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Elabd NS, Helal ML, Elkhayat M, Abd-ElKhalek HK, Ahmed DM, El-Shemy AM, Elsaadawy YS, Abdelmoneum RA, AboShabaan HS, Seddik RM. Insights into the Correlation between Toll-Like Receptor 2 Polymorphism and HBV-Related Disease Progression and Occurrence of Hepatocellular Carcinoma: A Case-Control Study in Egyptian Patients. THE CANADIAN JOURNAL OF INFECTIOUS DISEASES & MEDICAL MICROBIOLOGY = JOURNAL CANADIEN DES MALADIES INFECTIEUSES ET DE LA MICROBIOLOGIE MEDICALE 2024; 2024:5797895. [PMID: 39071840 PMCID: PMC11281855 DOI: 10.1155/2024/5797895] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 09/02/2023] [Revised: 02/18/2024] [Accepted: 06/27/2024] [Indexed: 07/30/2024]
Abstract
Methods In total, 170 chronic HBV patients and 50 healthy controls of comparable age and gender were included in this case-control study. Clinical, laboratory, and imaging evaluations were conducted. ELISA was used to determine serum IL-6 levels, and TLR2 (rs3804099) genotyping allelic discrimination assay was performed using real-time PCR. Results IL-6 values were significantly higher in the HCC group, followed by the cirrhotic group, than those in chronic hepatitis and control groups (p < 0.001), with a significant correlation with disease activity and progression parameters. TRL2 homozygous TT was the most frequent in the control group, but the CC genotype was significantly more prevalent in the HCC group than that in the other groups. Furthermore, the CC genetic variant was associated with higher levels of IL-6 and viral load in all HBV patients, whereas the TT genotype was associated with larger tumor size. Multivariate regression analysis demonstrated that in chronic HBV patients, viral load and TRL2 polymorphism are independent risk factors associated with the progression from chronic hepatitis to liver cirrhosis and to HCC. Similarly, the HBV viral load (p=0.03, OR = 2.45, and 95% CI: 1.69-3.65), IL-6 levels (p=0.04, OR = 3.45, and 95% CI: 2.01-6.9), and TRL2 variants (p=0.01, OR = 4.25, and 95% CI: 2.14-13.5) are independent risk factors associated with disease progression from cirrhosis to HCC. Conclusion In chronic HBV patients, TRL2 polymorphism and higher IL-6 levels were positively correlated with a higher likelihood of HCC and chronic hepatitis B disease activity and progression.
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Affiliation(s)
- Naglaa S. Elabd
- Department of Tropical MedicineFaculty of MedicineMenoufia University, Shebin El-Kom, Menoufia, Egypt
| | - Marwa L. Helal
- Department of Clinical Biochemistry and Molecular DiagnosticsNational Liver InstituteMenoufia University, Shebin El-Kom, Menoufia, Egypt
| | - Mohsen Elkhayat
- Department of Tropical MedicineFaculty of MedicineMenoufia University, Shebin El-Kom, Menoufia, Egypt
| | - Heba Kamal Abd-ElKhalek
- Department of Internal MedicineFaculty of MedicineMenoufia University, Shebin El-Kom, Menoufia, Egypt
| | - Doaa M. Ahmed
- Department of RadiologyFaculty of MedicineMenoufia University, Shebin El-Kom, Menoufia, Egypt
| | - Asmaa M. El-Shemy
- Department of Clinical PathologyFaculty of MedicineMenoufia University, Shebin El-Kom, Menoufia, Egypt
| | - Yara S. Elsaadawy
- Department of Medical Microbiology and ImmunologyFaculty of MedicineAin Shams University, Cairo, Egypt
| | - Rasha A. Abdelmoneum
- Department of Clinical Oncology and Nuclear MedicineFaculty of MedicineMenoufia University, Shebin El-Kom, Menoufia, Egypt
| | - Hind S. AboShabaan
- BiochemistryNational Liver Institute HospitalMenoufia University, Shebin El-Kom, Menoufia, Egypt
| | - Randa M. Seddik
- Department of Tropical MedicineFaculty of MedicineMenoufia University, Shebin El-Kom, Menoufia, Egypt
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Pessino G, Scotti C, Maggi M, Immuno-Hub Consortium. Hepatocellular Carcinoma: Old and Emerging Therapeutic Targets. Cancers (Basel) 2024; 16:901. [PMID: 38473265 DOI: 10.3390/cancers16050901] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2024] [Revised: 02/16/2024] [Accepted: 02/20/2024] [Indexed: 03/14/2024] Open
Abstract
Liver cancer, predominantly hepatocellular carcinoma (HCC), globally ranks sixth in incidence and third in cancer-related deaths. HCC risk factors include non-viral hepatitis, alcohol abuse, environmental exposures, and genetic factors. No specific genetic alterations are unequivocally linked to HCC tumorigenesis. Current standard therapies include surgical options, systemic chemotherapy, and kinase inhibitors, like sorafenib and regorafenib. Immunotherapy, targeting immune checkpoints, represents a promising avenue. FDA-approved checkpoint inhibitors, such as atezolizumab and pembrolizumab, show efficacy, and combination therapies enhance clinical responses. Despite this, the treatment of hepatocellular carcinoma (HCC) remains a challenge, as the complex tumor ecosystem and the immunosuppressive microenvironment associated with it hamper the efficacy of the available therapeutic approaches. This review explores current and advanced approaches to treat HCC, considering both known and new potential targets, especially derived from proteomic analysis, which is today considered as the most promising approach. Exploring novel strategies, this review discusses antibody drug conjugates (ADCs), chimeric antigen receptor T-cell therapy (CAR-T), and engineered antibodies. It then reports a systematic analysis of the main ligand/receptor pairs and molecular pathways reported to be overexpressed in tumor cells, highlighting their potential and limitations. Finally, it discusses TGFβ, one of the most promising targets of the HCC microenvironment.
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Affiliation(s)
- Greta Pessino
- Unit of Immunology and General Pathology, Department of Molecular Medicine, University of Pavia, 27100 Pavia, Italy
| | - Claudia Scotti
- Unit of Immunology and General Pathology, Department of Molecular Medicine, University of Pavia, 27100 Pavia, Italy
| | - Maristella Maggi
- Unit of Immunology and General Pathology, Department of Molecular Medicine, University of Pavia, 27100 Pavia, Italy
| | - Immuno-Hub Consortium
- Unit of Immunology and General Pathology, Department of Molecular Medicine, University of Pavia, 27100 Pavia, Italy
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Chen R, Wang X, Li Z, Dai Y, Du W, Wu L. Human Toll-like receptor 2 genetic polymorphisms with tuberculosis susceptibility: A systematic review and meta-analysis. Cytokine 2023; 172:156405. [PMID: 37883839 DOI: 10.1016/j.cyto.2023.156405] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2023] [Revised: 10/16/2023] [Accepted: 10/19/2023] [Indexed: 10/28/2023]
Abstract
BACKGROUND Toll-like receptor 2 (TLR2) is a crucial factor in the development of tuberculosis. However, no studies have explored the association between TLR2 polymorphisms and tuberculosis susceptibility. OBJECTIVES This study aimed to explore the correlation between tuberculosis susceptibility and TLR2 polymorphisms (rs3804099, rs3804100, rs1898830, rs5743708, rs121917864, and (-196-174) del). METHODS All relevant online databases including PubMed, CNKI, WANFANG DATA, and METSTR-FMRS were systematically searched. STATA17.0 (Stata Corp LP, College Station, Texas, USA) was used. RESULTS A total of 37 studies, covering six polymorphisms and comprising 9,474 cases and 10,295 controls, were included in this analysis. rs3804099(C vs T: OR = 1.00, 95 % CI: 0.93-1.08, CC + TC vs TT: OR = 1.04, 95 % CI: 0.98-1.10), rs3804100 (C vs T: OR = 1.19, 95 % CI: 0.93-1.07, CC + TC vs TT: OR = 0.97, 95 % CI: 0.89-1.06), rs1898830(G vs A: OR = 0.90, 95 % CI: 0.81-1.00, GG + AG vs AA: OR = 0.87, 95 % CI: 0.67-1.12), (-196 ∼174) del polymorphism (Del vs Ins: OR = 0.93,95 % CI: 0.76-1.14, DD + DI vs II: OR = 0.92,95 % CI: 0.72-1.17). CONCLUSIONS This study indicated that only the TLR2 rs5743708 polymorphism exhibited a significant association with a higher tuberculosis risk, while TLR2 rs3804099, rs3804100, rs1898830, rs121917864, and (-196-174) del polymorphisms were not associated with tuberculosis susceptibility.
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Affiliation(s)
- Ruifeng Chen
- Department of Medical Microbiology and Immunology, School of Basic Medical Sciences, Dali University, Dali, Yunnan 671000, China
| | - Xuan Wang
- Nanchang University Queen Mary School, Nanchang, Jiangxi 330031, China
| | - Zilin Li
- School of Basic Medical Sciences, Dali University, Dali, Yunnan 671000, China
| | - Yumei Dai
- Department of Medical Microbiology and Immunology, School of Basic Medical Sciences, Dali University, Dali, Yunnan 671000, China
| | - Wenya Du
- Department of Medical Microbiology and Immunology, School of Basic Medical Sciences, Dali University, Dali, Yunnan 671000, China
| | - Lixian Wu
- Department of Medical Microbiology and Immunology, School of Basic Medical Sciences, Dali University, Dali, Yunnan 671000, China.
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Aflouk Y, Inoubli O, Kenz A, Yacoub S, Zaafrane F, Gaha L, Bel Hadj Jrad B. Association between polymorphisms of TLR2-1-6 and bipolar disorder in a tunisian population. Mol Biol Rep 2023; 50:8877-8888. [PMID: 37688680 DOI: 10.1007/s11033-023-08758-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2023] [Accepted: 08/16/2023] [Indexed: 09/11/2023]
Abstract
BACKGROUND Bipolar disorder (BD) is a complex neuropsychiatric disease that has been strongly linked to immune dysregulation. In particular, an abnormal inflammatory response mediated by toll-like receptor 2 - 1/6 (TLR2-1/6) was described in BD. Nevertheless, genetic factors' contribution is still unknown. Thus, we suggested that functional polymorphisms of TLR2, 1 and 6 could be involved in BD predisposition. METHODS AND RESULTS TLR2, 1 and 6 polymorphisms were genotyped by PCR-RFLP in 292 controls and 131 patients from a Tunisian population. Polymorphisms and haplotype associations were explored in BD and binary logistic regression analysis was performed for more powerful associations. In dominant model, we found a significantly higher genotype and minor allele frequencies in healthy females compared to patients for TLR2-196-174Ins/Del (p = 0.04; OR = 0.3, p = 0.04; OR = 0.3, respectively) and for TLR6-S249P only with minor allele (p = 0.03; OR = 0.2). In contrast, TLR2-R677W CT + TT and T allele frequencies were significantly higher in BD (padjusted<10- 4; ORadjusted =46.6, p < 10- 4; OR = 6.3, respectively), specifically in females (CT + TT: 100%). Similarly, TLR1-R80T showed significantly increased GC + CC and C allele frequencies in patients compared to controls (padjusted=0.04; ORadjusted=4, p = 0.009; OR = 4.3, respectively). Moreover, haplotype investigation demonstrated that InsGTCGT (p < 10- 4, OR = 275) and delGCCGT (p = 0.03, OR = 18.5) were significantly overrepresented in BD patients compared to controls. CONCLUSIONS We suggest that TLR2-196-174Ins/Del and TLR6-S249P could be protective factors of females against BD. However, TLR2-R677W and TLR1-R80T could be strongly associated with higher risk of BD. Interestingly, TLR2-R677W could be a genetic marker for BD in females. However, further studies with larger groups are needed to confirm these findings.
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Affiliation(s)
- Youssef Aflouk
- Laboratory of Genetics, Biodiversity, and Valorization of Bioresources GBVB (LR11ES41), Higher Institute of Biotechnology of Monastir (ISBM), University of Monastir, Monastir, 5000, Tunisia.
| | - Oumaima Inoubli
- Laboratory of Genetics, Biodiversity, and Valorization of Bioresources GBVB (LR11ES41), Higher Institute of Biotechnology of Monastir (ISBM), University of Monastir, Monastir, 5000, Tunisia
| | - Amira Kenz
- Laboratory of Genetics, Biodiversity, and Valorization of Bioresources GBVB (LR11ES41), Higher Institute of Biotechnology of Monastir (ISBM), University of Monastir, Monastir, 5000, Tunisia
| | - Saloua Yacoub
- Regional Center of Blood Transfusion, University Hospital Farhat Hached, Sousse, Tunisia
| | - Ferid Zaafrane
- Department of Psychiatry and Vulnerability to Psychoses Laboratory-CHU Fattouma Bourguiba Monastir, University of Monastir, Monastir, Tunisia
| | - Lotfi Gaha
- Department of Psychiatry and Vulnerability to Psychoses Laboratory-CHU Fattouma Bourguiba Monastir, University of Monastir, Monastir, Tunisia
| | - Besma Bel Hadj Jrad
- Laboratory of Genetics, Biodiversity, and Valorization of Bioresources GBVB (LR11ES41), Higher Institute of Biotechnology of Monastir (ISBM), University of Monastir, Monastir, 5000, Tunisia
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Man SM, Jenkins BJ. Context-dependent functions of pattern recognition receptors in cancer. Nat Rev Cancer 2022; 22:397-413. [PMID: 35355007 DOI: 10.1038/s41568-022-00462-5] [Citation(s) in RCA: 78] [Impact Index Per Article: 26.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 03/01/2022] [Indexed: 02/07/2023]
Abstract
The immune system plays a critical role in shaping all facets of cancer, from the early initiation stage through to metastatic disease and resistance to therapy. Our understanding of the importance of the adaptive arm of the immune system in antitumour immunity has led to the implementation of immunotherapy with immune checkpoint inhibitors in numerous cancers, albeit with differing efficacy. By contrast, the clinical utility of innate immunity in cancer has not been exploited, despite dysregulated innate immunity being a feature of at least one-third of all cancers associated with tumour-promoting chronic inflammation. The past two decades have seen innate immune pattern recognition receptors (PRRs) emerge as critical regulators of the immune response to microbial infection and host tissue damage. More recently, it has become apparent that in many cancer types, PRRs play a central role in modulating a vast array of tumour-inhibiting and tumour-promoting cellular responses both in immune cells within the tumour microenvironment and directly in cancer cells. Herein, we provide a comprehensive overview of the fast-evolving field of PRRs in cancer, and discuss the potential to target PRRs for drug development and biomarker discovery in a wide range of oncology settings.
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Affiliation(s)
- Si Ming Man
- Division of Immunity, Inflammation and Infection, The John Curtin School of Medical Research, The Australian National University, Canberra, ACT, Australia
| | - Brendan J Jenkins
- Centre for Innate Immunity and Infectious Diseases, Hudson Institute of Medical Research, Clayton, VIC, Australia.
- Department of Molecular and Translational Science, School of Clinical Sciences, Monash University, Clayton, VIC, Australia.
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Öksüz Z, Üçbilek E, Serin MS, Yaraş S, Temel GÖ, Sezgin O. hsa-miR-17-5p: A Possible Predictor of Ombitasvir/Paritaprevir/Ritonavir + Dasabuvir ± Ribavirin Therapy Efficacy in Hepatitis C Infection. Curr Microbiol 2022; 79:186. [PMID: 35524830 DOI: 10.1007/s00284-022-02882-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2021] [Accepted: 04/18/2022] [Indexed: 11/25/2022]
Abstract
Although persistent sustained viral response rates are increased in hepatitis C infection following administration of direct-acting antiviral (DAA) agents, the pre-use predictive parameters of these antivirals and the clinical progression in patients post-treatment remain unknown. To obtain data pertaining to the predictive parameters prior to the use of ombitavir/paritaprevir/ritonavir + dasabuvir and the clinical progression in patients following antiviral treatment. The expression profiles of miR-223-3p, miR-17-5p, miR-24-3p, and TLR2 - 196 to - 174 del/ins polymorphisms from the blood/serum of 34 hepatitis C virus (HCV)-infected patients pre- and post-ombitavir/paritaprevir/ritonavir + dasabuvir treatment were determined by RT-qPCR. The expression levels of miR-17-5p (P < 0.001) and miR-24-3p (P = 0.011) were significantly downregulated post-treatment as compared with those pre-treatment; however, there was no significant difference between these two groups in terms of miR-223-3p expression. In addition, there was no significant difference in TLR2 genotype or allele distribution between pre-and post-treatment (P > 0.05); nevertheless, the TLR2 del allele was decreased post-treatment (16.2%) as compared with that pre-treatment (19.1%), although the difference was not statistically significant. Moreover, a significant difference was found between the mRNA levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), and HCV RNA pre-and post-treatment (P < 0.05). Further, miR-17-5p expression correlated with both ALT and AST mRNA levels post-treatment (P.
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Affiliation(s)
- Zehra Öksüz
- Department of Pharmaceutical Microbiology, Faculty of Pharmacy, Mersin University, Mersin, Turkey.
| | - Enver Üçbilek
- Department of Gastroenterology, Faculty of Medicine, Mersin University, Mersin, Turkey
| | - Mehmet Sami Serin
- Department of Pharmaceutical Microbiology, Faculty of Pharmacy, Mersin University, Mersin, Turkey
| | - Serkan Yaraş
- Department of Gastroenterology, Faculty of Medicine, Mersin University, Mersin, Turkey
| | - Gülhan Örekici Temel
- Department of Biostatistics, Faculty of Medicine, Mersin University, Mersin, Turkey
| | - Orhan Sezgin
- Department of Gastroenterology, Faculty of Medicine, Mersin University, Mersin, Turkey
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Xu Y, Xue W, Gao H, Cui J, Zhao L, You C. Association of toll-like receptors single nucleotide polymorphisms with HBV and HCV infection: research status. PeerJ 2022; 10:e13335. [PMID: 35462764 PMCID: PMC9029363 DOI: 10.7717/peerj.13335] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2021] [Accepted: 04/04/2022] [Indexed: 01/13/2023] Open
Abstract
Background Hepatitis B virus (HBV) and hepatitis C virus (HCV) infections have become increasingly severe worldwide and are a threat to public health. There have been a number of studies conducted recently on the relationship of single nucleotide polymorphisms (SNPs) to innate immune receptor genes such as toll-like receptors (TLRs). Some literature suggests that SNPs of TLRs are associated with HBV and HCV infection. We summarized the role of TLRs gene polymorphisms associated with HBV and HCV infections and explored their possible mechanisms of action. Methodology PubMed and Web of Science were used to perform the literature review. Related articles and references were identified and used to analyze the role of TLRs gene polymorphism in HBV and HCV infection. Results TLRs gene polymorphisms may have beneficial or detrimental effects in HBV and HCV infection, and some SNPs can affect disease progression or prognosis. They affect the disease state by altering gene expression or protein synthesis; however, the mechanism of action is not clearly understood. Conclusions Single nucleotide polymorphisms of TLRs play a role in HBV and HCV infection, but the mechanism of action still needs to be explored in future studies.
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Affiliation(s)
- Yaxin Xu
- Laboratory Medicine Center, Lanzhou University Second Hospital, Lanzhou City, Gansu Province, China
| | - Wentao Xue
- Laboratory Medicine Center, Lanzhou University Second Hospital, Lanzhou City, Gansu Province, China
| | - Hongwei Gao
- Laboratory Medicine Center, Lanzhou University Second Hospital, Lanzhou City, Gansu Province, China
| | - Jiabo Cui
- Laboratory Medicine Center, Lanzhou University Second Hospital, Lanzhou City, Gansu Province, China
| | - Lingzhi Zhao
- Laboratory Medicine Center, Lanzhou University Second Hospital, Lanzhou City, Gansu Province, China
| | - Chongge You
- Laboratory Medicine Center, Lanzhou University Second Hospital, Lanzhou City, Gansu Province, China
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Öksüz Z, Üçbilek E, Serin MS, Yaraş S, Temel GÖ, Sezgin O. Possible relationship between IL28B rs12979860 and TLR2 -196 to -174 del/ins polymorphisms and the liver fibrosis stage in hepatitis C patients. Arch Virol 2022; 167:153-161. [PMID: 34817649 DOI: 10.1007/s00705-021-05302-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2021] [Accepted: 10/01/2021] [Indexed: 10/19/2022]
Abstract
It has been shown that host factors play an important role in the progression of hepatitis C virus (HCV) infection. Toll-like receptor 2 (TLR2) del and interleukin 28B (IL28B) T alleles can mediate liver inflammation and pathogenesis of hepatocellular carcinoma. In the present study, the possible relationship between the IL28B rs12979860 C/T and TLR2 -196 to -174 del/ins gene variants and different fibrosis stages and host factors in hepatitis C patients was investigated. IL28B and TLR2 polymorphisms in the blood of 50 hepatitis C patients at different stages of fibrosis (24 mild/moderate, 26 advanced) and 24 healthy controls were examined by RT-qPCR. The highest frequency of the TLR2 del (26.9%) and IL28B T (46.2%) alleles was found in hepatitis C patients with the most advanced fibrosis, and the lowest frequency was found in healthy controls. There was a statistically significant difference between hepatitis C patients with advanced fibrosis and healthy controls in terms of the TLR2 del (p = 0.0062) and IL28B T (p = 0.0017) allele frequencies. However, no statistically significant difference was found between the mild/moderate fibrosis and severe fibrosis patient groups in terms of genotype or IL28B and TLR2 polymorphisms (p > 0.05). In addition, there was a significant difference between patients with mild/moderate or advanced fibrosis who carried the TLR2 del allele together with the IL28B CT genotype and healthy controls. The present study emphasizes that the TLR2 and IL28B gene variants cannot be single biomarkers for the determination of fibrosis stage in hepatitis C infection but together can play an important role in predicting severe disease.
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Affiliation(s)
- Zehra Öksüz
- Department of Pharmaceutical Microbiology, Mersin University Faculty of Pharmacy, Mersin, Turkey.
| | - Enver Üçbilek
- Department of Gastroenterology, Mersin University Faculty of Medicine, Mersin, Turkey
| | - Mehmet Sami Serin
- Department of Pharmaceutical Microbiology, Mersin University Faculty of Pharmacy, Mersin, Turkey
| | - Serkan Yaraş
- Department of Gastroenterology, Mersin University Faculty of Medicine, Mersin, Turkey
| | - Gülhan Örekici Temel
- Department of Biostatistics, Mersin University Faculty of Medicine, Mersin, Turkey
| | - Orhan Sezgin
- Department of Gastroenterology, Mersin University Faculty of Medicine, Mersin, Turkey
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Aflouk Y, Inoubli O, Saoud H, Zaafrane F, Gaha L, Bel Hadj Jrad B. Association between TLR2 polymorphisms (- 196-174 Ins/Del, R677W, R753Q, and P631H) and schizophrenia in a Tunisian population. Immunol Res 2021; 69:541-552. [PMID: 34546527 DOI: 10.1007/s12026-021-09238-9] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2021] [Accepted: 09/13/2021] [Indexed: 11/26/2022]
Abstract
Since immune dysregulation has been well studied in schizophrenia pathophysiology, recent studies showed a potent role of TLR2 in neuroinflammation process underlying schizophrenia pathogenesis. However, the genetic predisposition is still unclear. Thus, we hypothesized that TLR2 polymorphisms - 196-174 Ins/Del (rs111200466), R753Q (rs5743708), R677W (rs121917864), and P631H (rs5743704) could be involved in schizophrenia predisposition. A case-control study was performed on a Tunisian population composed of 250 healthy controls and 250 patients genotyped by PCR-RFLP. Genotype and allele distribution were evaluated with sex, schizophrenia subtypes, and other clinical features. We also assessed a haplotype analysis for TLR2 polymorphisms with schizophrenia. Our results showed higher ins/del genotype frequency in healthy women compared to patients (p = 0.006; OR = 0.2). In the other hand, logistic regression showed higher ins/del genotype frequency in controls compared to paranoid patients (p = 0.05; OR = 0.48, adjusted). Frequencies of CT and T allele of R677W were significantly higher in patients compared to controls (p < 10-4, OR = 10.39; p < 10-4, OR = 4, adjusted, respectively). R753Q polymorphism was exclusively detected in patients (GA + AA = 2.5%) particularly in men with disorganized subtype. P631H did not show any association with schizophrenia. Finally, haplotype analysis showed that InsGTC and delGTC were associated with higher risk of schizophrenia (p = 0.0001, OR = 8.58; p = 0.04, OR = 5.01, respectively). In the Tunisian population, our results suggested that TLR2 R677W could be associated with susceptibility for schizophrenia, while - 196-174 Ins/Del suggested a trend of protection in women. Otherwise, R753Q could have an effect on schizophrenia especially for disorganized subgroup.
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Affiliation(s)
- Youssef Aflouk
- Laboratory of Genetics, Biodiversity and Valorization of Bioresources GBVB (LR11ES41), Higher Institute of Biotechnology of Monastir (ISBM), University of Monastir, Monastir, Tunisia.
| | - Oumaima Inoubli
- Laboratory of Genetics, Biodiversity and Valorization of Bioresources GBVB (LR11ES41), Higher Institute of Biotechnology of Monastir (ISBM), University of Monastir, Monastir, Tunisia
| | - Hana Saoud
- Laboratory of Genetics, Biodiversity and Valorization of Bioresources GBVB (LR11ES41), Higher Institute of Biotechnology of Monastir (ISBM), University of Monastir, Monastir, Tunisia
| | - Ferid Zaafrane
- Department of Psychiatry and Vulnerability to Psychoses Laboratory-CHU Monastir, University of Monastir, Monastir, Tunisia
| | - Lotfi Gaha
- Department of Psychiatry and Vulnerability to Psychoses Laboratory-CHU Monastir, University of Monastir, Monastir, Tunisia
| | - Besma Bel Hadj Jrad
- Laboratory of Genetics, Biodiversity and Valorization of Bioresources GBVB (LR11ES41), Higher Institute of Biotechnology of Monastir (ISBM), University of Monastir, Monastir, Tunisia
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The Relationship between Torque teno Virus and TLR2 rs5743708 Polymorphism with Breast Cancer. JOURNAL OF MEDICAL MICROBIOLOGY AND INFECTIOUS DISEASES 2021. [DOI: 10.52547/jommid.9.3.116] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/18/2022] Open
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Li D, Wu M. Pattern recognition receptors in health and diseases. Signal Transduct Target Ther 2021; 6:291. [PMID: 34344870 PMCID: PMC8333067 DOI: 10.1038/s41392-021-00687-0] [Citation(s) in RCA: 849] [Impact Index Per Article: 212.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2020] [Revised: 05/23/2021] [Accepted: 06/22/2021] [Indexed: 02/07/2023] Open
Abstract
Pattern recognition receptors (PRRs) are a class of receptors that can directly recognize the specific molecular structures on the surface of pathogens, apoptotic host cells, and damaged senescent cells. PRRs bridge nonspecific immunity and specific immunity. Through the recognition and binding of ligands, PRRs can produce nonspecific anti-infection, antitumor, and other immunoprotective effects. Most PRRs in the innate immune system of vertebrates can be classified into the following five types based on protein domain homology: Toll-like receptors (TLRs), nucleotide oligomerization domain (NOD)-like receptors (NLRs), retinoic acid-inducible gene-I (RIG-I)-like receptors (RLRs), C-type lectin receptors (CLRs), and absent in melanoma-2 (AIM2)-like receptors (ALRs). PRRs are basically composed of ligand recognition domains, intermediate domains, and effector domains. PRRs recognize and bind their respective ligands and recruit adaptor molecules with the same structure through their effector domains, initiating downstream signaling pathways to exert effects. In recent years, the increased researches on the recognition and binding of PRRs and their ligands have greatly promoted the understanding of different PRRs signaling pathways and provided ideas for the treatment of immune-related diseases and even tumors. This review describes in detail the history, the structural characteristics, ligand recognition mechanism, the signaling pathway, the related disease, new drugs in clinical trials and clinical therapy of different types of PRRs, and discusses the significance of the research on pattern recognition mechanism for the treatment of PRR-related diseases.
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Affiliation(s)
- Danyang Li
- Hunan Provincial Tumor Hospital and the Affiliated Tumor Hospital of Xiangya Medical School, Central South University, Changsha, Hunan, China
- The Key Laboratory of Carcinogenesis of the Chinese Ministry of Health, The Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Cancer Research Institute, Central South University, Changsha, Hunan, China
| | - Minghua Wu
- Hunan Provincial Tumor Hospital and the Affiliated Tumor Hospital of Xiangya Medical School, Central South University, Changsha, Hunan, China.
- The Key Laboratory of Carcinogenesis of the Chinese Ministry of Health, The Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Cancer Research Institute, Central South University, Changsha, Hunan, China.
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-196 to -174del, rs4696480, rs3804099 polymorphisms of Toll-like receptor 2 gene impact the susceptibility of cancers: evidence from 37053 subjects. Biosci Rep 2020; 39:221065. [PMID: 31710083 PMCID: PMC6900473 DOI: 10.1042/bsr20191698] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2019] [Revised: 10/22/2019] [Accepted: 11/06/2019] [Indexed: 02/06/2023] Open
Abstract
Relationship between Toll-like receptor-2 (TLR2) and cancer risk has been illustrated in some studies, but their conclusions are inconsistent. Therefore, we designed this meta-analysis to explore a more accurate conclusion of whether TLR2 affects cancer risks. Articles were retrieved from various literature databases according to the criteria. We used STATA to calculate the odds ratio (OR) and 95% confidence interval (95% CI) to evaluate the relationship between certain polymorphism of TLR2 and cancer risk. Finally, 47 case-control studies met the criteria, comprising 15851 cases and 21182 controls. In the overall analysis, people are more likely to get cancer because of -196 to -174del in TLR2 in all five genetic models, B vs. A (OR = 1.468, 95% Cl = 1.129-1.91, P=0.005); BB vs. AA (OR = 1.716, 95% Cl = 1.178-2.5, P=0.005); BA vs. AA (OR = 1.408, 95% Cl = 1.092-1.816, P=0.008); BB+BA vs. AA (OR = 1.449, 95% Cl = 1.107-1.897, P=0.007); BB vs. BA+AA (OR = 1.517, 95% Cl = 1.092-2.107, P=0.013). Meanwhile, rs4696480 could significantly increase the risk of cancer in Caucasians, furthermore, rs3804099 significantly decreased cancer risk in overall analysis, but more subjects are necessary to confirm the results. All in all, this meta-analysis revealed that not only -196 to -174del increased the risk of among overall cancers, Caucasians are more likely to get cancer because of rs4696480, while rs3804099 polymorphism could reduce the risk of cancer in some genetic models. There is no direct evidence showing that rs5743708, rs3804100 and rs1898830 are related to cancer.
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Javaid N, Choi S. Toll-like Receptors from the Perspective of Cancer Treatment. Cancers (Basel) 2020; 12:E297. [PMID: 32012718 PMCID: PMC7072551 DOI: 10.3390/cancers12020297] [Citation(s) in RCA: 50] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2020] [Revised: 01/22/2020] [Accepted: 01/25/2020] [Indexed: 02/06/2023] Open
Abstract
Toll-like receptors (TLRs) represent a family of pattern recognition receptors that recognize certain pathogen-associated molecular patterns and damage-associated molecular patterns. TLRs are highly interesting to researchers including immunologists because of the involvement in various diseases including cancers, allergies, autoimmunity, infections, and inflammation. After ligand engagement, TLRs trigger multiple signaling pathways involving nuclear factor-κB (NF-κB), interferon-regulatory factors (IRFs), and mitogen-activated protein kinases (MAPKs) for the production of various cytokines that play an important role in diseases like cancer. TLR activation in immune as well as cancer cells may prevent the formation and growth of a tumor. Nonetheless, under certain conditions, either hyperactivation or hypoactivation of TLRs supports the survival and metastasis of a tumor. Therefore, the design of TLR-targeting agonists as well as antagonists is a promising immunotherapeutic approach to cancer. In this review, we mainly describe TLRs, their involvement in cancer, and their promising properties for anticancer drug discovery.
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Affiliation(s)
| | - Sangdun Choi
- Department of Molecular Science and Technology, Ajou University, Suwon 16499, Korea;
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14
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Increased risks between TLR2 (-196 to -174 ins/del) and TLR3 1377C>T variants and head and neck cancers in Tunisia. Cent Eur J Immunol 2019; 44:144-149. [PMID: 31530984 PMCID: PMC6745549 DOI: 10.5114/ceji.2019.87065] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2016] [Accepted: 02/07/2017] [Indexed: 12/14/2022] Open
Abstract
Introduction Previous studies have highlighted the importance of polymorphisms of toll-like receptors (TLRs) in the pathogenesis of certain cancers, including head and neck cancers (HNC). Aim of the study The aim of this study was to evaluate the association of TLR2 (-196 to -174 ins/del) and TLR3 (1377 C>T) as potential risk factors for HNC in Tunisians. Material and methods A case-control study including 246 HNC patients (174 nasopharyngeal carcinoma – NPC and 72 laryngeal cancer – LC) and 250 healthy controls. Genotyping was done by using PCR and PCR-RFLP methods. Results Higher minor allele frequencies of TLR2 (-196 to -174 ins/del) and TLR3 1377 C>T polymorphisms were seen in HNC, NPC, and LC compared to controls. In addition, higher increased HNC, NPC, and LC risk was associated with TLR2 ins/del and TLR2 del/del genotypes (p < 0.0001). Positive association with HNC, NPC, and LC risk was seen with TLR2 del-containing genotypes (ins/del + del/del) (p < 0.0001). The T/T genotype of TLR3 is associated with HNC, NPC, and LC susceptibility (p < 0.0001). Positive association with HNC and NPC risk was seen with TLR3 T allele carriers (C/T + T/T) (p < 0.0001). Increased frequency of T-ins, C-del, and T-del haplotypes was revealed in HNC and NPC cases than healthy controls; however, T-del was significantly higher in LC cases. Conclusions Our results demonstrate an increased risk of HNC, NPC, and LC with TLR2 ins/del, TLR2 del/del, and TLR3 T/T genotypes. And positive association with T-ins, C-del, and T-del haplotypes with HNC and NPC and T-del haplotype with LC.
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Huang J, Hang JJ, Qin XR, Huang J, Wang XY. Interaction of H. pylori with toll-like receptor 2-196 to -174 ins/del polymorphism is associated with gastric cancer susceptibility in southern China. Int J Clin Oncol 2019; 24:494-500. [PMID: 30554285 DOI: 10.1007/s10147-018-1379-z] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2018] [Accepted: 12/11/2018] [Indexed: 12/15/2022]
Abstract
BACKGROUND Genetic polymorphisms of Toll-like receptors play important roles in gastric carcinogenesis. The aim of this study was to determine the role of TLR2-196 to -174 ins/del polymorphism in gastric cancer susceptibility and prognosis. METHODS This study included 520 people from southern China. Samples were genotyped by the allele-specific polymerase chain reaction, among which 10% were randomly selected for sequencing. The serological method was used to determine Helicobacter pylori. RESULTS The TLR2 genotype was not associated with the risk of H. pylori infection. The del/del genotype exhibited significantly higher gastric cancer risk (adjusted OR 2.59, 95% CI 1.33‒5.07) than that of the ins/ins genotype. Further stratification analyses demonstrated that the del/del genotype was associated with a risk of intestinal gastric cancer (adjusted OR 2.62, 95% CI 1.34-5.14). In addition, the presence of the del/del genotype and the H. pylori infection conferred a synergistic effect (OR 3.04, 95% CI 1.33‒6.98) for the development of gastric cancer. The del/del genotype was not associated with a poor prognosis in gastric cancer patients. CONCLUSION The del/del genotype is associated with an increased gastric cancer risk in the southern Chinese population. However, TLR2 polymorphism is neither associated with H. pylori infection, nor with a poor prognosis.
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Affiliation(s)
- Jin Huang
- Department of Gastroenterology, Changzhou No. 2 People's Hospital, Xinglong Xiang 29, Changzhou, 213000, Jiangsu, China
| | - Jun-Jie Hang
- Department of Oncology, Changzhou No. 2 People's Hospital, Xinglong Xiang 29, Changzhou, 213000, China
| | - Xiang-Rong Qin
- Department of Gastroenterology, Changzhou No. 2 People's Hospital, Xinglong Xiang 29, Changzhou, 213000, Jiangsu, China
| | - Jian Huang
- Department of Gastroenterology, Changzhou No. 2 People's Hospital, Xinglong Xiang 29, Changzhou, 213000, Jiangsu, China
| | - Xiao-Yong Wang
- Department of Gastroenterology, Changzhou No. 2 People's Hospital, Xinglong Xiang 29, Changzhou, 213000, Jiangsu, China.
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Royo JL, Alarcón-Martín E, Díaz-Fuentes J, Colmenero JD, Bravo MJ. Discordance in TLR2 (-196 to -174) polymorphism effect on HIV infection risk. J Gene Med 2018; 20:e3051. [PMID: 30312505 DOI: 10.1002/jgm.3051] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2018] [Revised: 08/03/2018] [Accepted: 08/11/2018] [Indexed: 11/06/2022] Open
Affiliation(s)
- José Luis Royo
- Surgery, Biochemistry and Immunology Department, School of Medicine, University of Malaga, Málaga, Spain
| | - Emilio Alarcón-Martín
- Surgery, Biochemistry and Immunology Department, School of Medicine, University of Malaga, Málaga, Spain
| | - Jesús Díaz-Fuentes
- Surgery, Biochemistry and Immunology Department, School of Medicine, University of Malaga, Málaga, Spain
| | - Juan D Colmenero
- Infectious Diseases Service, Regional University Hospital, Málaga, Spain
| | - María José Bravo
- Surgery, Biochemistry and Immunology Department, School of Medicine, University of Malaga, Málaga, Spain
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Ermiş Karaali Z, Candan G, Aktuğlu MB, Velet M, Ergen A. Toll-Like Receptor 2 (TLR-2) Gene Polymorphisms in Type 2 Diabetes Mellitus. CELL JOURNAL 2018; 20:559-563. [PMID: 30124003 PMCID: PMC6099132 DOI: 10.22074/cellj.2019.5540] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Subscribe] [Scholar Register] [Received: 09/25/2017] [Accepted: 12/13/2017] [Indexed: 12/27/2022]
Abstract
Objective Innate immunity factors are associated with type 2 diabetes (T2DM) and its complications. Therefore, T2DM has
been suggested to be an immune-dependent disease. Elevated fasting glucose level and higher concentrations of innate
immunity soluble molecules are not only related with insulin resistance, but inflammation is also an important factor in beta
cell dysfunction in T2DM. Toll-like receptor 2 (TLR-2), which has an important role in inducing innate immune cells, is thought
to have suppressive roles on immune responses in T2DM. We therefore aimed to investigate the possible role of TLR-2 del
-196-174 and Arg753Gln variants in T2DM pathogenesis.
Materials and Methods This study was designed as a case-control study. Polymerase chain reaction-restriction fragment
length polymorphism (PCR-RFLP) technique was used to genotype the two variants in 100 T2DM patients and 98 age-
matched controls.
Results We found significantly higher frequencies of TLR-2 del -196-174 DD genotype (P=0.003), ID genotype
(P=0.009) and D allele (P=0.001) in patients compared with controls. In addition, the II genotype (P=0.001) and the I
allele (P=0.003) frequencies were elevated in healthy controls. We did not find any significant differences in frequency
distribution for the Arg753Gln variant in study groups.
Conclusion We suggest that carrying the D allele of the TLR-2 del -196-174 variant may be related as a risk factor for T2DM.
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Affiliation(s)
- Zeynep Ermiş Karaali
- Department of Internal Medicine, Haseki Training and Research Hospital, University of Health Sciences, Istanbul, Turkey
| | - Gonca Candan
- Department of Molecular Medicine, Aziz Sancar Institute of Experimental Medicine, Istanbul University, Istanbul, Turkey
| | - Mehmet Burak Aktuğlu
- Department of Internal Medicine, Haseki Training and Research Hospital, University of Health Sciences, Istanbul, Turkey
| | - Mustafa Velet
- Department of Internal Medicine, Haseki Training and Research Hospital, University of Health Sciences, Istanbul, Turkey
| | - Arzu Ergen
- Department of Molecular Medicine, Aziz Sancar Institute of Experimental Medicine, Istanbul University, Istanbul, Turkey. Electronic Address:
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Functional Polymorphisms in IRAKs Are Related to Hepatocellular Carcinoma Risk in Chinese Population. BIOMED RESEARCH INTERNATIONAL 2018; 2018:1252849. [PMID: 30112356 PMCID: PMC6077667 DOI: 10.1155/2018/1252849] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/09/2018] [Revised: 04/28/2018] [Accepted: 05/10/2018] [Indexed: 12/16/2022]
Abstract
Background Interleukin 1 receptor associated kinases (IRAKs) play a central role in TLR signaling pathway. Scarce literature has investigated the association of potential functional genetic variants of IRAKs with Hepatitis B Virus- (HBV-) related hepatocellular carcinoma (HCC). Methods A case-control study with 1,538 HBV-positive HCC patients and 1,465 chronic HBV carriers was conducted to evaluate the effects of common missense variants of IRAK family members on HCC. Proliferation assays and real-time polymerase chain reactions were carried out to evaluate the functions. Multivariable adjusted logistic regression was adopted to estimate effect size and identify risk factors. Results Association analysis indicated that rs4251545 A allele of IRAK4 (p.Ala428Thr) was positively associated with HBV-related HCC risk (OR = 1.30, 95% CI: 1.09–1.54, P = 0.003). Functional annotation indicated that rs4251545 reduced its own expression in liver (P = 0.031). Further molecular functional analysis detected that rs4251545 increased the proliferation rate of L02 cells (P < 0.05). Meanwhile, rs4251545 reduced mRNA expressions of IL-6, IL-8, CXCL-1, and CXCL-2 in L02 cells (P < 0.01). Conclusion rs4251545 of IRAK4 (p.Ala428Thr) modified the susceptibility to HBV-related HCC via increased proliferation rate and reduced production of inflammatory cytokines and chemokines. Further well-designed experiments are warranted to validate our findings.
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Devi KR, Mukherjee K, Chelleng PK, Kalita S, Das U, Narain K. Association of VDR gene polymorphisms and 22 bp deletions in the promoter region of TLR2Δ22 (-196-174) with increased risk of pulmonary tuberculosis: A case-control study in tea garden communities of Assam. J Clin Lab Anal 2018; 32:e22562. [PMID: 29727015 DOI: 10.1002/jcla.22562] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2018] [Accepted: 04/09/2018] [Indexed: 12/15/2022] Open
Abstract
BACKGROUND A high number of pulmonary tuberculosis (PTB) cases have been reported from tea garden communities of Assam. Till date, no molecular epidemiological study was performed to investigate the association of candidate gene(s) with the risk PTB in this region. The present case-control study was aimed to investigate the association of vitamin D receptor (VDR) gene polymorphisms and 22 bp deletion in the promoter region of toll-like receptor 2 (TLR2) gene with the risk of PTB in tea garden communities of Assam. METHODS Genotyping of VDR polymorphisms and TLR2Δ22 (-196-174) gene was carried out for 169 PTB cases and 227 apparently healthy community controls using blood samples by PCR-RFLP followed by DNA sequencing. For association study, both univariate and multivariate logistic regression analyses were performed. RESULTS This study has shown that BsmI and FokI polymorphisms of VDR gene significantly associated with an increased risk of PTB (AOR = 3.58, 95% CI = 1.64-7.80, P < .01 for B/b genotype of BsmI and AOR = 2.44, 95% CI = 1.40-4.24, P < .01 for F/f genotype of FokI polymorphism). No significant association of TaqI and ApaI polymorphism of VDR gene was found with the risk of PTB. Moreover, this study has revealed that person carrying deletion allele in their TLR2Δ22 (-196-174) gene is significantly associated with an increased risk of PTB having b/b or F/f genotypes in BsmI or FokI polymorphisms of VDR gene. CONCLUSION This study has revealed that BsmI and FokI polymorphisms of VDR gene significantly associated with an increased risk of PTB.
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Affiliation(s)
| | | | | | - Simanta Kalita
- ICMR-Regional Medical Research Centre, Dibrugarh, Assam, India
| | - Upasana Das
- ICMR-Regional Medical Research Centre, Dibrugarh, Assam, India
| | - Kanwar Narain
- ICMR-Regional Medical Research Centre, Dibrugarh, Assam, India
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20
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Makni L, Messadi A, Zidi S, Gazouani E, Mezlini A, Yacoubi-Loueslati B. TLR2 (-196 to -174 Ins/Del) and TLR3 (1377C>T) as biomarkers for nasopharyngeal cancer in Tunisia. Turk J Med Sci 2017; 47:1216-1222. [PMID: 29156866 DOI: 10.3906/sag-1608-17] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022] Open
Abstract
Background/aim: We evaluated the association of TLR2 (-196 to -174 Ins/Del) and TLR3 (1377 C>T) as potential risk factors for nasopharyngeal carcinoma (NPC) in Tunisians. Material and methods: The study subjects comprised 137 NPC patients and 164 cancer-free control subjects. TLR2 genotyping was done by PCR and TLR3 genotyping was performed by PCR-RFLP. Results: Minor allele frequency (MAF) and genotypes of TLR3 (1377 C>T) were comparable between NPC patients and controls. Significantly higher MAF and TLR2-containing Del allele genotypes of TLR2 (-196 to -174 Ins/Del) were seen in NPC patients compared to controls [OR (95% CI) = 2.10 (1.43-3.08), P < 0.001 and OR (95% CI) = 2.07 (1.27-3.37), P = 0.003]. In addition, higher increased NPC risk was associated with the TLR2-Del/Del genotype [OR (95% CI) = 2.74 (1.37-5.48), P = 0.004]. An increased frequency of the Del-T haplotype was seen in NPC cases compared to controls. Conclusion: Our results demonstrate an increased risk of NPC with the TLR2-Del/Del genotype and Del-T TLR2 and TLR3 haplotype, suggesting their potential use as biomarkers to evaluate NPC risk in Tunisians.
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21
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Vidyant S, Chatterjee A, Agarwal V, Dhole TN. Susceptibility to HIV-1 infection is influenced by toll like receptor-2 (-196 to -174) polymorphism in a north Indian population. J Gene Med 2017; 19. [PMID: 28730622 DOI: 10.1002/jgm.2971] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2016] [Revised: 04/30/2017] [Accepted: 07/14/2017] [Indexed: 01/12/2023] Open
Abstract
BACKGROUND Toll like receptors (TLRs) are pattern recognition receptors that recognize molecular patterns of pathogens and play an important role in innate immunity. Recent studies have identified that a single nucleotide polymorphism (SNP) in the TLR gene impairs the response to TLR ligands in some individuals and is associated with susceptibility to various infectious diseases. The present study aimed to investigate the role of four SNPs in the TLR2 gene [-196 to -174 Ins/Del, 2258 G/A (Arg753Gln), 2029 C/T (Arg677Trp) and 1892 C/A (Pro631His)] with respect to susceptibility and progression to HIV-1 in North Indian individuals. METHODS The study population consisted of 160 HIV-1 seropositive patients stratified on the basis of disease severity (stages I, II and III) and 270 HIV-1 seronegative individuals. The subjects were genotyped for TLR2 gene polymorphism by polymerase chain reaction restriction fragment length polymorphism. RESULTS In the present study, we found that the TLR2 Del mutant genotype [odds ratio (OR) = 2.138; p = 0.001] and allele (OR = 1.562; p = 0.002) was at a higher frequency in patients with HIV-1 infection compared to healthy controls and was significantly associated with the risk of HIV-1 infection and disease susceptibility. Furthermore, we also found that TLR2 Del homozygous genotype was at a lower frequency in stage III (19.35%) compared to stage I (50.87%; OR = 1.901) and stage II (43.05%; OR = 1.514) and was associated with a reduced risk of HIV-1 disease progression. CONCLUSIONS The present study reports for the first time that the TLR2-196 to -174 Ins/Del polymorphism is a risk factor for HIV-1 transmission in HIV-1 infected North Indian individuals.
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Affiliation(s)
- Sanjukta Vidyant
- Department of Microbiology, Sanjay Gandhi Post Graduate Institute of Medical Sciences, Lucknow, Uttar Pradesh, India
| | | | - Vikas Agarwal
- Department of Immunology, Sanjay Gandhi Post Graduate Institute of Medical Sciences, Lucknow, Uttar Pradesh, India
| | - Tapan N Dhole
- Department of Microbiology, Sanjay Gandhi Post Graduate Institute of Medical Sciences, Lucknow, Uttar Pradesh, India
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Zhai X, Xue Q, Liu Q, Guo Y, Chen Z. Classifier of cross talk genes predicts the prognosis of hepatocellular carcinoma. Mol Med Rep 2017; 16:3253-3261. [PMID: 28713927 PMCID: PMC5547992 DOI: 10.3892/mmr.2017.7003] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2016] [Accepted: 05/05/2017] [Indexed: 12/15/2022] Open
Abstract
The present study aimed to establish a prediction model for hepatocellular carcinoma (HCC) based on the cross talk genes from important biological pathways involved in HCC. Differentially expressed genes (DEGs) for HCC were identified from mRNA profiles of GSE36376, which were mapped to protein-protein interaction (PPI) networks from BioGrid and the human protein reference database. Then critical genes based on the deviation score and the degree of node were selected from the novel PPI network. Cross talk genes were screened from the network established based on the associations of gene-gene, gene-pathway and pathway-pathway. A classifier based on specific cross talk genes was constructed for prediction of HCC using the random forest algorithm. Finally, the diagnostic performance of this prediction model was verified by predicting survival time of patients with HCC from the genome cancer atlas (TCGA) and other independent gene expression omnibus (GEO) databases. From the novel PPI network, a total of 200 critical genes were screened out and they were significantly enriched in 23 pathways, which have been reported to be significantly associated with the development of HCC. Based on these identified pathways, cross talk genes were identified including AKT1, SOS1, EGF, MYC, IGF1, ERBB2, CDKN1B, SHC2, VEGFA and INS. The prediction model has a relative average classification accuracy of 0.94 for HCC, which has a stable predicting efficacy for survival time of HCC patients validated in the TCGA database and two other independent GEO datasets. In conclusion, a total of 39 cross talk genes in HCC were identified and a classifier based on the cross talk genes was constructed, which indicates a high prognosis prediction efficacy in several independent datasets. The results provide a novel perspective to develop a multiple gene diagnostic tool for HCC prognosis, which also provided potential biomarkers or therapeutic targets for HCC.
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Affiliation(s)
- Xiaofeng Zhai
- Department of Integrative Oncology, Changhai Hospital of Traditional Chinese Medicine, Second Military Medical University, Shanghai 200433, P.R. China
| | - Qingfeng Xue
- Department of Anesthesiology, Chinese People's Liberation Army 264 Hospital, Taiyuan, Shanxi 030001, P.R. China
| | - Qun Liu
- Department of Integrative Oncology, Changhai Hospital of Traditional Chinese Medicine, Second Military Medical University, Shanghai 200433, P.R. China
| | - Yuyu Guo
- Department of Integrative Oncology, Changhai Hospital of Traditional Chinese Medicine, Second Military Medical University, Shanghai 200433, P.R. China
| | - Zhe Chen
- Department of Integrative Oncology, Changhai Hospital of Traditional Chinese Medicine, Second Military Medical University, Shanghai 200433, P.R. China
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David S, Aguiar P, Antunes L, Dias A, Morais A, Sakuntabhai A, Lavinha J. Variants in the non-coding region of the TLR2 gene associated with infectious subphenotypes in pediatric sickle cell anemia. Immunogenetics 2017; 70:37-51. [DOI: 10.1007/s00251-017-1013-7] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2017] [Accepted: 06/07/2017] [Indexed: 12/14/2022]
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Cervical Carcinogenesis and Immune Response Gene Polymorphisms: A Review. J Immunol Res 2017; 2017:8913860. [PMID: 28280748 PMCID: PMC5322437 DOI: 10.1155/2017/8913860] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2016] [Revised: 11/28/2016] [Accepted: 12/18/2016] [Indexed: 12/13/2022] Open
Abstract
The local immune response is considered a key determinant in cervical carcinogenesis after persistent infection with oncogenic, high-risk human papillomavirus (HPV) infections. Genetic variation in various immune response genes has been shown to influence risk of developing cervical cancer, as well as progression and survival among cervical cancer patients. We reviewed the literature on associations of immunogenetic single nucleotide polymorphism, allele, genotype, and haplotype distributions with risk and progression of cervical cancer. Studies on HLA and KIR gene polymorphisms were excluded due to the abundance on literature on that subject. We show that multiple genes and loci are associated with variation in risk of cervical cancer. Rather than one single gene being responsible for cervical carcinogenesis, we postulate that variations in the different immune response genes lead to subtle differences in the effectiveness of the antiviral and antitumour immune responses, ultimately leading to differences in risk of developing cervical cancer and progressive disease after HPV infection.
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Herta T, Fischer J, Berg T. Genetik metabolischer und viraler Lebererkrankungen. DER GASTROENTEROLOGE 2017; 12:16-31. [DOI: 10.1007/s11377-016-0128-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/04/2025]
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Rehman SU, Rauf M, Abbas Z, Hamed MH, Qadri I. Role of Some Predominant Host Immunomodulators' Single Nucleotide Polymorphisms in Severity of Hepatitis B Virus and Hepatitis C Virus Infection. Viral Immunol 2016; 29:536-545. [PMID: 27676210 DOI: 10.1089/vim.2016.0062] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022] Open
Abstract
Hepatitis B and C infections can be either acute or chronic. The chronic infection can culminate in liver cirrhosis and hepatocellular carcinoma. Influence of the host genetic makeup on conversion of acute to chronic infection, development of cirrhosis, and hepatocellular carcinoma is an interesting area of research. Variability in different immune system genes may account for such differences in the outcome of infection. This article discusses single nucleotide polymorphisms in different host immunomodulator genes that have been frequently reported to influence the outcome of infection and severity of disease. The genetic variability could be utilized for the prediction of disease outcome and treatment responses.
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MESH Headings
- Carcinoma, Hepatocellular/immunology
- HLA Antigens/genetics
- HLA Antigens/immunology
- Hepacivirus/immunology
- Hepatitis B virus/immunology
- Hepatitis B, Chronic/complications
- Hepatitis B, Chronic/immunology
- Hepatitis C, Chronic/complications
- Hepatitis C, Chronic/immunology
- Humans
- Immunologic Factors/genetics
- Immunologic Factors/immunology
- Interleukins/genetics
- Interleukins/immunology
- Liver Cirrhosis/etiology
- Liver Cirrhosis/immunology
- Liver Neoplasms/immunology
- Mannose-Binding Lectin/genetics
- Mannose-Binding Lectin/immunology
- Polymorphism, Single Nucleotide
- Receptor, Interferon alpha-beta/genetics
- Receptor, Interferon alpha-beta/immunology
- Receptors, CCR5/genetics
- Receptors, CCR5/immunology
- Tumor Necrosis Factor-alpha/genetics
- Tumor Necrosis Factor-alpha/immunology
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Affiliation(s)
- Shafiq Ur Rehman
- 1 Department of Microbiology and Molecular Genetics, University of the Punjab , Lahore, Pakistan
| | - Mahd Rauf
- 1 Department of Microbiology and Molecular Genetics, University of the Punjab , Lahore, Pakistan
| | - Zaigham Abbas
- 1 Department of Microbiology and Molecular Genetics, University of the Punjab , Lahore, Pakistan
| | - Muhammed Haroon Hamed
- 2 Department of Biological Sciences, King Abdul Aziz University , Jeddah, Kingdom of Saudi Arabia
| | - Ishtiaq Qadri
- 2 Department of Biological Sciences, King Abdul Aziz University , Jeddah, Kingdom of Saudi Arabia
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Zou H, Wang WK, Liu YL, Braddock M, Zheng MH, Huang DS. Toll-like receptors in hepatocellular carcinoma: potential novel targets for pharmacological intervention. Expert Opin Ther Targets 2016; 20:1127-1135. [PMID: 26998881 DOI: 10.1517/14728222.2016.1168809] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
INTRODUCTION Toll-like receptors (TLRs) are expressed by a wide variety of cell types including immune cells. They play a crucial role in the inflammatory and host defense response against microorganisms, and triggering TLRs can mediate the activation of innate immunity. Furthermore, research suggests that various TLRs may function differently on different tumor cells. The change in TLR activity may elicit an anti-tumor activity in hepatocellular carcinoma (HCC) cells and may serve as a novel therapeutic target for HCC therapy. AREAS COVERED This review discusses the role of the TLR family in HCC and the underlying signaling pathway of TLRs as a form of pattern recognition receptor in mediating inflammation and HCC immunity responses. Agonists and antagonists of TLRs, which render TLRs as potential therapeutic targets, activate downstream molecules, subsequently causing HCC cell survival. The proliferation or protection against the development of HCC is also described. EXPERT OPINION A series of studies have highlighted a crucial role of TLRs in HCC and consider TLR signaling pathways as potential therapeutic targets for HCC. However, the conclusions of these studies are in part paradoxical and controversial. Thus, it is necessary to extend further research to help determine the signaling pathways involved.
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Affiliation(s)
- Hai Zou
- a Department of Infection Diseases , Zhejiang Provincial People's Hospital , Hangzhou , China
| | - Wu-Ke Wang
- b Department of Hepatobiliary Surgery , the Fifth Affiliated Hospital of Wenzhou Medical University , Lishui , China
| | - Yan-Long Liu
- c College of Pharmaceutical Sciences , Wenzhou Medical University , Wenzhou , China
| | - Martin Braddock
- d Global Medicines Development , AstraZeneca R&D , Alderley Park , UK
| | - Ming-Hua Zheng
- e Department of Hepatology , Liver Research Center, The First Affiliated Hospital of Wenzhou Medical University , Wenzhou , China
- f Institute of Hepatology , Wenzhou Medical University , Wenzhou , China
| | - Dong-Sheng Huang
- g Department of Hepatobiliary Surgery , Zhejiang Provincial People's Hospital , Hangzhou , China
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Su F, Bai F, Zhou H, Zhang Z. Reprint of: Microglial toll-like receptors and Alzheimer's disease. Brain Behav Immun 2016; 55:166-178. [PMID: 27255539 DOI: 10.1016/j.bbi.2016.05.016] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/16/2015] [Revised: 10/09/2015] [Accepted: 10/15/2015] [Indexed: 01/04/2023] Open
Abstract
Microglial activation represents an important pathological hallmark of Alzheimer's disease (AD), and emerging data highlight the involvement of microglial toll-like receptors (TLRs) in the course of AD. TLRs have been observed to exert both beneficial and detrimental effects on AD-related pathologies, and transgenic animal models have provided direct and credible evidence for an association between TLRs and AD. Moreover, analyses of genetic polymorphisms have suggested interactions between genetic polymorphisms in TLRs and AD risk, further supporting the hypothesis that TLRs are involved in AD. In this review, we summarize the key evidence in this field. Future studies should focus on exploring the mechanisms underlying the potential roles of TLRs in AD.
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Affiliation(s)
- Fan Su
- Department of Neurology, Affiliated ZhongDa Hospital, School of Medicine, Southeast University, Nanjing, Jiangsu 210009, China
| | - Feng Bai
- Department of Neurology, Affiliated ZhongDa Hospital, School of Medicine, Southeast University, Nanjing, Jiangsu 210009, China.
| | - Hong Zhou
- Department of Neurology, Affiliated ZhongDa Hospital, School of Medicine, Southeast University, Nanjing, Jiangsu 210009, China
| | - Zhijun Zhang
- Department of Neurology, Affiliated ZhongDa Hospital, School of Medicine, Southeast University, Nanjing, Jiangsu 210009, China
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De Re V, De Zorzi M, Caggiari L, Lauletta G, Tornesello ML, Fognani E, Miorin M, Racanelli V, Quartuccio L, Gragnani L, Russi S, Pavone F, Ghersetti M, Costa EG, Casarin P, Bomben R, Mazzaro C, Basaglia G, Berretta M, Vaccher E, Izzo F, Buonaguro FM, De Vita S, Zignego AL, De Paoli P, Dolcetti R. HCV-related liver and lymphoproliferative diseases: association with polymorphisms of IL28B and TLR2. Oncotarget 2016; 7:37487-37497. [PMID: 27183918 PMCID: PMC5122326 DOI: 10.18632/oncotarget.9303] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2016] [Accepted: 04/19/2016] [Indexed: 12/29/2022] Open
Abstract
To explore the relationship between innate immunity and hepatitis C Virus (HCV) in determining the risk of cirrhosis (CIR), hepatocellular carcinoma (HCC), mixed cryoglobulinemia syndrome (MCS) and non-Hodgkin lymphoma (NHL), we investigated the impact of the toll-like receptor-2 (TLR2) and interleukin-28B (IL28B) genetic variants. TLR2 -174 del variant was associated with TLR2 expression and with specific downstream molecules that drive the expression of different interleukins; rs12979860 Il28B was important in response to interferon-treatment and in spontaneous clearance of HCV. The risk for liver and lymphoproliferative diseases in HCV progression was clarified by stratifying 862 HCV-positive patients into groups based on liver (CIR, HCC) and lymphoproliferative HCV-related diseases (MCS, NHL) and compared with chronic HCV (CHC) infection. Analysis of TLR2-IL28B haplotypes showed an association of wild type haplotype with the lymphoproliferative diseases (OR 1.77, p = 0.029) and a slight increase in HCV viral load (HR 1.38, p = 0.054). Wild type haplotype (TLR2 ins/ins- IL28B C/C) was also found associated with older age in patients with an hepatic diseases (in CIR and in HCC p = 0.038 and p = 0.020, respectively) supporting an effect of innate immunity in the liver disease progression. TLR2 and IL28B polymorphisms in combination showed a role in the control of HCV viral load and different HCV disease progression.
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Affiliation(s)
- Valli De Re
- Bio-Proteomics Facility/ Cancer Bioimmunotherapy, Department of Translational Research, Centro di Riferimento Oncologico (CRO), National Cancer Institute, Aviano, Italy
| | - Mariangela De Zorzi
- Bio-Proteomics Facility/ Cancer Bioimmunotherapy, Department of Translational Research, Centro di Riferimento Oncologico (CRO), National Cancer Institute, Aviano, Italy
| | - Laura Caggiari
- Bio-Proteomics Facility/ Cancer Bioimmunotherapy, Department of Translational Research, Centro di Riferimento Oncologico (CRO), National Cancer Institute, Aviano, Italy
| | - Gianfranco Lauletta
- Liver Unit, Division of Internal Medicine and Clinical Oncology, Department of Biomedical Sciences and Human Oncology, University of Bari Medical School, Bari, Italy
| | - Maria Lina Tornesello
- Molecular Biology and Viral Oncology Unit, Istituto Nazionale Tumori “Fondazione G. Pascale” - IRCCS, Napoli, Italy
| | - Elisa Fognani
- Interdepartmental Center for Systemic Manifestations of Hepatitis Virus MASVE, Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy
| | - Marta Miorin
- Cytogenetics and Molecular Biology Unit, Santa Maria degli Angeli Hospital Pordenone, Pordenone, Italy
| | - Vito Racanelli
- Immunology Section, Department of Biomedical Sciences and Human Oncology, University of Bari Medical School, Bari, Italy
| | - Luca Quartuccio
- Clinic of Rheumatology, Department of Medical and Biological Sciences, University Hospital “Santa Maria della Misericordia”, Udine, Italy
| | - Laura Gragnani
- Interdepartmental Center for Systemic Manifestations of Hepatitis Virus MASVE, Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy
| | - Sabino Russi
- Liver Unit, Division of Internal Medicine and Clinical Oncology, Department of Biomedical Sciences and Human Oncology, University of Bari Medical School, Bari, Italy
| | - Fabio Pavone
- Liver Unit, Division of Internal Medicine and Clinical Oncology, Department of Biomedical Sciences and Human Oncology, University of Bari Medical School, Bari, Italy
| | - Michela Ghersetti
- Internal Medicine-Liver Unit, Santa Maria degli Angeli Hospital Pordenone, Pordenone, Italy
| | - Elena Garlatti Costa
- Internal Medicine-Liver Unit, Santa Maria degli Angeli Hospital Pordenone, Pordenone, Italy
| | - Pietro Casarin
- Internal Medicine-Liver Unit, Santa Maria degli Angeli Hospital Pordenone, Pordenone, Italy
| | - Riccardo Bomben
- Clinical and Experimental Onco-Hematology Unit, Centro di Riferimento Oncologico (CRO), National Cancer Institute, Aviano, Italy
| | - Cesare Mazzaro
- Clinical and Experimental Onco-Hematology Unit, Centro di Riferimento Oncologico (CRO), National Cancer Institute, Aviano, Italy
| | - Giancarlo Basaglia
- Microbiology-Immunology and Virology Unit, Centro di Riferimento Oncologico (CRO), National Cancer Institute, Aviano, Italy
| | - Massimiliano Berretta
- Medical Oncology, Centro di Riferimento Oncologico (CRO), National Cancer Institute, Aviano, Italy
| | - Emanuela Vaccher
- Medical Oncology, Centro di Riferimento Oncologico (CRO), National Cancer Institute, Aviano, Italy
| | - Francesco Izzo
- Hepatobiliary Unit, Istituto Nazionale Tumori “Fondazione G. Pascale” - IRCCS, Napoli, Italy
| | - Franco Maria Buonaguro
- Molecular Biology and Viral Oncology Unit, Istituto Nazionale Tumori “Fondazione G. Pascale” - IRCCS, Napoli, Italy
| | - Salvatore De Vita
- Clinic of Rheumatology, Department of Medical and Biological Sciences, University Hospital “Santa Maria della Misericordia”, Udine, Italy
| | - Anna Linda Zignego
- Interdepartmental Center for Systemic Manifestations of Hepatitis Virus MASVE, Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy
| | - Paolo De Paoli
- Scientific Directorate, Centro di Riferimento Oncologico (CRO), National Cancer Institute, Aviano, Italy
| | - Riccardo Dolcetti
- Cancer Bio-Immunotherapy, Department of Translational Research, Centro di Riferimento Oncologico (CRO), National Cancer Institute, Aviano, Italy
- University of Queensland Diamantina Institute, Translational Research Institute, Brisbane, Queensland, Australia
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Khan A, Khan Z, Warnakulasuriya S. Cancer-associated toll-like receptor modulation and insinuation in infection susceptibility: association or coincidence? Ann Oncol 2016; 27:984-997. [PMID: 26861598 DOI: 10.1093/annonc/mdw053] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 08/29/2023] Open
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Kondkar AA, Mousa A, Azad TA, Sultan T, Osman EA, Al-Obeidan SA, Abu-Amero KK. Analysis of Toll-Like Receptor 2 Polymorphism (rs5743704) in Saudi Patients with Primary Open-Angle Glaucoma. Genet Test Mol Biomarkers 2016; 20:216-9. [PMID: 26866668 DOI: 10.1089/gtmb.2015.0310] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/04/2023] Open
Abstract
AIMS To investigate whether the single-nucleotide polymorphism (SNP) rs5743704 in the toll-like receptor 2 gene is associated with primary open-angle glaucoma (POAG) or any of its clinical indices in a Saudi cohort. METHOD Ninety-five unrelated POAG cases and 95 controls of Saudi origin were genotyped utilizing a TaqMan(®) assay. The association between genotypes and various clinical indices important for POAG were investigated. RESULTS The genotypic and allelic frequencies among cases were not significantly different when compared to controls. The minor allele frequency was 0.021 in cases and 0.011 in controls. No significant association was seen with intraocular pressure and cup/disc ratio. However, carriers of the C/A genotype had higher number of anti-glaucoma medications compared to controls (p = 0.04). CONCLUSION SNP rs5773704 is not associated with POAG in a Saudi population. Despite sample size limitation, the association of the minor allele A with higher number of anti-glaucoma medications suggests a possible indirect role for this SNP in predicting disease severity.
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Affiliation(s)
- Altaf A Kondkar
- 1 Department of Ophthalmology, College of Medicine, King Saud University , Riyadh, Saudi Arabia
- 2 Glaucoma Research Chair, Department of Ophthalmology, College of Medicine, King Saud University , Riyadh, Saudi Arabia
| | - Ahmed Mousa
- 1 Department of Ophthalmology, College of Medicine, King Saud University , Riyadh, Saudi Arabia
- 2 Glaucoma Research Chair, Department of Ophthalmology, College of Medicine, King Saud University , Riyadh, Saudi Arabia
| | - Taif A Azad
- 1 Department of Ophthalmology, College of Medicine, King Saud University , Riyadh, Saudi Arabia
- 2 Glaucoma Research Chair, Department of Ophthalmology, College of Medicine, King Saud University , Riyadh, Saudi Arabia
| | - Tahira Sultan
- 1 Department of Ophthalmology, College of Medicine, King Saud University , Riyadh, Saudi Arabia
- 2 Glaucoma Research Chair, Department of Ophthalmology, College of Medicine, King Saud University , Riyadh, Saudi Arabia
| | - Essam A Osman
- 1 Department of Ophthalmology, College of Medicine, King Saud University , Riyadh, Saudi Arabia
- 2 Glaucoma Research Chair, Department of Ophthalmology, College of Medicine, King Saud University , Riyadh, Saudi Arabia
| | - Saleh A Al-Obeidan
- 1 Department of Ophthalmology, College of Medicine, King Saud University , Riyadh, Saudi Arabia
- 2 Glaucoma Research Chair, Department of Ophthalmology, College of Medicine, King Saud University , Riyadh, Saudi Arabia
| | - Khaled K Abu-Amero
- 1 Department of Ophthalmology, College of Medicine, King Saud University , Riyadh, Saudi Arabia
- 2 Glaucoma Research Chair, Department of Ophthalmology, College of Medicine, King Saud University , Riyadh, Saudi Arabia
- 3 Department of Ophthalmology, College of Medicine, University of Florida , Jacksonville, Florida
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Su F, Bai F, Zhou H, Zhang Z. Microglial toll-like receptors and Alzheimer's disease. Brain Behav Immun 2016; 52:187-198. [PMID: 26526648 DOI: 10.1016/j.bbi.2015.10.010] [Citation(s) in RCA: 55] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/16/2015] [Revised: 10/09/2015] [Accepted: 10/15/2015] [Indexed: 02/08/2023] Open
Abstract
Microglial activation represents an important pathological hallmark of Alzheimer's disease (AD), and emerging data highlight the involvement of microglial toll-like receptors (TLRs) in the course of AD. TLRs have been observed to exert both beneficial and detrimental effects on AD-related pathologies, and transgenic animal models have provided direct and credible evidence for an association between TLRs and AD. Moreover, analyses of genetic polymorphisms have suggested interactions between genetic polymorphisms in TLRs and AD risk, further supporting the hypothesis that TLRs are involved in AD. In this review, we summarize the key evidence in this field. Future studies should focus on exploring the mechanisms underlying the potential roles of TLRs in AD.
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Affiliation(s)
- Fan Su
- Department of Neurology, Affiliated ZhongDa Hospital, School of Medicine, Southeast University, Nanjing, Jiangsu 210009, China.
| | - Feng Bai
- Department of Neurology, Affiliated ZhongDa Hospital, School of Medicine, Southeast University, Nanjing, Jiangsu 210009, China.
| | - Hong Zhou
- Department of Neurology, Affiliated ZhongDa Hospital, School of Medicine, Southeast University, Nanjing, Jiangsu 210009, China.
| | - Zhijun Zhang
- Department of Neurology, Affiliated ZhongDa Hospital, School of Medicine, Southeast University, Nanjing, Jiangsu 210009, China.
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Al-Harras MF, Houssen ME, Shaker ME, Farag K, Farouk O, Monir R, El-Mahdy R, Abo-Hashem EM. Polymorphisms of glutathione S-transferase π 1 and toll-like receptors 2 and 9: Association with breast cancer susceptibility. Oncol Lett 2016; 11:2182-2188. [PMID: 26998146 DOI: 10.3892/ol.2016.4159] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2014] [Accepted: 09/04/2015] [Indexed: 12/24/2022] Open
Abstract
Polymorphisms in antioxidant enzymes and innate immune receptors have been implicated in the development of various types of cancer. The present study aimed to investigate whether polymorphisms of glutathione S-transferase π 1 (GSTP1) and toll-like receptors (TLRs) 2 and 9 are associated with susceptibility to breast cancer among females. The study was conducted on 72 Egyptian female patients with breast cancer, along with 100 healthy volunteers. Polymorphisms of GSTP1 (codon 105 Ile/Val) and TLR9 rs187084 (1237T/C) genes were assessed by polymerase chain reaction (PCR)-restriction fragment length polymorphism, while the -196 to -174 deletion/insertion (del/ins) polymorphism of TLR2 was detected by PCR. The results indicated a decrease in GSTP1 Val allele frequency in breast cancer patients compared with healthy controls, at rates of 22.9 vs. 32.5%, respectively. In addition, the breast cancer group demonstrated a decreased TLR9 C allele frequency compared with the control group, at rates of 36.1 vs. 51.5%, respectively (P=0.0047). A non-significant difference was detected in the frequency of the TLR2 -196 to -174 del allele in breast cancer patients when compared to normal controls. In conclusion, these results suggested that the GSTP1 Val and TLR9 1237C alleles, but not TLR2 -196 to -174 del, are likely to be associated with breast cancer development among females.
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Affiliation(s)
- Mohammad F Al-Harras
- Department of Clinical Pathology, Faculty of Medicine, Mansoura University, Mansoura 35516, Egypt
| | - Maha E Houssen
- Department of Biochemistry, Faculty of Pharmacy, Damanhour University, Damanhour 71515, Egypt
| | - Mohamed E Shaker
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Mansoura University, Mansoura 35516, Egypt
| | - Kamel Farag
- Department of Oncology, Faculty of Medicine, Mansoura University, Mansoura 35516, Egypt
| | - Omar Farouk
- Surgical Oncology and Breast Surgery, Oncology Center, Faculty of Medicine, Mansoura University, Mansoura 35516, Egypt
| | - Rehan Monir
- Department of Medical Biochemistry, Faculty of Medicine, Mansoura University, Mansoura 35516, Egypt
| | - Rasha El-Mahdy
- Department of Medical Microbiology and Immunology, Faculty of Medicine, Mansoura University, Mansoura 35516, Egypt
| | - Ekbal M Abo-Hashem
- Department of Clinical Pathology, Faculty of Medicine, Mansoura University, Mansoura 35516, Egypt
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Lopes JAG, Borges-Canha M, Pimentel-Nunes P. Innate immunity and hepatocarcinoma: Can toll-like receptors open the door to oncogenesis? World J Hepatol 2016; 8:162-182. [PMID: 26839640 PMCID: PMC4724579 DOI: 10.4254/wjh.v8.i3.162] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/28/2015] [Accepted: 12/08/2015] [Indexed: 02/06/2023] Open
Abstract
Hepatocarcinoma (HCC) is a highly prevalent cancer worldwide and its inflammatory background was established long ago. Recent studies have shown that innate immunity is closely related to the HCC carcinogenesis. An effective innate immunity response relies on the toll-like receptors (TLR) found in several different liver cells which, through different ligands and many signaling pathways can elicit, not only a pro-inflammatory but also an oncogenic or anti-oncogenic response. Our aim was to study the role of TLRs in the liver oncogenesis and as a consequence their value as potential therapeutic targets. We performed a systematic review of PubMed searching for original articles studying the relationship between HCC and TLRs until March 2015. TLR2 appears to be a fundamental stress-sensor as its absence reveals an augmented tendency to accumulate DNA-damages and to cell survival. However, pathways are still not fully understood as TLR2 up-regulation was also associated to enhanced tumorigenesis. TLR3 has a well-known protective role influencing crucial processes like angiogenesis, cell growth or proliferation. TLR4 works as an interesting epithelial-mesenchymal transition’s inducer and a promoter of cell survival probably inducing HCC carcinogenesis even though an anti-cancer role has already been observed. TLR9’s influence on carcinogenesis is also controversial and despite a potential anti-cancer capacity, a pro-tumorigenic role is more likely. Genetic polymorphisms in some TLRs have been found and its influence on the risk of HCC has been reported. As therapeutic targets, TLRs are already in use and have a great potential. In conclusion, TLRs have been shown to be an interesting influence on the HCC’s microenvironment, with TLR3 clearly determining an anti-tumour influence. TLR4 and TLR9 are considered to have a positive relationship with tumour development even though, in each of them anti-tumorigenic signals have been described. TLR2 presents a more ambiguous role, possibly depending on the stage of the inflammation-HCC axis.
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TLR2∆22 (-196-174) significantly increases the risk of breast cancer in females carrying proline allele at codon 72 of TP53 gene: a case-control study from four ethnic groups of North Eastern region of India. Tumour Biol 2015; 36:9995-10002. [PMID: 26188904 DOI: 10.1007/s13277-015-3795-2] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2015] [Accepted: 07/10/2015] [Indexed: 12/13/2022] Open
Abstract
Breast cancer (BC) is the second most common cancer in women. In the North Eastern Region (NER) of India, BC is emerging as an important concern as evidenced by the data available from population and hospital-based cancer registries. Studies on genetic susceptibility to BC are important to understand the increase in the incidence of BC in NER. The present case control study was conducted to investigate the association between tumour suppressor gene TP53 codon 72 polymorphism and innate immune pathway gene TLR2∆22 (-196-174) polymorphism with BC in females of NER of India for the identification of novel biomarker of BC. Four hundred sixty-two histopathologically confirmed BC cases from four states of NER of India, and 770 healthy controls were included by organizing community surveys from the neighbourhood of cases. In our study, no significant association between TP53 codon 72 polymorphisms and the risk of BC was found. However, our study has shown that TP53 codon 72 polymorphism is an important effect modifier. In the present study it was found that females carrying 22 base-pair deletion in the promoter region of their TLR2 gene had two times (AOR= 2.18, 95 % CI 1.13-4.21, p=0.019 in dominant model; AOR= 2.17, 95 % CI 1.09-4.34, p=0.027 in co-dominant model) increased risk of BC whwn they also carry proline allele at codon 72 of their TP53 gene.
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36
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Lewandowska M, Garczyńska P, Jędrychowska-Dańska K, Kopczyńska P, Masłowska A, Witas H. Frequency of P2RX7 A1513C and TLR2 -196 to -174 ins/del in healthy Polish individuals. Int J Immunogenet 2015; 42:195-9. [PMID: 25726710 DOI: 10.1111/iji.12185] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2014] [Revised: 01/30/2015] [Accepted: 02/02/2015] [Indexed: 02/06/2023]
Abstract
Polymorphisms within genes coding innate immune response proteins are involved in genetic susceptibility to various conditions. We investigated the frequency of P2RX7 A1513C and TLR2 -196 to -174 ins/del polymorphisms in healthy Polish population. Frequency of minor alleles was relatively similar to the pattern presented by Caucasian populations while it differed significantly when compared to non-European populations, which could be a result of variable selection pressure put upon studied alleles or hindered gene flow between populations.
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Affiliation(s)
- M Lewandowska
- Department of Molecular Biology, Faculty of Biomedical Sciences and Postgraduate Education, Medical University, Lodz, Poland
| | - P Garczyńska
- Department of Molecular Biology, Faculty of Biomedical Sciences and Postgraduate Education, Medical University, Lodz, Poland
| | - K Jędrychowska-Dańska
- Department of Molecular Biology, Faculty of Biomedical Sciences and Postgraduate Education, Medical University, Lodz, Poland
| | - P Kopczyńska
- Department of Molecular Biology, Faculty of Biomedical Sciences and Postgraduate Education, Medical University, Lodz, Poland
| | - A Masłowska
- Department of Molecular Biology, Faculty of Biomedical Sciences and Postgraduate Education, Medical University, Lodz, Poland
| | - H Witas
- Department of Molecular Biology, Faculty of Biomedical Sciences and Postgraduate Education, Medical University, Lodz, Poland
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Li S, Sun R, Chen Y, Wei H, Tian Z. TLR2 limits development of hepatocellular carcinoma by reducing IL18-mediated immunosuppression. Cancer Res 2015; 75:986-95. [PMID: 25600646 DOI: 10.1158/0008-5472.can-14-2371] [Citation(s) in RCA: 51] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
Immune mechanisms underlying hepatocellular carcinoma (HCC) are not well understood. Here, we show that the Toll-like receptor TLR2 inhibits production of the proinflammatory cytokine IL18 and protects mice from DEN-induced liver carcinogenesis. On this protocol, Tlr2(-/-) mice exhibited more aggressive HCC development associated with impaired CD8(+) T-cell function. Furthermore, Ly6C(high)IL18Rα(+) myeloid-derived suppressor cells (MDSC) were increased in number in the livers of Tlr2(-/-) mice before tumor onset. MDSC in this setting exhibited higher iNOS levels that could inhibit IFNγ production and CD8(+) T-cell proliferation in vitro. Notably, Tlr2(-/-) hepatocytes produced more mature IL18 after DEN treatment that was sufficient to drive MDSC accumulation there. IL18 administration was sufficient to induce accumulation of MDSC, whereas hepatocyte-specific silencing of IL18 in Tlr2(-/-) mice decreased the proportion of MDSC, increased the proportion of functional CD8(+) T cells, and alleviated HCC progression. IL18 production was mediated by caspase-8 insofar as the decrease in its silencing was sufficient to attenuate levels of mature IL18 in Tlr2(-/-) mice. Furthermore, the TLR2 agonist Pam3CSK4 inhibited both caspase-8 and IL18 expression, decreasing MDSC, increasing CD8(+) T-cell function, and promoting HCC regression. Overall, our findings show how TLR2 deficiency accelerates IL18-mediated immunosuppression during liver carcinogenesis, providing new insights into immune control that may assist the design of effective immunotherapies to treat HCC.
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Affiliation(s)
- Shinan Li
- Institute of Immunology and CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Life Sciences and Medical Center, University of Science and Technology of China, Hefei, Anhui, China
| | - Rui Sun
- Institute of Immunology and CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Life Sciences and Medical Center, University of Science and Technology of China, Hefei, Anhui, China. Hefei National Laboratory for Physical Sciences at Microscale, Hefei, Anhui, China
| | - Yongyan Chen
- Institute of Immunology and CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Life Sciences and Medical Center, University of Science and Technology of China, Hefei, Anhui, China
| | - Haiming Wei
- Institute of Immunology and CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Life Sciences and Medical Center, University of Science and Technology of China, Hefei, Anhui, China. Hefei National Laboratory for Physical Sciences at Microscale, Hefei, Anhui, China
| | - Zhigang Tian
- Institute of Immunology and CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Life Sciences and Medical Center, University of Science and Technology of China, Hefei, Anhui, China. Hefei National Laboratory for Physical Sciences at Microscale, Hefei, Anhui, China. Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang, China.
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Mukherjee S, Ganguli D, Majumder PP. Global footprints of purifying selection on Toll-like receptor genes primarily associated with response to bacterial infections in humans. Genome Biol Evol 2014; 6:551-8. [PMID: 24554585 PMCID: PMC3971583 DOI: 10.1093/gbe/evu032] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022] Open
Abstract
Toll-like receptors (TLRs) are directly involved in host–pathogen interactions. Polymorphisms in these genes are associated with susceptibility to infectious diseases. To understand the influence of environment and pathogen diversity on the evolution of TLR genes, we have undertaken a large-scale population-genetic study. Our study included two hunter–gatherer tribal populations and one urbanized nontribal population from India with distinct ethnicities (n = 266) and 14 populations inhabiting four different continents (n = 1,092). From the data on DNA sequences of cell-surface TLR genes, we observed an excess of rare variants and a large number of low frequency haplotypes in each gene. Nonsynonymous changes were few in every population and the commonly used statistical tests for detecting natural selection provided evidence of purifying selection. The evidence of purifying selection acting on the cell-surface TLRs of the innate immune system is not consistent with Haldane’s theory of coevolution of immunity genes, at least of innate immunity genes, with pathogens. Our study provides evidence that genes of the cell-surface TLRs, that is, TLR2 and TLR4, have been so optimized to defend the host against microbial infections that new mutations in these genes are quickly eliminated.
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Affiliation(s)
- Souvik Mukherjee
- National Institute of Biomedical Genomics, Kalyani, West Bengal, India
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Aranda F, Vacchelli E, Obrist F, Eggermont A, Galon J, Sautès-Fridman C, Cremer I, Henrik ter Meulen J, Zitvogel L, Kroemer G, Galluzzi L. Trial Watch: Toll-like receptor agonists in oncological indications. Oncoimmunology 2014; 3:e29179. [PMID: 25083332 PMCID: PMC4091055 DOI: 10.4161/onci.29179] [Citation(s) in RCA: 66] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2014] [Accepted: 05/09/2014] [Indexed: 12/20/2022] Open
Abstract
Toll-like receptors (TLRs) are an evolutionarily conserved group of enzymatically inactive, single membrane-spanning proteins that recognize a wide panel of exogenous and endogenous danger signals. Besides constituting a crucial component of the innate immune response to bacterial and viral pathogens, TLRs appear to play a major role in anticancer immunosurveillance. In line with this notion, several natural and synthetic TLR ligands have been intensively investigated for their ability to boost tumor-targeting immune responses elicited by a variety of immunotherapeutic and chemotherapeutic interventions. Three of these agents are currently approved by the US Food and Drug Administration (FDA) or equivalent regulatory agencies for use in cancer patients: the so-called bacillus Calmette-Guérin, monophosphoryl lipid A, and imiquimod. However, the number of clinical trials testing the therapeutic potential of both FDA-approved and experimental TLR agonists in cancer patients is stably decreasing, suggesting that drug developers and oncologists are refocusing their interest on alternative immunostimulatory agents. Here, we summarize recent findings on the use of TLR agonists in cancer patients and discuss how the clinical evaluation of FDA-approved and experimental TLR ligands has evolved since the publication of our first Trial Watch dealing with this topic.
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Affiliation(s)
- Fernando Aranda
- Gustave Roussy; Villejuif, France
- INSERM, UMRS1138; Paris, France
- Equipe 11 labellisée par la Ligue Nationale contre le Cancer, Centre de Recherche des Cordeliers; Paris, France
- Université Paris-Sud/Paris XI; Paris, France
| | - Erika Vacchelli
- Gustave Roussy; Villejuif, France
- INSERM, UMRS1138; Paris, France
- Equipe 11 labellisée par la Ligue Nationale contre le Cancer, Centre de Recherche des Cordeliers; Paris, France
- Université Paris-Sud/Paris XI; Paris, France
| | - Florine Obrist
- Gustave Roussy; Villejuif, France
- INSERM, UMRS1138; Paris, France
- Equipe 11 labellisée par la Ligue Nationale contre le Cancer, Centre de Recherche des Cordeliers; Paris, France
- Université Paris-Sud/Paris XI; Paris, France
| | | | - Jérôme Galon
- INSERM, UMRS1138; Paris, France
- Université Paris Descartes/Paris V, Sorbonne Paris Cité; Paris, France
- Laboratory of Integrative Cancer Immunology, Centre de Recherche des Cordeliers; Paris, France
| | - Catherine Sautès-Fridman
- INSERM, UMRS1138; Paris, France
- Université Paris Descartes/Paris V, Sorbonne Paris Cité; Paris, France
- Université Pierre et Marie Curie/Paris VI; Paris, France
- Equipe 13, Centre de Recherche des Cordeliers; Paris, France
| | - Isabelle Cremer
- INSERM, UMRS1138; Paris, France
- Université Paris Descartes/Paris V, Sorbonne Paris Cité; Paris, France
- Université Pierre et Marie Curie/Paris VI; Paris, France
- Equipe 13, Centre de Recherche des Cordeliers; Paris, France
| | | | - Laurence Zitvogel
- Gustave Roussy; Villejuif, France
- INSERM, U1015; CICBT507; Villejuif, France
| | - Guido Kroemer
- INSERM, UMRS1138; Paris, France
- Equipe 11 labellisée par la Ligue Nationale contre le Cancer, Centre de Recherche des Cordeliers; Paris, France
- Université Paris Descartes/Paris V, Sorbonne Paris Cité; Paris, France
- Pôle de Biologie, Hôpital Européen Georges Pompidou, AP-HP; Villejuif, France
- Metabolomics and Cell Biology Platforms, Gustave Roussy; Villejuif, France
| | - Lorenzo Galluzzi
- Gustave Roussy; Villejuif, France
- Equipe 11 labellisée par la Ligue Nationale contre le Cancer, Centre de Recherche des Cordeliers; Paris, France
- Université Paris Descartes/Paris V, Sorbonne Paris Cité; Paris, France
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Castaño-Rodríguez N, Kaakoush NO, Pardo AL, Goh KL, Fock KM, Mitchell HM. Genetic polymorphisms in the Toll-like receptor signalling pathway in Helicobacter pylori infection and related gastric cancer. Hum Immunol 2014; 75:808-15. [PMID: 24929142 DOI: 10.1016/j.humimm.2014.06.001] [Citation(s) in RCA: 54] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2014] [Revised: 06/03/2014] [Accepted: 06/03/2014] [Indexed: 12/28/2022]
Abstract
BACKGROUND Gastric cancer (GC) is a progressive process initiated by Helicobacter pylori-induced inflammation. Initial recognition of H. pylori involves Toll-like receptors (TLRs), central molecules in the host inflammatory response. Here, we investigated the association between novel polymorphisms in genes involved in the TLR signalling pathway, including TLR2, TLR4, LBP, MD-2, CD14 and TIRAP, and risk of H. pylori infection and related GC. METHODS A case-control study comprising 310 ethnic Chinese individuals (87 non-cardia GC cases and 223 controls with functional dyspepsia) was conducted. Twenty-five polymorphisms were detected by MALDI-TOF mass spectrometry, PCR, PCR-RFLP and real-time PCR. RESULTS Seven polymorphisms showed significant associations with GC (TLR4 rs11536889, TLR4 rs10759931, TLR4 rs1927911, TLR4 rs10116253, TLR4 rs10759932, TLR4 rs2149356 and CD14 -260 C/T). In multivariate analyses, TLR4 rs11536889 remained a risk factor for GC (OR: 3.58, 95% CI: 1.20-10.65). TLR4 rs10759932 decreased the risk of H. pylori infection (OR: 0.59, 95% CI: 0.41-0.86). Statistical analyses assessing the joint effect of H. pylori infection and the selected polymorphisms revealed strong associations with GC (TLR2, TLR4, MD-2, LBP and TIRAP polymorphisms). CONCLUSIONS Novel polymorphisms in TLR2, TLR4, MD-2, LBP, CD14 and TIRAP, genes encoding important molecules of the TLR signalling pathway, showed clear associations with H. pylori-related GC in Chinese.
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Affiliation(s)
- Natalia Castaño-Rodríguez
- School of Biotechnology and Biomolecular Sciences, The University of New South Wales, Sydney, NSW 2052, Australia
| | - Nadeem O Kaakoush
- School of Biotechnology and Biomolecular Sciences, The University of New South Wales, Sydney, NSW 2052, Australia
| | - Aryce L Pardo
- School of Statistics, National University of Colombia, Medellin, Colombia
| | - Khean-Lee Goh
- Department of Medicine, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia
| | - Kwong Ming Fock
- Division of Gastroenterology, Department of Medicine, Changi General Hospital, Singapore, Singapore
| | - Hazel M Mitchell
- School of Biotechnology and Biomolecular Sciences, The University of New South Wales, Sydney, NSW 2052, Australia.
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Lin W, Chen J, Zhu B, Xu X, Dong Z. Role of toll-like receptors gene polymorphism in hepatocellular carcinoma. J Recept Signal Transduct Res 2014; 34:345-7. [PMID: 24641696 DOI: 10.3109/10799893.2014.903419] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022]
Abstract
Toll-like receptors (TLRs), evolutionarily conserved innate, play important roles in the development of autoimmunity. TLRs proteins are localized on the cell surface or in endosomes and play critical roles in innate immune responses against different pathogens. Aberrant stimulation of the innate immune system through intracellular TLRs may lead to hyperactive immune responses and contribute to the pathogenesis of hepatocellular carcinoma (HCC). HCC is the seventh most common cancer and the third leading cause of cancer deaths worldwide, and innate immune takes a most important role in HCC. There was no review to sum up the role of TLRs gene polymorphism in HCC. This review was performed to sum up the role of TLRs gene polymorphism in HCC.
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Affiliation(s)
- Wei Lin
- Department of Surgery, Affiliated Hospital of PuTian University , Putian , PR China
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MyD88-dependent immunity to a natural model of vaccinia virus infection does not involve Toll-like receptor 2. J Virol 2014; 88:3557-67. [PMID: 24403581 DOI: 10.1128/jvi.02776-13] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
Abstract
UNLABELLED Although the pattern recognition receptor Toll-like receptor 2 (TLR2) is typically thought to recognize bacterial components, it has been described to alter the induction of both innate and adaptive immunity to a number of viruses, including vaccinia virus (VACV). However, many pathogens that reportedly encode TLR2 agonists may actually be artifactually contaminated during preparation, possibly with cellular debris or merely with molecules that sensitize cells to be activated by authentic TLR2 agonists. In both humans and mice, the most relevant natural route of infection with VACV is through intradermal infection of the skin. Therefore, we examined the requirement for TLR2 and its signaling adaptor MyD88 in protective immunity to VACV after intradermal infection. We find that although TLR2 may recognize virus preparations in vitro and have a minor role in preventing dissemination of VACV following systemic infection with large doses of virus, it is wholly disposable in both control of virus replication and induction of adaptive immunity following intradermal infection. In contrast, MyD88 is required for efficient induction of CD4 T cell and B cell responses and for local control of virus replication following intradermal infection. However, even MyD88 is not required to induce local inflammation, inflammatory cytokine production, or recruitment of cells that restrict virus from spreading systemically after peripheral infection. Thus, an effective antiviral response does require MyD88, but TLR2 is not required for control of a peripheral VACV infection. These findings emphasize the importance of studying relevant routes of infection when examining innate sensing mechanisms. IMPORTANCE Vaccinia virus (VACV) provides the backbone for some of the most widely used and successful viral vaccine vectors and is also related to the human pathogens Cantagalo virus and molluscum contagiosum virus that infect the skin of patients. Therefore, it is vital to understand the mechanisms that induce a strong innate immune response to the virus following dermal infection. Here, we compare the ability of the innate sensing molecule Toll-like receptor 2 (TLR2) and the signaling molecule MyD88 to influence the innate and adaptive immune response to VACV following systemic or dermal infection.
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Zhu L, Yuan H, Jiang T, Wang R, Ma H, Zhang S. Association of TLR2 and TLR4 polymorphisms with risk of cancer: a meta-analysis. PLoS One 2013; 8:e82858. [PMID: 24376595 PMCID: PMC3869723 DOI: 10.1371/journal.pone.0082858] [Citation(s) in RCA: 33] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2013] [Accepted: 10/29/2013] [Indexed: 01/15/2023] Open
Abstract
BACKGROUNDS The activation of Toll-like receptors (TLRs) may be an important event in the immune evasion of tumor cell. Recently, numerous studies have investigated the associations between TLR2 -196 to -174 del and two SNPs of TLR4 (rs4986790 and rs4986791) and the susceptibility to different types of cancer; however, the results remain conflicting. The aim of this study was to assess the association between TLR2 and TLR4 polymorphisms and cancer risk in a meta-analysis with eligible published studies. METHODOLOGY/PRINCIPLE FINDINGS A dataset composed of 14627 cases and 17438 controls from 34 publications were included in a meta-analysis to evaluate the association between overall cancer risk or cancer-specific risk and three SNPs of TLRs (TLR2 -196 to -174 del, TLR4 rs4986790 and rs4986791). The results showed that all of these three polymorphisms were significantly associated with the increased cancer risk (dominant model: OR = 1.64, 95% CI: 1.04-2.60 for TLR2 -196 to -174 del; OR = 1.19, 95% CI: 1.01-1.41 for TLR4 rs4986790; and OR = 1.47, 95% CI: 1.120-1.80 for TLR4 rs4986791; respectively). In stratified analysis, we found the effect of TLR2 -196 to -174 del on cancer risk remained significant in the subgroup of Caucasians and South Asians, but not in East Asians. However, the association between rs4986791 and cancer risk was significant in both South Asians and East Asians, but not in Caucasians. Furthermore, the association between rs4986790 and cancer risk was statistically significant in digestive cancers (dominant model: OR = 1.76, 95% CI: 1.13-2.73) and female-specific cancers (dominant model: OR = 1.50, 95% CI: 1.16-1.94). However, no significant association with risk of digestive system cancers was observed for TLR2 -196 to -174 del and TLR4 rs4986791. CONCLUSIONS/SIGNIFICANCE This meta-analysis presented additional evidence for the association between TLR2 and TLR4 polymorphisms and cancer risk. Further well-designed investigations with large sample sizes are required to confirm this conclusion.
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Affiliation(s)
- Longbiao Zhu
- Institute of Stomatology, Nanjing Medical University, Nanjing, China
- Section of Clinical Epidemiology, Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Cancer Center, Nanjing Medical University, Nanjing, China
| | - Hua Yuan
- Institute of Stomatology, Nanjing Medical University, Nanjing, China
- Section of Clinical Epidemiology, Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Cancer Center, Nanjing Medical University, Nanjing, China
| | - Tao Jiang
- Department of Epidemiology and Biostatistics, MOE Key Laboratory of Modern Toxicology, School of Public Health, Nanjing Medical University, Nanjing, China
| | - Ruixia Wang
- Institute of Stomatology, Nanjing Medical University, Nanjing, China
| | - Hongxia Ma
- Section of Clinical Epidemiology, Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Cancer Center, Nanjing Medical University, Nanjing, China
- Department of Epidemiology and Biostatistics, MOE Key Laboratory of Modern Toxicology, School of Public Health, Nanjing Medical University, Nanjing, China
- * E-mail: (HM); (SZ)
| | - Shuangyue Zhang
- Central Lab, Huai’an First People’s Hospital, Nanjing Medical University, Huai’an, China
- * E-mail: (HM); (SZ)
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Spengler U, Nischalke HD, Nattermann J, Strassburg CP. Between Scylla and Charybdis: The role of the human immune system in the pathogenesis of hepatitis C. World J Gastroenterol 2013; 19:7852-7866. [PMID: 24307779 PMCID: PMC3848133 DOI: 10.3748/wjg.v19.i44.7852] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/28/2013] [Revised: 10/25/2013] [Accepted: 11/13/2013] [Indexed: 02/06/2023] Open
Abstract
Hepatitis C virus (HCV) frequently elicits only mild immune responses so that it can often establish chronic infection. In this case HCV antigens persist and continue to stimulate the immune system. Antigen persistence then leads to profound changes in the infected host’s immune responsiveness, and eventually contributes to the pathology of chronic hepatitis. This topic highlight summarizes changes associated with chronic hepatitis C concerning innate immunity (interferons, natural killer cells), adaptive immune responses (immunoglobulins, T cells, and mechanisms of immune regulation (regulatory T cells). Our overview clarifies that a strong anti-HCV immune response is frequently associated with acute severe tissue damage. In chronic hepatitis C, however, the effector arms of the immune system either become refractory to activation or take over regulatory functions. Taken together these changes in immunity may lead to persistent liver damage and cirrhosis. Consequently, effector arms of the immune system will not only be considered with respect to antiviral defence but also as pivotal mechanisms of inflammation, necrosis and progression to cirrhosis. Thus, avoiding Scylla - a strong, sustained antiviral immune response with inital tissue damage - takes the infected host to virus-triggered immunopathology, which ultimately leads to cirrhosis and liver cancer - the realm of Charybdis.
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Aravalli RN. Role of innate immunity in the development of hepatocellular carcinoma. World J Gastroenterol 2013; 19:7500-7514. [PMID: 24282342 PMCID: PMC3837249 DOI: 10.3748/wjg.v19.i43.7500] [Citation(s) in RCA: 47] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/27/2013] [Revised: 09/29/2013] [Accepted: 10/18/2013] [Indexed: 02/06/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is the most common form of liver cancer worldwide. It is caused by a variety of risk factors, most common ones being infection with hepatitis viruses, alcohol, and obesity. HCC often develops in the background of underlying cirrhosis, and even though a number of interventional treatment methods are currently in use, recurrence is fairly common among patients who have had a resection. Therefore, whole liver transplantation remains the most practical treatment option for HCC. Due to the growing incidence of HCC, intense research efforts are being made to understand cellular and molecular mechanisms of the disease so that novel therapeutic strategies can be developed to combat liver cancer. In recent years, it has become clear that innate immunity plays a critical role in the development of a number of liver diseases, including HCC. In particular, the activation of Toll-like receptor signaling results in the generation of immune responses that often results in the production of pro-inflammatory cytokines and chemokines, and could cause acute inflammation in the liver. In this review, the current knowledge on the role of innate immune responses in the development and progression of HCC is examined, and emerging therapeutic strategies based on molecular mechanisms of HCC are discussed.
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Pothlichet J, Quintana-Murci L. The genetics of innate immunity sensors and human disease. Int Rev Immunol 2013; 32:157-208. [PMID: 23570315 DOI: 10.3109/08830185.2013.777064] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
Since their discovery, innate immunity microbial sensors have been increasingly studied and shown to play a critical role in innate responses to microbes in several experimental in vitro, ex vivo, and animal models. However, their role in the human response to infection in natural conditions has just started to be deciphered, by means of clinical studies of primary immunodeficiencies and epidemiological genetic studies. Here, we summarize the major findings concerning the genetic diversity of the various families of microbial sensors in humans, and of other molecules involved in the signaling pathways they trigger. Specifically, we review the genetic associations, revealed by both clinical and epidemiological genetics studies, of microbial sensors from five different families: Toll-like receptors, C-type lectin receptors, NOD-like receptors, RIG-I-like receptors, and cytosolic DNA sensors. In particular, we consider the relationships between variation at the genes encoding these molecules and susceptibility to and the severity of infectious diseases and other clinical conditions associated with immune dysfunction, including autoimmunity, inflammation, allergy, and cancer. Despite the fact that the genetic links between innate immunity sensors and human disorders remain still limited, human genetics studies are increasingly improving our understanding of the genuine functions of microbial sensors and downstream signaling molecules in the natural setting.
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Affiliation(s)
- Julien Pothlichet
- Institut Pasteur, Unit of Human Evolutionary Genetics, Paris, France
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Lin H, Liu XB, Yu JJ, Hua F, Hu ZW. Antioxidant N-acetylcysteine attenuates hepatocarcinogenesis by inhibiting ROS/ER stress in TLR2 deficient mouse. PLoS One 2013; 8:e74130. [PMID: 24098333 PMCID: PMC3788783 DOI: 10.1371/journal.pone.0074130] [Citation(s) in RCA: 42] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2013] [Accepted: 07/29/2013] [Indexed: 12/19/2022] Open
Abstract
Hepatocellular carcinoma (HCC) remains one of the most deadly solid tumor malignancies worldwide. We recently find that the loss of toll-like receptor 2 (TLR2) activities promotes the diethylnitrosamine (DEN) induced hepatocellular carcinogenesis and tumor progression, which associates with an abundant accumulation of reactive oxygen species (ROS) and endoplasmic reticulum (ER) stress. This finding suggests that the ROS/ER stress plays a role in TLR2 modulated carcinogenesis of HCC. To investigate the mechanism of TLR2 activity defending against hepatocarcinogenesis, the TLR2-deficient mice were treated with or without antioxidant N-acetylcysteine (NAC) before DEN administration. We found that pretreatment of these animals with NAC attenuated carcinogenesis and progression of HCC in the TLR2-deficient mice, declined ROS/ER stress, and alleviated the unfold protein response and inflammatory response in TLR2-deficient liver tissue. Moreover, the NAC treatment significantly reduced the enhanced aggregation of p62 and Mallory-Denk bodies in the DEN-induced HCC liver tissue, suggesting that NAC treatment improves the suppressive autophagic flux in the TLR2-deficient liver. These findings indicate that TLR2 activity defends against hepatocarcinogenesis through diminishing the accumulation of ROS and alleviating ER stress and unfold protein response mediated inflammatory response in the liver.
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Affiliation(s)
- Heng Lin
- Molecular Immunology and Pharmacology Group, State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Beijing Key Laboratory of New Drug Mechanisms and Pharmacological Evaluation Study (NO. BZ0150), Institute of Materia Medica, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China
| | - Xiao-bo Liu
- Molecular Immunology and Pharmacology Group, State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Beijing Key Laboratory of New Drug Mechanisms and Pharmacological Evaluation Study (NO. BZ0150), Institute of Materia Medica, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China
| | - Jiao-jiao Yu
- Molecular Immunology and Pharmacology Group, State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Beijing Key Laboratory of New Drug Mechanisms and Pharmacological Evaluation Study (NO. BZ0150), Institute of Materia Medica, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China
| | - Fang Hua
- Molecular Immunology and Pharmacology Group, State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Beijing Key Laboratory of New Drug Mechanisms and Pharmacological Evaluation Study (NO. BZ0150), Institute of Materia Medica, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China
| | - Zhuo-wei Hu
- Molecular Immunology and Pharmacology Group, State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Beijing Key Laboratory of New Drug Mechanisms and Pharmacological Evaluation Study (NO. BZ0150), Institute of Materia Medica, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China
- * E-mail:
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Khan AUH, Aslam MA, Hussain I, Naz AG, Rana IA, Ahmad MM, Ali M, Ahmad S. Role of Toll-like receptor 2 (-196 to -174) polymorphism in susceptibility to pulmonary tuberculosis in Pakistani population. Int J Immunogenet 2013; 41:105-11. [PMID: 23998736 DOI: 10.1111/iji.12086] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2012] [Revised: 07/05/2013] [Accepted: 08/08/2013] [Indexed: 12/22/2022]
Abstract
Tuberculosis (TB) is a global public health problem and a source of preventable deaths each year, with 8.8 million new cases of TB and 1.6 million deaths worldwide. Pakistan ranks sixth on the list of 22 high-burden tuberculosis countries in the world. The transitions from infection to clinical disease are very few signifying that host-defence factors could lead to the development of active disease. Toll-like receptor (TLR) 2 polymorphisms have been associated with regulation of TLR expression and development of active TB. In this study, blood samples of 187 subjects including 100 healthy and 87 TB positive were collected from three districts of Pakistan. DNA was extracted from blood and TLR 2 (-196 to -174del) polymorphism was analysed by polymerase chain reaction (PCR). The results suggest that the frequency of -196 to -174del/del polymorphism of TLR2 was significantly higher in TB-positive patients compared with healthy. Results revealed that (-196 to -174del) polymorphism may increase the susceptibility to TB in healthy population of Pakistan. Moreover, males with heterozygous genotype (I/D) are more prone to TB than females with the same genotype. The occurrence of TB infection has been found positively associated with the age, suggesting that the population within the range of 21-45 years is more susceptible to Mycobacterium tuberculosis than other age groups studied. A significant association is also observed between smoking and the chances of developing TB, confirming that smoking strongly promotes its incidence.
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Affiliation(s)
- Abrar-Ul-Haq Khan
- Institute of Microbiology, University of Agriculture Faisalabad, Faisalabad, Pakistan
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Wang XQ, Liu L, Liu Y, Zhang K. TLR-2 gene polymorphisms and susceptibility to cancer: evidence from meta-analysis. Genet Test Mol Biomarkers 2013; 17:864-72. [PMID: 23992203 DOI: 10.1089/gtmb.2013.0246] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/27/2023] Open
Abstract
The ability to respond properly to Toll-like receptor (TLR) ligands may be impaired by polymorphisms within the TLR family of genes, which results in an altered susceptibility to cancers. However, the results of epidemiological studies remained inconsistent. To assess the effect of four selected polymorphisms (rs5743708, -196 to -174 del polymorphism, rs3804099, and rs3804100) in TLR-2 on cancer, we conducted a meta-analysis, up to November 2012; 20 case-control studies were available. Summary odds ratios (OR) and corresponding 95% confidence intervals (CIs) for polymorphisms in TLR-2 and cancer risk were estimated. Our meta-analysis identified that elevated cancer risk was statistically associated with -196 to -174 del allele in -196 to -174 del polymorphism (OR=1.63, 95% CI=1.10-2.41 for allele comparison; OR=1.64, 95% CI=1.05-2.57 for dominant model; OR=2.26, 95% CI=1.24-4.12 for recessive model; OR=2.57, 95% CI=1.30-5.08 for DD vs. II and OR=1.53, 95% CI=1.01-2.32 for ID vs. II in codominant model); whereas rs3804099 in TLR-2 was associated with decreased cancer risk. Moreover, in terms of stratified analyses by cancer type for -196 to -174 del polymorphism, significantly elevated risk was observed to be associated with -196 to -174 del allele in "other cancers." These findings indicate that polymorphisms in TLR-2 may play a role, although modest, in cancer development.
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Affiliation(s)
- Xiao-Qin Wang
- 1 Department of Pediatric Cardiology, West-China Second University Hospital , Sichuan University, Cheng Du, People's Republic of China
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50
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Vacchelli E, Eggermont A, Sautès-Fridman C, Galon J, Zitvogel L, Kroemer G, Galluzzi L. Trial Watch: Toll-like receptor agonists for cancer therapy. Oncoimmunology 2013; 2:e25238. [PMID: 24083080 PMCID: PMC3782517 DOI: 10.4161/onci.25238] [Citation(s) in RCA: 120] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2013] [Accepted: 05/31/2013] [Indexed: 12/19/2022] Open
Abstract
Toll-like receptors (TLRs) have long been known for their ability to initiate innate immune responses upon exposure to conserved microbial components such as lipopolysaccharide (LPS) and double-stranded RNA. More recently, this family of pattern recognition receptors has been attributed a critical role in the elicitation of anticancer immune responses, raising interest in the development of immunochemotherapeutic regimens based on natural or synthetic TLR agonists. In spite of such an intense wave of preclinical and clinical investigation, only three TLR agonists are currently licensed by FDA for use in cancer patients: bacillus Calmette-Guérin (BCG), an attenuated strain of Mycobacterium bovis that operates as a mixed TLR2/TLR4 agonist; monophosphoryl lipid A (MPL), a derivative of Salmonella minnesota that functions as a potent agonist of TLR4; and imiquimod, a synthetic imidazoquinoline that activates TLR7. One year ago, in the August and September issues of OncoImmunology, we described the main biological features of TLRs and discussed the progress of clinical studies evaluating the safety and therapeutic potential of TLR agonists in cancer patients. Here, we summarize the latest developments in this exciting area of research, focusing on preclinical studies that have been published during the last 13 mo and clinical trials launched in the same period to investigate the antineoplastic activity of TLR agonists.
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Affiliation(s)
- Erika Vacchelli
- Institut Gustave Roussy; Villejuif, France
- Université Paris-Sud/Paris XI; Le Kremlin-Bicêtre; Paris, France
- INSERM, U848; Villejuif, France
| | | | - Catherine Sautès-Fridman
- Université Paris Descartes/Paris V; Sorbonne Paris Cité; Paris, France
- Equipe 13, Centre de Recherche des Cordeliers; Paris, France
- Pôle de Biologie, Hôpital Européen Georges Pompidou, Assistance Publique-Hôpitaux de Paris; Paris, France
| | - Jérôme Galon
- Université Paris Descartes/Paris V; Sorbonne Paris Cité; Paris, France
- Equipe 15, Centre de Recherche des Cordeliers; Paris, France
- INSERM, U872; Paris, France
- Université Pierre et Marie Curie/Paris VI; Paris, France
| | - Laurence Zitvogel
- Université Paris-Sud/Paris XI; Le Kremlin-Bicêtre; Paris, France
- INSERM, U1015; Villejuif, France
| | - Guido Kroemer
- INSERM, U848; Villejuif, France
- Université Paris Descartes/Paris V; Sorbonne Paris Cité; Paris, France
- Pôle de Biologie, Hôpital Européen Georges Pompidou, Assistance Publique-Hôpitaux de Paris; Paris, France
- Equipe 11 labelisée par la Ligue Nationale contre le Cancer, Centre de Recherche des Cordeliers; Paris, France
- Metabolomics and Cell Biology Platform; Institut Gustave Roussy; Villejuif, France
| | - Lorenzo Galluzzi
- Institut Gustave Roussy; Villejuif, France
- Université Paris Descartes/Paris V; Sorbonne Paris Cité; Paris, France
- Equipe 11 labelisée par la Ligue Nationale contre le Cancer, Centre de Recherche des Cordeliers; Paris, France
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