and immunocompetent macrophages and dendritic cells. In the 3D setup, controlled inflammation can be induced allowing the mimicking of pathophysiological changes occurring in vivo in the inflamed intestine. Different combinations of proinflammatory stimuli (lipopolysaccharides from Escherichia coli and Salmonella typhimurium, interleukin-1β, interferon-γ) and intestinal epithelial cell lines (Caco-2, HT-29, T84) were evaluated, and only Caco-2 cells were responsive to stimulation, with interleukin-1β being the strongest stimulator. Caco-2 cells responded to the proinflammatory stimulus with a moderate upregulation of proinflammatory markers and a slight, but significant, decrease (20%) of transepithelial electrical resistance (TEER) indicating changes in the epithelial barrier properties. Setting up the coculture model, macrophages and dendritic cells derived from periphery blood monocytes were embedded in a collagen layer on a Transwell filter insert and Caco-2 cells were seeded atop. Even in the presence of immunocompetent cells Caco-2 cells formed a tight monolayer. Addition of IL-1β increased inflammatory cytokine response more strongly compared to Caco-2 single culture and stimulated immunocompetent cells proved to be highly active in sampling apically applied nanoparticles. Thus the 3D coculture provides additional complexity and information compared to the stimulated single cell model. The coculture system may serve as a valuable tool for developing drugs and formulations for the treatment of inflammatory bowel diseases, as well as for studying the interaction of xenobiotics and nanoparticles with the intestinal epithelial barrier in the state of inflammation.
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Affiliation(s)
- Fransisca Leonard
- Department of Biopharmaceutics and Pharmaceutical Technology and Helmholtz-Institute for Pharmaceutical Research Saarland, Saarland University, Saarland 66123, Germany
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36
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Zaki MH, Vogel P, Body-Malapel M, Lamkanfi M, Kanneganti TD. IL-18 production downstream of the Nlrp3 inflammasome confers protection against colorectal tumor formation. JOURNAL OF IMMUNOLOGY (BALTIMORE, MD. : 1950) 2010; 185:4912-20. [PMID: 20855874 PMCID: PMC3104023 DOI: 10.4049/jimmunol.1002046] [Citation(s) in RCA: 329] [Impact Index Per Article: 21.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Colorectal cancer is a leading cause of cancer-related deaths worldwide. Chronic inflammation is recognized as a predisposing factor for the development of colon cancer, but the molecular mechanisms linking inflammation and tumorigenesis have remained elusive. Recent studies revealed a crucial role for the NOD-like receptor protein Nlrp3 in regulating inflammation through the assembly of proinflammatory protein complexes termed inflammasomes. However, its role in colorectal tumor formation remains unclear. In this study, we showed that mice deficient for Nlrp3 or the inflammasome effector caspase-1 were highly susceptible to azoxymethane/dextran sodium sulfate-induced inflammation and suffered from dramatically increased tumor burdens in the colon. This was a consequence of markedly reduced IL-18 levels in mice lacking components of the Nlrp3 inflammasome, which led to impaired production and activation of the tumor suppressors IFN-γ and STAT1, respectively. Thus, IL-18 production downstream of the Nlrp3 inflammasome is critically involved in protection against colorectal tumorigenesis.
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Affiliation(s)
- Md. Hasan Zaki
- Department of Immunology, St. Jude Children’s Research Hospital, Memphis, TN, 38105, USA
| | - Peter Vogel
- Animal Resources Center and the Veterinary Pathology Core, St. Jude Children’s Research Hospital, Memphis, TN, 38105, USA
| | - Mathilde Body-Malapel
- Department of Physiopathology of inflammatory bowel diseases, INSERM U995, Lille, France
| | - Mohamed Lamkanfi
- Department of Medical Protein Research, VIB, B-9000 Ghent, Belgium
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Nishigami T, Kataoka TR, Torii I, Sato A, Tamura K, Hirano H, Hida N, Ikeuchi H, Tsujimura T. Concomitant adenocarcinoma and colonic non-Hodgkin's lymphoma in a patient with ulcerative colitis: a case report and molecular analysis. Pathol Res Pract 2010; 206:846-50. [PMID: 20846793 DOI: 10.1016/j.prp.2010.07.007] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/01/2010] [Revised: 05/01/2010] [Accepted: 07/09/2010] [Indexed: 11/30/2022]
Abstract
Ulcerative colitis (UC) complicated by colonic lymphoma is rare, although UC is often accompanied by adenocarcinoma of the colon. A concurrent existence of adenocarcinoma and lymphoma in a patient with UC is extremely rare, and has not yet been analyzed at the molecular level. We report a 64-year-old female patient with concomitant adenocarcinoma and diffuse large B-cell lymphoma (DLBCL) in the colon of UC. The genetic changes in these two neoplasms were analyzed. The colon adenocarcinomas had a mutation in MSH6 gene, DNA methylation in CDKN2A gene, and increased microsatellite instability (MSI), although these genetic changes were not recognized in either DLBCL or non-neoplastic UC mucosa. The DLBCL was diagnosed as primary colonic lymphoma, and confirmed Epstein-Barr virus (EBV) infection. The adenocarcinomas and the non-neoplastic UC mucosa were EBV-negative. Our case presented here clearly shows that the development of adenocarcinoma and lymphoma in the colon with UC was caused by individual mechanisms.
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Affiliation(s)
- Takashi Nishigami
- Department of Pathology, Hyogo College of Medicine, Nishinomiya, Hyogo, Japan
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38
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Brophy K, Ryan AW, Turner G, Trimble V, Patel KD, O'Morain C, Kennedy NP, Egan B, Close E, Lawlor G, MacMathuna P, Stevens FM, Abuzakouk M, Feighery C, Kelleher D, McManus R. Evaluation of 6 candidate genes on chromosome 11q23 for coeliac disease susceptibility: a case control study. BMC MEDICAL GENETICS 2010; 11:76. [PMID: 20478055 PMCID: PMC2880976 DOI: 10.1186/1471-2350-11-76] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 06/26/2009] [Accepted: 05/17/2010] [Indexed: 11/14/2022]
Abstract
BACKGROUND Recent whole genome analysis and follow-up studies have identified many new risk variants for coeliac disease (CD, gluten intolerance). The majority of newly associated regions encode candidate genes with a clear functional role in T-cell regulation. Furthermore, the newly discovered risk loci, together with the well established HLA locus, account for less than 50% of the heritability of CD, suggesting that numerous additional loci remain undiscovered. Linkage studies have identified some well-replicated risk regions, most notably chromosome 5q31 and 11q23. METHODS We have evaluated six candidate genes in one of these regions (11q23), namely CD3E, CD3D, CD3G, IL10RA, THY1 and IL18, as risk factors for CD using a 2-phase candidate gene approach directed at chromosome 11q. 377 CD cases and 349 ethnically matched controls were used in the initial screening, followed by an extended sample of 171 additional coeliac cases and 536 additional controls. RESULTS Promotor SNPs (-607, -137) in the IL18 gene, which has shown association with several autoimmune diseases, initially suggested association with CD (P < 0.05). Follow-up analyses of an extended sample supported the same, moderate effect (P < 0.05) for one of these. Haplotype analysis of IL18-137/-607 also supported this effect, primarily due to one relatively rare haplotype IL18-607C/-137C (P < 0.0001), which was independently associated in two case-control comparisons. This same haplotype has been noted in rheumatoid arthritis. CONCLUSION Haplotypes of the IL18 promotor region may contribute to CD risk, consistent with this cytokine's role in maintaining inflammation in active CD.
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Affiliation(s)
- Karen Brophy
- Department of Clinical Medicine, Trinity Centre for Health Sciences, Trinity College Dublin, St James's Hospital, Dublin, Ireland
- Institute of Molecular Medicine, Trinity Centre for Health Sciences, St James's Hospital, Dublin, Ireland
| | - Anthony W Ryan
- Department of Clinical Medicine, Trinity Centre for Health Sciences, Trinity College Dublin, St James's Hospital, Dublin, Ireland
- Institute of Molecular Medicine, Trinity Centre for Health Sciences, St James's Hospital, Dublin, Ireland
| | - Graham Turner
- Department of Clinical Medicine, Trinity Centre for Health Sciences, Trinity College Dublin, St James's Hospital, Dublin, Ireland
- Institute of Molecular Medicine, Trinity Centre for Health Sciences, St James's Hospital, Dublin, Ireland
| | - Valerie Trimble
- Department of Clinical Medicine, Trinity Centre for Health Sciences, Trinity College Dublin, St James's Hospital, Dublin, Ireland
- Institute of Molecular Medicine, Trinity Centre for Health Sciences, St James's Hospital, Dublin, Ireland
| | - Kunal D Patel
- Department of Clinical Medicine, Trinity Centre for Health Sciences, Trinity College Dublin, St James's Hospital, Dublin, Ireland
- Institute of Molecular Medicine, Trinity Centre for Health Sciences, St James's Hospital, Dublin, Ireland
| | - Colm O'Morain
- Department of Clinical Medicine, Trinity College, Trinity Centre for Health Sciences, The Adelaide & Meath Hospital Dublin, Incorporating The National Children's Hospital, Tallaght, Dublin, Ireland
| | - Nicholas P Kennedy
- Department of Clinical Medicine, Trinity Centre for Health Sciences, Trinity College Dublin, St James's Hospital, Dublin, Ireland
| | - Brian Egan
- Department of Clinical Medicine, Trinity College, Trinity Centre for Health Sciences, The Adelaide & Meath Hospital Dublin, Incorporating The National Children's Hospital, Tallaght, Dublin, Ireland
| | - Eimear Close
- Gastrointestinal Unit, Mater Misericordiae University Hospital, Dublin, Ireland
| | - Garrett Lawlor
- Gastrointestinal Unit, Mater Misericordiae University Hospital, Dublin, Ireland
| | - Padraic MacMathuna
- Gastrointestinal Unit, Mater Misericordiae University Hospital, Dublin, Ireland
| | - Fiona M Stevens
- Department of Medicine, National University of Ireland, Galway, Ireland
| | - Mohamed Abuzakouk
- Department of Immunology, Trinity College, Trinity Centre for Health Sciences, St James's Hospital, Dublin, Ireland
- Department of Immunology, Hull Royal Infirmary, Hull, UK
| | - Conleth Feighery
- Institute of Molecular Medicine, Trinity Centre for Health Sciences, St James's Hospital, Dublin, Ireland
- Department of Immunology, Trinity College, Trinity Centre for Health Sciences, St James's Hospital, Dublin, Ireland
| | - Dermot Kelleher
- Department of Clinical Medicine, Trinity Centre for Health Sciences, Trinity College Dublin, St James's Hospital, Dublin, Ireland
- Institute of Molecular Medicine, Trinity Centre for Health Sciences, St James's Hospital, Dublin, Ireland
| | - Ross McManus
- Department of Clinical Medicine, Trinity Centre for Health Sciences, Trinity College Dublin, St James's Hospital, Dublin, Ireland
- Institute of Molecular Medicine, Trinity Centre for Health Sciences, St James's Hospital, Dublin, Ireland
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Association of polymorphisms in the human IL-10 and IL-18 genes with rheumatoid arthritis. Mol Biol Rep 2010; 38:379-85. [PMID: 20424918 DOI: 10.1007/s11033-010-0119-x] [Citation(s) in RCA: 54] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2009] [Accepted: 03/17/2010] [Indexed: 02/05/2023]
Abstract
The decrease of anti-inflammatory cytokine and increase of pro-inflammatory cytokine was observed in rheumatoid arthritis (RA). Interleukin-10 (IL-10), a potent anti-inflammatory cytokine, has been demonstrated to suppress joint swelling and deformation in RA animal model. Interleukin-18 (IL-18), a widely distributed pro-inflammatory cytokine, induces the production of IFN-γ, activate NK cells, and promote inflammation. Recent studies demonstrated that the serum IL-10 and IL-18 levels may be influenced by genetics and related to susceptibility to several autoimmune diseases. In the present study, using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) and DNA sequencing techniques, we analyzed the genotype and allele distributions of two single nucleotide polymorphisms (SNP) loci in the promoter region of IL-10 and IL-18 genes (IL-10-592 A/C and IL-18-607 A/C loci, respectively). Our results indicated that IL-10-592 allelic and genotypic frequencies were significantly different between the RA patients and normal subjects (P<0.05). In addition, significant differences of IL-10-592 allelic and genotypic frequencies were also detected between the patients with or without anti-cyclic citrullinated peptide antibody (anti-CCP) (P<0.05). In contrast, allelic and genotypic frequencies of IL-18-607 did not show significant difference between RA patients and normal subjects (P>0.05) or between anti-CCP-positive and anti-CCP-negative RA patients (P>0.05). Furthermore, ELISA detection of IL-10 and IL-18 serum levels revealed that the genotype of IL-10-592 was associated with IL-10 serum level (P<0.05), but the genotype and allele frequency of IL-18-607 was not associated with IL-18 serum level (P>0.05). Taken together, our findings provide new insight for the polymorphism of IL-10 gene in the pathogenesis of RA.
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Palomino-Morales RJ, Vazquez-Rodriguez TR, Torres O, Morado IC, Castañeda S, Miranda-Filloy JA, Callejas-Rubio JL, Fernandez-Gutierrez B, Gonzalez-Gay MA, Martin J. Association between IL-18 gene polymorphisms and biopsy-proven giant cell arteritis. Arthritis Res Ther 2010; 12:R51. [PMID: 20331879 PMCID: PMC2888200 DOI: 10.1186/ar2962] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2009] [Revised: 03/02/2010] [Accepted: 03/23/2010] [Indexed: 11/10/2022] Open
Abstract
INTRODUCTION The objective was to investigate the potential implication of the IL18 gene promoter polymorphisms in the susceptibility to giant-cell arteritis (GCA). METHODS In total, 212 patients diagnosed with biopsy-proven GCA were included in this study. DNA from patients and matched controls was obtained from peripheral blood. Samples were genotyped for the IL18-137 G>C (rs187238), the IL18-607 C>A (rs1946518), and the IL18-1297 T>C (rs360719) gene polymorphisms with polymerase chain reaction, by using a predesigned TaqMan allele discrimination assay. RESULTS No significant association between the IL18-137 G>C polymorphism and GCA was found. However, the IL18 -607 allele A was significantly increased in GCA patients compared with controls (47.8% versus 40.9% in patients and controls respectively; P = 0.02; OR, 1.32; 95% CI, 1.04 to 1.69). It was due to an increased frequency of homozygosity for the IL18 -607 A/A genotype in patients with GCA (20.4%) compared with controls (13.4%) (IL18 -607 A/A versus IL18 -607 A/C plus IL18 -607 C/C genotypes: P = 0.04; OR, 1.59; 95% CI, 1.02 to 2.46). Also, the IL18-1297 allele C was significantly increased in GCA patients (30.7%) compared with controls (23.0%) (P = 0.003; OR, 1.48; 95% CI, 1.13 to 1.95). In this regard, an increased susceptibility to GCA was observed in individuals carrying the IL18-1297 C/C or the IL18-1297 C/T genotypes compared with those carrying the IL18-1297 T/T genotype (IL18-1297 C/C plus IL18-1297 T/C versus IL18-1297 T/T genotype in GCA patients compared with controls: P = 0.005; OR, 1.61; 95% CI, 1.15 to 2.25). We also found an additive effect of the IL18 -1297 and -607 polymorphisms with TLR4 Asp299Gly polymorphism. The OR for GCA was 1.95 for combinations of genotypes with one or two risk alleles, whereas carriers of three or more risk alleles have an OR of 3.7. CONCLUSIONS Our results show for the first time an implication of IL18 gene-promoter polymorphisms in the susceptibility to biopsy-proven GCA. In addition, an additive effect between the associated IL18 and TLR4 genetic variants was observed.
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Affiliation(s)
- Rogelio J Palomino-Morales
- Instituto de Parasitología y Biomedicina Lopez-Neyra, CSIC, Parque Tecnológico de Ciencias de la Salud, Avenida del Conocimiento s/n Armilla, Granada-18100, Spain
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Andrie E, Michos A, Kalampoki V, Pourtsidis A, Moschovi M, Polychronopoulou S, Athanasiadou-Piperopoulou F, Kalmanti M, Hatzakis A, Paraskevis D, Nieters A, Petridou ET. Genetic variants in immunoregulatory genes and risk for childhood lymphomas. Eur J Haematol 2009; 83:334-342. [PMID: 19508433 DOI: 10.1111/j.1600-0609.2009.01288.x] [Citation(s) in RCA: 30] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
Abstract
To investigate whether single nucleotide polymorphisms (SNPs) in key cytokine and innate immunity genes influence risk for childhood lymphomas, we genotyped 37 children with Hodgkin's (HL) and 48 with non-Hodgkin's lymphoma (NHL), aged (1 month-14 yr), along with their 85 age- and gender-matched controls suffering from mild medical conditions. Genotypic analysis was performed for 10 SNPs from nine genes with important role in immunoregulatory pathways (IL4, IL4R, IL6, IL10, IL12, IL18, TNFalpha, IFNgamma, CD14). Analysis of SNPs genotypes revealed that the CD14 -159 C>T polymorphism was associated with significantly increased risk for HL regarding both the CC and CT genotypes (OR(CC): 5.36; 95% CI, 1.30-22.14; P = 0.02, OR(CT): 3.76; 95% CI, 1.00-14.16; P = 0.05). An indicative association between IL18-137 G>C polymorphism with the CC genotype and NHL did not reach, however, statistical significance (OR(CC), 3.78; 95% CI, 0.87-16.38; P = 0.08). In conclusion, our findings suggest that genetic variation in the CD14-159 loci may be associated with childhood HL risk; these preliminary findings need to be further confirmed in sizeable multi-centre studies along with determination of cytokines, which could provide an insight on the biologic basis underlying these findings.
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Affiliation(s)
- Elisabeth Andrie
- Department of Hygiene, Epidemiology and Medical Statistics, Athens University Medical School, 75 Mikras Asias Str., Goudi, Athens, Greece
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Sánchez E, Palomino-Morales RJ, Ortego-Centeno N, Jiménez-Alonso J, González-Gay MA, López-Nevot MA, Sánchez-Román J, de Ramón E, González-Escribano MF, Pons-Estel BA, D'Alfonso S, Sebastiani GD, Alarcón-Riquelme ME, Martín J. Identification of a new putative functional IL18 gene variant through an association study in systemic lupus erythematosus. Hum Mol Genet 2009; 18:3739-48. [DOI: 10.1093/hmg/ddp301] [Citation(s) in RCA: 45] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022] Open
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Chen SY, Wan L, Huang YC, Sheu JJC, Lan YC, Lai CH, Lin CW, Chang JS, Tsai Y, Liu SP, Lin YJ, Tsai FJ. Interleukin-18 gene 105A/C genetic polymorphism is associated with the susceptibility of Kawasaki disease. J Clin Lab Anal 2009; 23:71-6. [PMID: 19288449 DOI: 10.1002/jcla.20292] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/28/2022] Open
Abstract
Interleukin-18 (IL-18)-656T/G, -607A/C, and -137C/G promoter polymorphisms had been reported associated with Kawasaki disease (KD). An IL-18 genetic A/C polymorphism at coding position 105 (rs549908) has been linked with asthma, rheumatoid, and systemic lupus erythematosus. We tested a hypothesis that the IL-18 105A/C genetic polymorphism confers KD susceptibility. Study participants were Taiwanese KD patients and a healthy control group. Our data indicated that the frequency of C allele was significantly higher in the patient group (13.9%) than in the control group (2.7%; P<0.0001, odds ratio [OR]=5.93; 95% confidence interval [CI]=2.57-13.73). Therefore, persons with the C allele may have higher risk of developing KD. In addition, compared with the haplotype frequencies between case and control groups, the KD patients with TACC haplotype appeared to be a significant "at-risk" haplotype compared with other haplotypes (OR: 4.62, 95% CI: 1.71-12.43; P=0.001). KD patient with the TAGA haplotype appeared to be a significant "protective" haplotype compared with other haplotypes (OR: 0.51, 95% CI:0.29-0.89; P=0.017). Our results suggest that 105A/C polymorphism and the haplotypes in IL-18 gene are associated with the risk of KD in Taiwanese population.
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Affiliation(s)
- Shih-Yin Chen
- Department of Medical Research, Department of Medical Genetics, China Medical University Hospital, No. 2 Yuh Der Road, Taichung, Taiwan
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Sharma A, Chakraborti A, Das A, Dhiman RK, Chawla Y. Elevation of interleukin-18 in chronic hepatitis C: implications for hepatitis C virus pathogenesis. Immunology 2008; 128:e514-22. [PMID: 19740312 DOI: 10.1111/j.1365-2567.2008.03021.x] [Citation(s) in RCA: 44] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/01/2023] Open
Abstract
The outcome of hepatitis C virus (HCV) infection is determined by the interplay between the virus and the host immune response. Interleukin (IL)-18, an interferon-gamma-inducing factor, plays a critical role in the T helper type 1 (Th1) response required for host defence against viruses, and antibodies to IL-18 have been found to prevent liver damage in a murine model. The present study was conducted to investigate the possible role of IL-18 in the pathogenesis and persistence of HCV. IL-18 levels were measured in sera of 50 patients at various stages of HCV infection (resolved, chronic and cirrhosis) and compared with those of normal controls. IL-18 gene expression was studied in peripheral blood mononuclear cells (PBMC) from each group, and in liver biopsy tissue from patients with chronic hepatitis C. The mean levels of IL-18 in sera were markedly elevated in patients with chronic hepatitis and cirrhosis, and were reduced in patients with resolved HCV infection. The serum IL-18 concentrations were related to the Child-Pugh severity of liver disease in cirrhotic patients. There also existed a strong positive correlation of IL-18 levels with histological activity score and necrosis. IL-18 mRNA expression was significantly up-regulated in the PBMC of cirrhotic patients when compared with other groups, while in the liver, higher levels of IL-18 transcripts were expressed in patients with chronic hepatitis C. The results of our study indicate that IL-18 levels reflect the severity and activity of HCV infection, and may contribute to the pathogenesis and progression of liver disease associated with HCV.
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Affiliation(s)
- Arpita Sharma
- Department of Hepatology, Postgraduate Institute of Medical Education and Research, Chandigarh, India.
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45
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Economou M, Pappas G. New global map of Crohn's disease: Genetic, environmental, and socioeconomic correlations. Inflamm Bowel Dis 2008; 14:709-20. [PMID: 18095316 DOI: 10.1002/ibd.20352] [Citation(s) in RCA: 126] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/22/2023]
Abstract
Seventy-five years after the initial characterization of Crohn's disease (CD), much remains obscure about its etiology. The authors sought to evaluate the incidence trends of the last 25 years worldwide, and the existence of potential correlations with genetic, environmental, and socioeconomic factors that could be etiologically implicated in the pathogenesis of CD. Relevant medical literature for individual countries on the incidence of CD, on the incidence of associated genetic mutations, and on the incidence of suggested etiologic infectious agents such as Mycobacterium avium paratuberculosis were retrieved from published medical literature, reports from relevant international congresses, and through official reports from national health authorities. Increasing trends have been observed almost worldwide, with a broad north-south gradient still prevailing in Europe. Distinct regions of New Zealand, Canada, Scotland, France, the Netherlands, and Scandinavia represent the highest incidence areas. Industrialized status and affluence are the common denominators between endemic areas, but are too broad as terms to strongly indicate any particular etiological role. The increasing trends observed in Asia still account for a low prevalence of the disease and may represent increased detection and diagnostic ability of local health systems. Genetic associations are variably reproduced worldwide, in a manner inconsistent with a strong etiologic relationship. Data on paratuberculosis incidence are scarce, and the existing ones are ambivalent regarding an even indirect correlation between CD and an infectious trigger.
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Fan H, Duan XY, Zhuang X, Lv JF, Shou ZX. Effect of Wumeiwan on NF-κB p65 in colon tissue of rats with ulcerative colitis. Shijie Huaren Xiaohua Zazhi 2008; 16:896-899. [DOI: 10.11569/wcjd.v16.i8.896] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To compare the effects of Wumeiwan (WMW) and solfasalazine (SASP) on NF-κB p65 in colon tissue of rats with ulcerative colitis (UC) and to analyze their mechanism of action.
METHODS: A model of UC was induced by administration of dinitro-chlorobenzene (DNCB) and acetic acid. Fifty-six SD rats (28 males and 28 females) were randomly divided into normal control group (n = 14), model group (n = 14), SASP group (n = 14), and WMW group (n = 14). Changes of NF-κB p65 in rat colon tissue were observed after treatment with DNCB and acetic acid.
RESULTS: NF-κB p65 was not expressed or weakly expressed in normal colon tissue. The positive expression rate of NF-κB p65 was significantly higher in WMW and SASP groups than in normal control group(26.32% ± 9.65%, 31.23% ± 5.18% vs 45.67% ± 4.2%, P < 0.01). The positive expression rate of NF-κB p65 was significantly lower in WMW group than in model group. There were significant differences between WMW and SASP groups (P < 0.05).
CONCLUSION: NF-κB is closely related with the development of UC. WMW can treat UC by suppressing the activity of NF-κB p65.
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Yuan BS, Zhu RM, Braddock M, Zhang XH, Shi W, Zheng MH. Interleukin-18: a pro-inflammatory cytokine that plays an important role in acute pancreatitis. Expert Opin Ther Targets 2007; 11:1261-71. [PMID: 17907957 DOI: 10.1517/14728222.11.10.1261] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
A large body of clinical and experimental evidence suggests that cytokines play a key role in the pathogenesis of local and systemic complications of acute pancreatitis. IL-18 is a pro-inflammatory cytokine that plays a key role in many human diseases, including acute pancreatitis. This review focuses on the present understanding in IL-18 and its potential role in acute pancreatitis. IL-18 levels reflect the severity of acute pancreatitis and display a significant negative correlation with the concentrations of antioxidative damage factors, serum selenium and glutathione peroxidases (GPx). The relationship between IL-18 and other pro-inflammatory cytokines shows that IL-18 is one of the key mediators of inflammation in the pathogenesis of acute pancreatitis. Elevation of serum IL-18 levels may mediate acute pancreatitis associated liver injury. The use of IL-18 antagonists as direct routes to block IL-18 activity and P2X7 receptor antagonists and interleukin-1beta-converting enzyme (ICE) inhibitors as indirect routes to block IL-18 activity suggest that specific therapeutic inhibition of IL-18 is a promising therapeutic approach for acute pancreatitis.
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Affiliation(s)
- Bo-Si Yuan
- Department of Gastroenterology, Clinical School of Nanjing, Southern Medical University, Jinling Hospital, Nanjing, Jiangsu Province, China.
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Bossù P, Ciaramella A, Moro ML, Bellincampi L, Bernardini S, Federici G, Trequattrini A, Macciardi F, Spoletini I, Di Iulio F, Caltagirone C, Spalletta G. Interleukin 18 gene polymorphisms predict risk and outcome of Alzheimer's disease. J Neurol Neurosurg Psychiatry 2007; 78:807-11. [PMID: 17299019 PMCID: PMC2117732 DOI: 10.1136/jnnp.2006.103242] [Citation(s) in RCA: 40] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/04/2022]
Abstract
BACKGROUND AND AIM Inflammation has been extensively implicated in the pathogenesis of Alzheimer's disease (AD). Although there is evidence of a key role for cytokines in neuroinflammation processes, so far the proinflammatory cytokine interleukin (IL)-18 has not been associated with AD. The aim of this study was to investigate the impact of two polymorphisms of the human IL-18 gene promoter at positions -607 (C/A) and -137 (G/C) on both susceptibility to and progression of AD. RESULTS The results revealed that the genotype distribution of the -607 (C/A) polymorphism was different between patients with AD and control subjects (chi2 = 7.99, df = 2, p = 0.0184). In particular, carriers of the CC genotype were at increased risk of developing AD (OR 2.33; 95% CI 1.29 to 4.22; p = 0.0052). The observed genotypes were in Hardy-Weinberg equilibrium, as for the -607 polymorphism, whereas the -137 polymorphism appeared in Hardy-Weinberg disequilibrium only in the patient group (p = 0.0061). Finally, in a 2 year follow-up study, the -137 CC genotype was strongly and specifically associated with a faster cognitive decline (F = 4.024; df = 4,192; p = 0.0037 for time by IL-18 -137 G/C group interaction) with no interaction effect with the apolipoprotein E epsilon4/non-epsilon4 allele presence. CONCLUSION As IL-18 cytokine promoter gene polymorphisms have been previously described to have functional consequences on IL-18 expression, it is possible that individuals with a prevalent IL-18 gene variant have a dysregulated immune response, suggesting that IL-18 mediated immune mechanisms may play a crucial role in AD.
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Thompson SR, Humphries SE. Interleukin-18 genetics and inflammatory disease susceptibility. Genes Immun 2007; 8:91-9. [PMID: 17215860 DOI: 10.1038/sj.gene.6364366] [Citation(s) in RCA: 69] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
Abstract
IL18 was mapped to 11q22.2-22.3 in 1998. Owing to interleukin (IL)-18's important and novel role in immunomodulation, the gene itself has been subject to scrutiny, with the aim of discovering variants that may impact on disease susceptibility and/or progression. Despite being sequenced numerous times in different populations, no non-synonymous variants have been found. However, a number of polymorphisms within the proximal promoter have been verified that may interfere with transcription-factor-binding sites. Much of the subsequent association analyses have centred on these variants, but have yielded no consistent results, despite numerous different study populations being genotyped. IL18 has recently been resequenced in its entirety, enabling the tagging-single-nucleotide polymorphism (tSNP) methodology to be adopted. This approach has yielded interesting results, with genetic variation being shown to affect protein levels, and risk. This review aims to compile and reflect on the association data of interest published to date, with a focus on the diseases related to aberrant inflammatory control.
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Affiliation(s)
- S R Thompson
- The Department of Cardiovascular Genetics, The Rayne Institute, London, UK
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Bombardieri M, McInnes IB, Pitzalis C. Interleukin-18 as a potential therapeutic target in chronic autoimmune/inflammatory conditions. Expert Opin Biol Ther 2006; 7:31-40. [PMID: 17150017 DOI: 10.1517/14712598.7.1.31] [Citation(s) in RCA: 29] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/12/2023]
Abstract
Interleukin-18 (IL-18), a recently identified immunoregulatory and inflammatory cytokine, has attracted a profound interest as a potential therapeutic target in autoimmune/inflammatory disorders. In this review the authors focus on: IL-18 biology as an important link between innate and adaptive immunity; evidence of its pro-inflammatory role in several human autoimmune and chronic inflammatory disorders; and data indicating that IL-18 blockade in animal models results in prevention/amelioration of the disease process and preservation of the target tissue integrity and function. Finally, the authors analyse strategies presently under development to block IL-18 function and potential pitfalls resulting from IL-18 blockade that should be considered in ongoing/future clinical trials.
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Affiliation(s)
- Michele Bombardieri
- Kings College London, Rheumatology Department, Guy's Hospital, St Thomas Street, London, SE1 9RT, UK.
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