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1
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Richter P, Sebald K, Fischer K, Schnieke A, Jlilati M, Mittermeier-Klessinger V, Somoza V. Gastric digestion of the sweet-tasting plant protein thaumatin releases bitter peptides that reduce H. pylori induced pro-inflammatory IL-17A release via the TAS2R16 bitter taste receptor. Food Chem 2024; 448:139157. [PMID: 38569411 DOI: 10.1016/j.foodchem.2024.139157] [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: 12/23/2023] [Revised: 03/08/2024] [Accepted: 03/25/2024] [Indexed: 04/05/2024]
Abstract
About half of the world's population is infected with the bacterium Helicobacter pylori. For colonization, the bacterium neutralizes the low gastric pH and recruits immune cells to the stomach. The immune cells secrete cytokines, i.e., the pro-inflammatory IL-17A, which directly or indirectly damage surface epithelial cells. Since (I) dietary proteins are known to be digested into bitter tasting peptides in the gastric lumen, and (II) bitter tasting compounds have been demonstrated to reduce the release of pro-inflammatory cytokines through functional involvement of bitter taste receptors (TAS2Rs), we hypothesized that the sweet-tasting plant protein thaumatin would be cleaved into anti-inflammatory bitter peptides during gastric digestion. Using immortalized human parietal cells (HGT-1 cells), we demonstrated a bitter taste receptor TAS2R16-dependent reduction of a H. pylori-evoked IL-17A release by up to 89.7 ± 21.9% (p ≤ 0.01). Functional involvement of TAS2R16 was demonstrated by the study of specific antagonists and siRNA knock-down experiments.
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Affiliation(s)
- Phil Richter
- TUM School of Life Sciences Weihenstephan, Technical University of Munich, Alte Akademie 8, 85354 Freising, Germany; Leibniz Institute for Food Systems Biology at the Technical University of Munich, Lise-Meitner-Str. 34, 85354 Freising, Germany.
| | - Karin Sebald
- Leibniz Institute for Food Systems Biology at the Technical University of Munich, Lise-Meitner-Str. 34, 85354 Freising, Germany.
| | - Konrad Fischer
- Livestock Biotechnology, TUM School of Life Sciences, Technical University of Munich, Liesel-Beckmann-Str. 1, 85,354 Freising, Germany.
| | - Angelika Schnieke
- Livestock Biotechnology, TUM School of Life Sciences, Technical University of Munich, Liesel-Beckmann-Str. 1, 85,354 Freising, Germany.
| | - Malek Jlilati
- Leibniz Institute for Food Systems Biology at the Technical University of Munich, Lise-Meitner-Str. 34, 85354 Freising, Germany
| | - Verena Mittermeier-Klessinger
- Food Chemistry and Molecular Sensory Science, Technical University of Munich, Lise-Meitner-Str. 34, 85354 Freising, Germany.
| | - Veronika Somoza
- Leibniz Institute for Food Systems Biology at the Technical University of Munich, Lise-Meitner-Str. 34, 85354 Freising, Germany; Nutritional Systems Biology, TUM School of Life Sciences, Technical University of Munich, Lise-Meitner-Str. 34, 85,354 Freising, Germany; Department of Physiological Chemistry, Faculty of Chemistry, University of Vienna, Josef-Holaubek-Platz 2 (UZA II), 1090 Wien, Austria.
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Jafarzadeh A, Jafarzadeh Z, Nemati M, Yoshimura A. The Interplay Between Helicobacter pylori and Suppressors of Cytokine Signaling (SOCS) Molecules in the Development of Gastric Cancer and Induction of Immune Response. Helicobacter 2024; 29:e13105. [PMID: 38924222 DOI: 10.1111/hel.13105] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/25/2024] [Revised: 06/04/2024] [Accepted: 06/06/2024] [Indexed: 06/28/2024]
Abstract
Helicobacter pylori (H. pylori) colonizes the stomach and leads to the secretion of a vast range of cytokines by infiltrated leukocytes directing immune/inflammatory response against the bacterium. To regulate immune/inflammatory responses, suppressors of cytokine signaling (SOCS) proteins bind to multiple signaling components located downstream of cytokine receptors, such as Janus kinase (JAK), signal transducers and activators of transcription (STAT). Dysfunctional SOCS proteins in immune cells may facilitate the immune evasion of H. pylori, allowing the bacteria to induce chronic inflammation. Dysregulation of SOCS expression and function can contribute to the sustained H. pylori-mediated gastric inflammation which can lead to gastric cancer (GC) development. Among SOCS molecules, dysregulated expression of SOCS1, SOCS2, SOCS3, and SOCS6 were indicated in H. pylori-infected individuals as well as in GC tissues and cells. H. pylori-induced SOCS1, SOCS2, SOCS3, and SOCS6 dysregulation can contribute to the GC development. The expression of SOCS molecules can be influenced by various factors, such as epigenetic DNA methylation, noncoding RNAs, and gene polymorphisms. Modulation of the expression of SOCS molecules in gastric epithelial cells and immune cells can be considered to control gastric carcinogenesis as well as regulate antitumor immune responses, respectively. This review aimed to explain the interplay between H. pylori and SOCS molecules in GC development and immune response induction as well as to provide insights regarding potential therapeutic strategies modulating SOCS molecules.
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Affiliation(s)
- Abdollah Jafarzadeh
- Department of Immunology, School of Medicine, Kerman University of Medical Sciences, Kerman, Iran
- Applied Cellular and Molecular Research Center, Kerman University of Medical Sciences, Kerman, Iran
| | - Zahra Jafarzadeh
- Student Research Committee, Faculty of Pharmacy, Kerman University of Medical Sciences, Kerman, Iran
| | - Maryam Nemati
- Department of Hematology and Laboratory Sciences, School of Para-Medicine, Kerman University of Medical Sciences, Kerman, Iran
- Immunology of Infectious Diseases Research Center, Research Institute of Basic Medical Sciences, Rafsanjan University of Medical Sciences, Rafsanjan, Iran
| | - Akihiko Yoshimura
- Department of Microbiology and Immunology, Keio University School of Medicine, Tokyo, Japan
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Yamaguchi N, Sakaguchi T, Taira M, Fukuda D, Ohnita K, Hirayama T, Yashima K, Isomoto H, Tsukamoto K. Autophagy-Related Gene ATG7 Polymorphism Could Potentially Serve as a Biomarker of the Progression of Atrophic Gastritis. J Clin Med 2024; 13:629. [PMID: 38276136 PMCID: PMC10817077 DOI: 10.3390/jcm13020629] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2023] [Revised: 01/09/2024] [Accepted: 01/19/2024] [Indexed: 01/27/2024] Open
Abstract
Cytotoxin-associated gene A (CagA) is an oncoprotein that H. pylori injects into the host's gastric epithelial cells and that induces proinflammatory cytokines, such as interleukin (IL)-18 and IL-1β. As a result, it leads to atrophic gastritis (AG), a precancerous lesion of gastric cancer. On the other hand, host cells degrade CagA using autophagy systems. However, few studies exist about the single nucleotide polymorphisms (SNPs) in MAP1LC3A, MAP1LC3B, ATG4A, ATG4B, ATG4C, ATG7, and ATG13, which belong to the autophagy-related genes concerning AG. This study aimed to detect biomarkers associated with AG. Herein, H. pylori-positive subjects (n = 200) were divided into the AG (n = 94) and non-AG (n = 106) groups. Thirty tag SNPs were selected from the above seven candidate genes. The SNP frequency between the two groups was analyzed. The frequency of the C/T or T/T genotype at rs4683787 of ATG7 was significantly lower in the AG group than in the non-AG group (p = 0.034, odds ratio = 0.535). Based on multivariate analysis, the C/C genotype of rs4684787 and age were independently associated with gastric mucosal atrophy. This finding helps stratify the patients needing timely endoscopic screening or early eradication of H. pylori.
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Affiliation(s)
- Naoyuki Yamaguchi
- Department of Gastroenterology and Hepatology, Nagasaki University Graduate School of Biological Sciences, 1-7-1 Sakamoto, Nagasaki 852-8501, Japan
| | - Takuki Sakaguchi
- Department of Gastroenterology and Nephrology, Faculty of Medicine, Tottori University, 36-1 Nishi-cho, Yonago 683-8504, Japan
| | - Miki Taira
- Department of Pharmacotherapeutics, Nagasaki University Graduate School of Biomedical Sciences, 1-7-1 Sakamoto, Nagasaki 852-8501, Japan
| | - Daisuke Fukuda
- Department of Gastroenterology and Hepatology, Nagasaki University Graduate School of Biological Sciences, 1-7-1 Sakamoto, Nagasaki 852-8501, Japan
- Department of Surgical Oncology, Nagasaki University Graduate School of Biological Science, 1-7-1 Sakamoto, Nagasaki 852-8501, Japan
- Fukuda Yutaka Clinic, 3-5 Hamaguchi-machi, Nagasaki 852-8107, Japan
| | - Ken Ohnita
- Department of Gastroenterology and Hepatology, Nagasaki University Graduate School of Biological Sciences, 1-7-1 Sakamoto, Nagasaki 852-8501, Japan
- Shunkaikai Inoue Hospital, 6-12 Takara-machi, Nagasaki 850-0045, Japan
| | - Tatsuro Hirayama
- Department of Pharmacotherapeutics, Nagasaki University Graduate School of Biomedical Sciences, 1-7-1 Sakamoto, Nagasaki 852-8501, Japan
| | - Kazuo Yashima
- Department of Gastroenterology and Nephrology, Faculty of Medicine, Tottori University, 36-1 Nishi-cho, Yonago 683-8504, Japan
| | - Hajime Isomoto
- Department of Gastroenterology and Hepatology, Nagasaki University Graduate School of Biological Sciences, 1-7-1 Sakamoto, Nagasaki 852-8501, Japan
- Department of Gastroenterology and Nephrology, Faculty of Medicine, Tottori University, 36-1 Nishi-cho, Yonago 683-8504, Japan
| | - Kazuhiro Tsukamoto
- Department of Pharmacotherapeutics, Nagasaki University Graduate School of Biomedical Sciences, 1-7-1 Sakamoto, Nagasaki 852-8501, Japan
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Zhou Y, Yu S, Zhang W. NOD-like Receptor Signaling Pathway in Gastrointestinal Inflammatory Diseases and Cancers. Int J Mol Sci 2023; 24:14511. [PMID: 37833958 PMCID: PMC10572711 DOI: 10.3390/ijms241914511] [Citation(s) in RCA: 13] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2023] [Revised: 09/15/2023] [Accepted: 09/23/2023] [Indexed: 10/15/2023] Open
Abstract
Nucleotide-binding and oligomerization domain (NOD)-like receptors (NLRs) are intracellular proteins with a central role in innate and adaptive immunity. As a member of pattern recognition receptors (PRRs), NLRs sense specific pathogen-associated molecular patterns, trigger numerous signaling pathways and lead to the secretion of various cytokines. In recent years, cumulative studies have revealed the significant impacts of NLRs in gastrointestinal (GI) inflammatory diseases and cancers. Deciphering the role and molecular mechanism of the NLR signaling pathways may provide new opportunities for the development of therapeutic strategies related to GI inflammatory diseases and GI cancers. This review presents the structures and signaling pathways of NLRs, summarizes the recent advances regarding NLR signaling in GI inflammatory diseases and GI cancers and describes comprehensive therapeutic strategies based on this signaling pathway.
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Affiliation(s)
- Yujie Zhou
- School of Medicine, Southern University of Science and Technology, Shenzhen 518055, China; (Y.Z.); (S.Y.)
| | - Songyan Yu
- School of Medicine, Southern University of Science and Technology, Shenzhen 518055, China; (Y.Z.); (S.Y.)
| | - Wenyong Zhang
- School of Medicine, Southern University of Science and Technology, Shenzhen 518055, China; (Y.Z.); (S.Y.)
- Key University Laboratory of Metabolism and Health of Guangdong, Southern University of Science and Technology, Shenzhen 518055, China
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Yamaguchi N, Sakaguchi T, Isomoto H, Inamine T, Ueda H, Fukuda D, Ohnita K, Kanda T, Kurumi H, Matsushima K, Hirayama T, Yashima K, Tsukamoto K. ATG16L1 and ATG12 Gene Polymorphisms Are Involved in the Progression of Atrophic Gastritis. J Clin Med 2023; 12:5384. [PMID: 37629426 PMCID: PMC10455120 DOI: 10.3390/jcm12165384] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2023] [Revised: 08/08/2023] [Accepted: 08/17/2023] [Indexed: 08/27/2023] Open
Abstract
Helicobacter pylori (H. pylori) infection causes a progression to atrophic gastritis and results in gastric cancer. Cytotoxin-associated gene A (CagA), a major virulence factor of H. pylori, is injected into gastric epithelial cells using the type IV secretion system. On the other hand, gastric epithelial cells degrade CagA using an autophagy system, which is strictly regulated by the autophagy-related (ATG) genes. This study aimed to identify SNPs in ATG5, ATG10, ATG12, and ATG16L1 associated with gastric mucosal atrophy (GMA). Here, two-hundred H. pylori-positive participants without gastric cancer were included. The degree of GMA was evaluated via the pepsinogen method. Twenty-five SNPs located in the four candidate genes were selected as tag SNPs. The frequency of each SNP between the GMA and the non-GMA group was evaluated. The rs6431655, rs6431659, and rs4663136 in ATG16L1 and rs26537 in ATG12 were independently associated with GMA. Of these four SNPs, the G/G genotype of rs6431659 in ATG16L1 has the highest odd ratio (Odds ratio = 3.835, 95% confidence intervals = 1.337-1.005, p = 0.008). Further functional analyses and prospective analyses with a larger sample size are required.
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Affiliation(s)
- Naoyuki Yamaguchi
- Department of Gastroenterology and Hepatology, Nagasaki University Graduate School of Biological Sciences, 1-7-1 Sakamoto, Nagasaki 852-8501, Japan
| | - Takuki Sakaguchi
- Department of Gastroenterology and Nephrology, Faculty of Medicine, Tottori University, 36-1 Nishi-cho, Yonago 683-8504, Japan
| | - Hajime Isomoto
- Department of Gastroenterology and Hepatology, Nagasaki University Graduate School of Biological Sciences, 1-7-1 Sakamoto, Nagasaki 852-8501, Japan
- Department of Gastroenterology and Nephrology, Faculty of Medicine, Tottori University, 36-1 Nishi-cho, Yonago 683-8504, Japan
| | - Tatsuo Inamine
- Department of Pharmacotherapeutics, Nagasaki University Graduate School of Biomedical Sciences, 1-7-1 Sakamoto, Nagasaki 852-8501, Japan
| | - Haruka Ueda
- Department of Pharmacotherapeutics, Nagasaki University Graduate School of Biomedical Sciences, 1-7-1 Sakamoto, Nagasaki 852-8501, Japan
| | - Daisuke Fukuda
- Department of Gastroenterology and Hepatology, Nagasaki University Graduate School of Biological Sciences, 1-7-1 Sakamoto, Nagasaki 852-8501, Japan
- Department of Surgical Oncology, Nagasaki University Graduate School of Biological Science, 1-7-1 Sakamoto, Nagasaki 852-8501, Japan
- Fukuda Yutaka Clinic, 3-5 Hamaguchi-machi, Nagasaki 852-8107, Japan
| | - Ken Ohnita
- Department of Gastroenterology and Hepatology, Nagasaki University Graduate School of Biological Sciences, 1-7-1 Sakamoto, Nagasaki 852-8501, Japan
- Shunkaikai Inoue Hospital, 6-12 Takara-machi, Nagasaki 850-0045, Japan
| | - Tsutomu Kanda
- Department of Gastroenterology and Hepatology, Nagasaki University Graduate School of Biological Sciences, 1-7-1 Sakamoto, Nagasaki 852-8501, Japan
- Department of Gastroenterology and Nephrology, Faculty of Medicine, Tottori University, 36-1 Nishi-cho, Yonago 683-8504, Japan
| | - Hiroki Kurumi
- Department of Gastroenterology and Nephrology, Faculty of Medicine, Tottori University, 36-1 Nishi-cho, Yonago 683-8504, Japan
| | - Kayoko Matsushima
- Department of Gastroenterology and Hepatology, Nagasaki University Graduate School of Biological Sciences, 1-7-1 Sakamoto, Nagasaki 852-8501, Japan
| | - Tatsuro Hirayama
- Department of Pharmacotherapeutics, Nagasaki University Graduate School of Biomedical Sciences, 1-7-1 Sakamoto, Nagasaki 852-8501, Japan
| | - Kazuo Yashima
- Department of Gastroenterology and Nephrology, Faculty of Medicine, Tottori University, 36-1 Nishi-cho, Yonago 683-8504, Japan
| | - Kazuhiro Tsukamoto
- Department of Pharmacotherapeutics, Nagasaki University Graduate School of Biomedical Sciences, 1-7-1 Sakamoto, Nagasaki 852-8501, Japan
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6
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Li L, Wang S, Wang W. Knockdown of ELF4 aggravates renal injury in ischemia/reperfusion mice through promotion of pyroptosis, inflammation, oxidative stress, and endoplasmic reticulum stress. BMC Mol Cell Biol 2023; 24:22. [PMID: 37474923 PMCID: PMC10360327 DOI: 10.1186/s12860-023-00485-2] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2023] [Accepted: 07/13/2023] [Indexed: 07/22/2023] Open
Abstract
BACKGROUND Renal ischemia/reperfusion (I/R) injury is a major cause of acute kidney injury (AKI). Dysfunction of E74-like ETS transcription factor 4 (ELF4) leads to inflammation. This research intended to look into the function and mechanisms of ELF4 in I/R and oxygen-glucose deprivation/reperfusion (OGD/R) model. RESULTS In I/R and OGD/R model, ELF4 expression was downregulated. ELF4 knockout aggravated I/R-induced kidney injury, oxidative stress (OS), endoplasmic reticulum stress (ERS), apoptosis, inflammation, and pyroptosis in mice. In HK-2 cells treated with OGD/R, suppression of ELF4 expression inhibited cell proliferation and promoted cell apoptosis, OS, ERS, inflammation, and pyroptosis. Moreover, ELF4 overexpression led to the opposite results. CONCLUSION ELF4 deficiency aggravated I/R induced AKI, which was involved in apoptosis, OS, ERS, inflammation, and pyroptosis. Targeting ELF4 may be a promising new therapeutic strategy for preventing inflammation after IR-AKI.
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Affiliation(s)
- Li Li
- Department of Nephrology, Jinan City People's Hospital, No. 001, Changshao North Road, Laiwu District, Jinan, Shandong, 271199, People's Republic of China.
| | - Shunying Wang
- Department of Cadre Health Section, Jinan City People's Hospital, Jinan, Shandong, 271199, People's Republic of China
| | - Wenming Wang
- Department of Cadre Health Section, Jinan City People's Hospital, Jinan, Shandong, 271199, People's Republic of China
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Tran LS, Ying L, D'Costa K, Wray-McCann G, Kerr G, Le L, Allison CC, Ferrand J, Chaudhry H, Emery J, De Paoli A, Colon N, Creed S, Kaparakis-Liaskos M, Como J, Dowling JK, Johanesen PA, Kufer TA, Pedersen JS, Mansell A, Philpott DJ, Elgass KD, Abud HE, Nachbur U, Croker BA, Masters SL, Ferrero RL. NOD1 mediates interleukin-18 processing in epithelial cells responding to Helicobacter pylori infection in mice. Nat Commun 2023; 14:3804. [PMID: 37365163 DOI: 10.1038/s41467-023-39487-1] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2020] [Accepted: 06/15/2023] [Indexed: 06/28/2023] Open
Abstract
The interleukin-1 family members, IL-1β and IL-18, are processed into their biologically active forms by multi-protein complexes, known as inflammasomes. Although the inflammasome pathways that mediate IL-1β processing in myeloid cells have been defined, those involved in IL-18 processing, particularly in non-myeloid cells, are still not well understood. Here we report that the host defence molecule NOD1 regulates IL-18 processing in mouse epithelial cells in response to the mucosal pathogen, Helicobacter pylori. Specifically, NOD1 in epithelial cells mediates IL-18 processing and maturation via interactions with caspase-1, instead of the canonical inflammasome pathway involving RIPK2, NF-κB, NLRP3 and ASC. NOD1 activation and IL-18 then help maintain epithelial homoeostasis to mediate protection against pre-neoplastic changes induced by gastric H. pylori infection in vivo. Our findings thus demonstrate a function for NOD1 in epithelial cell production of bioactive IL-18 and protection against H. pylori-induced pathology.
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Affiliation(s)
- L S Tran
- Centre for Innate Immunity and Infectious Diseases, Hudson Institute of Medical Research, Melbourne, VIC, Australia
- Department of Molecular and Translational Science, Monash University, Melbourne, VIC, Australia
| | - L Ying
- Centre for Innate Immunity and Infectious Diseases, Hudson Institute of Medical Research, Melbourne, VIC, Australia
- Department of Molecular and Translational Science, Monash University, Melbourne, VIC, Australia
| | - K D'Costa
- Centre for Innate Immunity and Infectious Diseases, Hudson Institute of Medical Research, Melbourne, VIC, Australia
| | - G Wray-McCann
- Centre for Innate Immunity and Infectious Diseases, Hudson Institute of Medical Research, Melbourne, VIC, Australia
| | - G Kerr
- Department of Anatomy and Developmental Biology, Development and Stem Cells Program, Biomedicine Discovery Institute, Monash University, Melbourne, VIC, Australia
| | - L Le
- Centre for Innate Immunity and Infectious Diseases, Hudson Institute of Medical Research, Melbourne, VIC, Australia
- Department of Microbiology, Biomedicine Discovery Institute, Monash University, Melbourne, VIC, Australia
| | - C C Allison
- Centre for Innate Immunity and Infectious Diseases, Hudson Institute of Medical Research, Melbourne, VIC, Australia
| | - J Ferrand
- Centre for Innate Immunity and Infectious Diseases, Hudson Institute of Medical Research, Melbourne, VIC, Australia
| | - H Chaudhry
- Centre for Innate Immunity and Infectious Diseases, Hudson Institute of Medical Research, Melbourne, VIC, Australia
| | - J Emery
- Centre for Innate Immunity and Infectious Diseases, Hudson Institute of Medical Research, Melbourne, VIC, Australia
- Department of Molecular and Translational Science, Monash University, Melbourne, VIC, Australia
| | - A De Paoli
- Centre for Innate Immunity and Infectious Diseases, Hudson Institute of Medical Research, Melbourne, VIC, Australia
| | - N Colon
- Centre for Innate Immunity and Infectious Diseases, Hudson Institute of Medical Research, Melbourne, VIC, Australia
| | - S Creed
- Monash Micro Imaging, Monash University, Melbourne, VIC, Australia
| | - M Kaparakis-Liaskos
- Centre for Innate Immunity and Infectious Diseases, Hudson Institute of Medical Research, Melbourne, VIC, Australia
| | - J Como
- Centre for Innate Immunity and Infectious Diseases, Hudson Institute of Medical Research, Melbourne, VIC, Australia
| | - J K Dowling
- Centre for Innate Immunity and Infectious Diseases, Hudson Institute of Medical Research, Melbourne, VIC, Australia
| | - P A Johanesen
- Department of Microbiology, Biomedicine Discovery Institute, Monash University, Melbourne, VIC, Australia
| | - T A Kufer
- Department of Immunology, University of Hohenheim, Institute of Nutritional Medicine, Stuttgart, Germany
| | | | - A Mansell
- Centre for Innate Immunity and Infectious Diseases, Hudson Institute of Medical Research, Melbourne, VIC, Australia
- Department of Molecular and Translational Science, Monash University, Melbourne, VIC, Australia
| | - D J Philpott
- Department of Immunology, University of Toronto, Toronto, ON, Canada
| | - K D Elgass
- Monash Micro Imaging, Monash University, Melbourne, VIC, Australia
| | - H E Abud
- Department of Anatomy and Developmental Biology, Development and Stem Cells Program, Biomedicine Discovery Institute, Monash University, Melbourne, VIC, Australia
| | - U Nachbur
- Cell Signalling and Cell Death Division, WEHI, Melbourne, VIC, Australia
| | - B A Croker
- Boston Children's Hospital, Harvard Medical School, Boston, MA, USA
- Inflammation Division, WEHI, Melbourne, VIC, Australia
| | - S L Masters
- Inflammation Division, WEHI, Melbourne, VIC, Australia
| | - R L Ferrero
- Centre for Innate Immunity and Infectious Diseases, Hudson Institute of Medical Research, Melbourne, VIC, Australia.
- Department of Microbiology, Biomedicine Discovery Institute, Monash University, Melbourne, VIC, Australia.
- Inflammation Division, WEHI, Melbourne, VIC, Australia.
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8
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Yamaguchi N, Sakaguchi T, Isomoto H, Inamine T, Tsukamoto R, Fukuda D, Ohnita K, Kanda T, Matsushima K, Hirayama T, Yashima K, Tsukamoto K. Polymorphism in autophagy-related genes LRP1 and CAPZA1 may promote gastric mucosal atrophy. Genes Environ 2023; 45:18. [PMID: 37198664 DOI: 10.1186/s41021-023-00274-5] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2023] [Accepted: 04/27/2023] [Indexed: 05/19/2023] Open
Abstract
BACKGROUND Helicobacter pylori secretes cytotoxin-associated gene A (CagA) into the gastric epithelium, causing gastric mucosal atrophy (GMA) and gastric cancer. In contrast, host cells degrade CagA via autophagy. However, the association between polymorphisms in autophagy-related genes and GMA must be fully elucidated. RESULTS We evaluated the association between single nucleotide polymorphisms (SNPs) in autophagy-related genes (low-density lipoprotein receptor-related protein 1, LRP1; capping actin protein of muscle Z-line alpha subunit 1, CAPAZ1; and lysosomal-associated membrane protein 1, LAMP1) and GMA in 200 H. pylori-positive individuals. The frequency of the T/T genotype at rs1800137 in LRP1 was significantly lower in the GMA group than in the non-GMA group (p = 0.018, odds ratio [OR] = 0.188). The frequencies of the G/A or A/A genotype at rs4423118 and T/A or A/A genotype at rs58618380 of CAPAZ1 in the GMA group were significantly higher than those in the non-GMA group (p = 0.029 and p = 0.027, respectively). Multivariate analysis revealed that C/C or C/T genotype at rs1800137, T/A or A/A genotype at rs58618380, and age were independent risk factors for GMA (p = 0.038, p = 0.023, and p = 0.006, respectively). Furthermore, individuals with the rs1800137 C/C or C/T genotype of LRP1 had a 5.3-fold higher susceptibility to GMA. These genetic tests may provide future directions for precision medicine for individuals more likely to develop GMA. CONCLUSION LRP1 and CAPZA1 polymorphisms may be associated with the development of GMA.
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Affiliation(s)
- Naoyuki Yamaguchi
- Department of Gastroenterology and Hepatology, Nagasaki University Graduate School of Biological Sciences, 1-7-1 Sakamoto, Nagasaki, 852-8501, Japan
| | - Takuki Sakaguchi
- Department of Gastroenterology and Nephrology, Faculty of Medicine, Tottori University, 36-1 Nishi-Cho, Yonago, 683-8504, Japan.
| | - Hajime Isomoto
- Department of Gastroenterology and Hepatology, Nagasaki University Graduate School of Biological Sciences, 1-7-1 Sakamoto, Nagasaki, 852-8501, Japan.
- Department of Gastroenterology and Nephrology, Faculty of Medicine, Tottori University, 36-1 Nishi-Cho, Yonago, 683-8504, Japan.
| | - Tatsuo Inamine
- Department of Pharmacotherapeutics, Nagasaki University Graduate School of Biomedical Sciences, 1-7-1 Sakamoto, Nagasaki, 852-8501, Japan
| | - Ryoya Tsukamoto
- Department of Pharmacotherapeutics, Nagasaki University Graduate School of Biomedical Sciences, 1-7-1 Sakamoto, Nagasaki, 852-8501, Japan
| | - Daisuke Fukuda
- Department of Gastroenterology and Hepatology, Nagasaki University Graduate School of Biological Sciences, 1-7-1 Sakamoto, Nagasaki, 852-8501, Japan
- Department of Surgical Oncology, Nagasaki University Graduate School of Biological Sciences, 1-7-1 Sakamoto, Nagasaki, 852-8501, Japan
- Fukuda Yutaka Clinic, 3-5 Hamaguchi-machi, Nagasaki, 852-8107, Japan
| | - Ken Ohnita
- Department of Gastroenterology and Hepatology, Nagasaki University Graduate School of Biological Sciences, 1-7-1 Sakamoto, Nagasaki, 852-8501, Japan
- Shunkaikai Inoue Hospital, 6-12 Takara-machi, Nagasaki, 850-0045, Japan
| | - Tsutomu Kanda
- Department of Gastroenterology and Hepatology, Nagasaki University Graduate School of Biological Sciences, 1-7-1 Sakamoto, Nagasaki, 852-8501, Japan
- Department of Gastroenterology and Nephrology, Faculty of Medicine, Tottori University, 36-1 Nishi-Cho, Yonago, 683-8504, Japan
| | - Kayoko Matsushima
- Department of Gastroenterology and Hepatology, Nagasaki University Graduate School of Biological Sciences, 1-7-1 Sakamoto, Nagasaki, 852-8501, Japan
| | - Tatsuro Hirayama
- Department of Pharmacotherapeutics, Nagasaki University Graduate School of Biomedical Sciences, 1-7-1 Sakamoto, Nagasaki, 852-8501, Japan
| | - Kazuo Yashima
- Department of Gastroenterology and Nephrology, Faculty of Medicine, Tottori University, 36-1 Nishi-Cho, Yonago, 683-8504, Japan
| | - Kazuhiro Tsukamoto
- Department of Pharmacotherapeutics, Nagasaki University Graduate School of Biomedical Sciences, 1-7-1 Sakamoto, Nagasaki, 852-8501, Japan
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9
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Zhang Y, Zhang Y, Yang A, Xia F. Downregulation of IRF2 Alleviates Sepsis-Related Acute Kidney Injury in vitro and in vivo. Drug Des Devel Ther 2022; 15:5123-5132. [PMID: 34992348 PMCID: PMC8710674 DOI: 10.2147/dddt.s334518] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2021] [Accepted: 11/25/2021] [Indexed: 01/20/2023] Open
Abstract
Objective We investigated the roles and mechanisms of IRF2 in sepsis-related acute kidney injury (S-AKI) in a lipopolysaccharide (LPS)-induced HK-2 cell line and caecal ligation and puncture (CLP)-induced IRF2−/− mouse model. Methods Quantitative real-time polymerase chain reaction assay was used to detect IRF2 in the serum of S-AKI patients and LPS-induced HK-2 cells. Cell proliferation, death, and apoptosis were analysed by CCK-8, lactate dehydrogenase release, and flow cytometry assays, respectively. The levels of interleukin (IL)-1β, IL-18, IL-6, tumour necrosis factor (TNF)-α, non-canonical inflammasomes, including caspase-4 and gasdermin-D (GSDMD), and canonical inflammasomes, such as caspase-1, NLR family pyrin domain containing 3 (NLRP3), and apoptosis-associated speck-like protein (ASC) in S-AKI cells or animal models were analysed by enzyme-linked immunosorbent assay or Western blotting. Results IRF2 was upregulated in the serum of S-AKI patients and LPS-induced HK-2 cells. IRF2 downregulation promoted cell proliferation and inhibited cell death and apoptosis, respectively. IRF2 inhibition reduced the levels of IL-1β, IL-18, IL-6, and TNF-α in S-AKI cells and animal models. IRF2 knockdown inhibited LPS-treated HK-2 cell pyroptosis by decreasing the expression of caspase-4 and GSDMD, instead of affecting caspase-1, NLRP3, and ASC. An elevated survival rate and alleviated pathological features and scores were observed in the CLP-induced IRF2−/− animal models. IRF2 deficiency also suppressed inflammation and pyroptosis by inhibiting non-canonical inflammasomes as indicated by the decreased expression of caspase-11 and GSDMD. Conclusion Our findings suggest that IRF2 downregulation protects against S-AKI in vitro and in vivo.
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Affiliation(s)
- Yanyan Zhang
- Department of Critical Care Medicine, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou, 215008, Jiangsu, People's Republic of China
| | - Yun Zhang
- Department of Critical Care Medicine, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou, 215008, Jiangsu, People's Republic of China
| | - Aixiang Yang
- Department of Critical Care Medicine, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou, 215008, Jiangsu, People's Republic of China
| | - Fei Xia
- Department of Critical Care Medicine, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou, 215008, Jiangsu, People's Republic of China
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10
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Churchill MJ, Mitchell PS, Rauch I. Epithelial Pyroptosis in Host Defense. J Mol Biol 2022; 434:167278. [PMID: 34627788 PMCID: PMC10010195 DOI: 10.1016/j.jmb.2021.167278] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2021] [Revised: 09/17/2021] [Accepted: 09/25/2021] [Indexed: 12/28/2022]
Abstract
Pyroptosis is a lytic form of cell death that is executed by a family of pore-forming proteins called gasdermins (GSDMs). GSDMs are activated upon proteolysis by host proteases including the proinflammatory caspases downstream of inflammasome activation. In myeloid cells, GSDM pore formation serves two primary functions in host defense: the selective release of processed cytokines to initiate inflammatory responses, and cell death, which eliminates a replicative niche of the pathogen. Barrier epithelia also undergo pyroptosis. However, unique mechanisms are required for the removal of pyroptotic epithelial cells to maintain epithelial barrier integrity. In the following review, we discuss the role of epithelial inflammasomes and pyroptosis in host defense against pathogens. We use the well-established role of inflammasomes in intestinal epithelia to highlight principles of epithelial pyroptosis in host defense of barrier tissues, and discuss how these principles might be shared or distinctive across other epithelial sites.
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Affiliation(s)
- Madeline J Churchill
- Department of Molecular Microbiology & Immunology, Oregon Health and Science University, Portland, OR, USA
| | | | - Isabella Rauch
- Department of Molecular Microbiology & Immunology, Oregon Health and Science University, Portland, OR, USA.
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11
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Mommersteeg M, Simovic I, Yu B, van Nieuwenburg S, Bruno IM, Doukas M, Kuipers E, Spaander M, Peppelenbosch M, Castaño-Rodríguez N, Fuhler G. Autophagy mediates ER stress and inflammation in Helicobacter pylori-related gastric cancer. Gut Microbes 2022; 14:2015238. [PMID: 34965181 PMCID: PMC8726742 DOI: 10.1080/19490976.2021.2015238] [Citation(s) in RCA: 39] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023] Open
Abstract
Autophagy is a cellular degradation mechanism, which is triggered by the bacterium Helicobacter pylori. A single nucleotide polymorphism (SNP) in the autophagy gene ATG16L1 (rs2241880, G-allele) has been shown to dysregulate autophagy and increase intestinal endoplasmic reticulum (ER) stress. Here, we investigate the role of this SNP in H.pylori-mediated gastric carcinogenesis and its molecular pathways. ATG16L1 rs2241880 was genotyped in subjects from different ethnic cohorts (Dutch and Australian) presenting with gastric (pre)malignant lesions of various severity. Expression of GRP78 (a marker for ER stress) was assessed in gastric tissues. The effect of ATG16L1 rs2241880 on H.pylori-mediated ER stress and pro-inflammatory cytokine induction was investigated in organoids and CRISPR/Cas9 modified cell lines. Development of gastric cancer was associated with the ATG16L1 rs2241880 G-allele. Intestinal metaplastic cells in gastric tissue of patients showed increased levels of ER-stress. In vitro models showed that H.pylori increases autophagy while reducing ER stress, which appeared partly mediated by the ATG16L1 rs2241880 genotype. H.pylori-induced IL-8 production was increased while TNF-α production was decreased, in cells homozygous for the G-allele. The ATG16L1 rs2241880 G-allele is associated with progression of gastric premalignant lesions and cancer. Modulation of H.pylori-induced ER stress pathways and pro-inflammatory mediators by ATG16L1 rs2441880 may underlie this increased risk.
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Affiliation(s)
- M.C. Mommersteeg
- Department of Gastroenterology and Hepatology, Erasmus University Medical Center, Rotterdam, The Netherlands
| | - I. Simovic
- School of Biotechnology and Biomolecular Sciences, Unsw, Sydney, Australia
| | - B. Yu
- Department of Gastroenterology and Hepatology, Erasmus University Medical Center, Rotterdam, The Netherlands
| | - S.A.V. van Nieuwenburg
- Department of Gastroenterology and Hepatology, Erasmus University Medical Center, Rotterdam, The Netherlands
| | - I, M.J. Bruno
- Department of Gastroenterology and Hepatology, Erasmus University Medical Center, Rotterdam, The Netherlands
| | - M. Doukas
- Department of Pathology, Erasmus University Medical Center, Rotterdam, Netherlands
| | - E.J. Kuipers
- Department of Gastroenterology and Hepatology, Erasmus University Medical Center, Rotterdam, The Netherlands
| | - M.C.W. Spaander
- Department of Gastroenterology and Hepatology, Erasmus University Medical Center, Rotterdam, The Netherlands
| | - M.P. Peppelenbosch
- Department of Gastroenterology and Hepatology, Erasmus University Medical Center, Rotterdam, The Netherlands
| | - N. Castaño-Rodríguez
- School of Biotechnology and Biomolecular Sciences, Unsw, Sydney, Australia,CONTACT N. Castaño-Rodríguez School of Biotechnology and Biomolecular Sciences, UNSW Sydney, NSW 2052, Australia
| | - G.M. Fuhler
- Department of Gastroenterology and Hepatology, Erasmus University Medical Center, Rotterdam, The Netherlands,G.M. Fuhler PhD Department of Gastroenterology and Hepatology, Erasmus University Medical Center, Unsw, Rotterdam, The Netherlands
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12
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Tilahun M, Gedefie A, Belayhun C, Sahle Z, Abera A. Helicobacter pylori Pathogenicity Islands and Giardia lamblia Cysteine Proteases in Role of Coinfection and Pathogenesis. Infect Drug Resist 2022; 15:21-34. [PMID: 35023934 PMCID: PMC8747529 DOI: 10.2147/idr.s346705] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2021] [Accepted: 12/21/2021] [Indexed: 12/18/2022] Open
Abstract
Helicobacter pylori is a well-known human-specific stomach pathogen that infects more than half of the world’s population. The infection with this bacterium can cause a variety of gastrointestinal problems, including chronic gastritis, peptic ulcers, and even cancer. H. pylori is a highly infectious bacterium. H. pylori causes an increase in gastric mucosa pH or gastric mucosa intestinal metaplasia. These modifications in the stomach environment are necessary for G. lamblia colonization to occur. Giardia lamblia is a flagellate protozoan parasite that can cause giardiasis in humans and other mammals. It dwells in the duodenum and upper jejunum. Globally, over 280 million cases of human giardiasis are predicted to occur each year. Simultaneous human colonization by G. lamblia and H. pylori is a typical occurrence since the viruses’ predisposing factors are similar in both groups. Giardiasis is a parasitic infection that affects both children and adults worldwide. Infection with Giardia is more common in underdeveloped countries. Globally, more than 200 million cases of giardiasis are detected each year. In contrast, the presence of G. lamblia in the host body triggers an immunological response comparable to that of H. pylori, with lymphocytes strongly polarized towards Th1. As a result, their combined presence exacerbates host tissue damage. The major goal of this seminar is to describe the pathophysiology, immunology, and clinical aspects of G. lamblia and H. pylori coinfection using a comprehensive search of PubMed, Lancet, and Google Scholar sources. Upper gastrointestinal problems such as upper abdominal pain, abdominal bloating, nausea, vomiting, epigastric pain/burning, and belching are all caused by both organisms. Differentiation by physical examination is impossible in people infected with both bacteria. For this coinfection distinction, a laboratory diagnosis is required. G. lamblia and H. pylori, when present together, have a synergistic effect on the host and can cause serious damage. As a result, researchers should delve deeper into the mechanics underlying this potential microbial interaction.
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Affiliation(s)
- Mihret Tilahun
- Department of Medical Laboratory Sciences, College of Medicine and Health Science, Wollo University, Dessie, Ethiopia
| | - Alemu Gedefie
- Department of Medical Laboratory Sciences, College of Medicine and Health Science, Wollo University, Dessie, Ethiopia
| | - Chernet Belayhun
- Department of Medical Laboratory Science, Mehal Meda Hospital, North Showa, Ethiopia
| | - Zenawork Sahle
- Department of Medical Laboratory Science, Debre Birhan Health Science College, North Showa, Ethiopia
| | - Admasu Abera
- Department of Medical Laboratory Science, Debre Birhan Health Science College, North Showa, Ethiopia
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13
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Yan ZB, Zhang JY, Lv YP, Tian WQ, Shan ZG, Mao FY, Liu YG, Chen WY, Wang P, Yang Y, Cheng P, Peng LS, Liao YL, Yue GY, Xu XL, Zhao YL, Lü MH, Zhuang Y. Helicobacter pylori-induced REDD1 modulates Th17 cell responses that contribute to gastritis. Clin Sci (Lond) 2021; 135:2541-2558. [PMID: 34730176 DOI: 10.1042/cs20210753] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2021] [Revised: 10/21/2021] [Accepted: 11/03/2021] [Indexed: 12/29/2022]
Abstract
OBJECTIVE Regulated in development and DNA damage responses-1 (REDD1) is a conserved and ubiquitous protein, which is induced in response to multiple stimuli. However, the regulation, function and clinical relevance of REDD1 in Helicobacter pylori-associated gastritis are presently unknown. APPROACH Immunohistochemistry, real-time PCR and Western blot analyses were performed to examine the levels of REDD1 in gastric samples from H. pylori-infected patients and mice. Gastric tissues from Redd1-/- and wildtype (WT, control) mice were examined for inflammation. Gastric epithelial cells (GECs), monocytes and T cells were isolated, stimulated and/or cultured for REDD1 regulation and functional assays. RESULTS REDD1 was increased in gastric mucosa of H. pylori-infected patients and mice. H. pylori induced GECs to express REDD1 via the phosphorylated cytotoxin associated gene A (cagA) that activated MAPKp38 pathway to mediate NF-κB directly binding to REDD1 promoter. Human gastric REDD1 increased with the severity of gastritis, and mouse REDD1 from non-marrow chimera-derived cells promoted gastric inflammation that was characterized by the influx of MHCII+ monocytes. Importantly, gastric inflammation, MHCII+ monocyte infiltration, IL-23 and IL-17A were attenuated in Redd1-/- mice. Mechanistically, REDD1 in GECs regulated CXCL1 production, which attracted MHCII+ monocytes migration by CXCL1-CXCR2 axis. Then H. pylori induced MHCII+ monocytes to secrete IL-23, which favored IL-17A-producing CD4+ cell (Th17 cell) polarization, thereby contributing to the development of H. pylori-associated gastritis. CONCLUSIONS The present study identifies a novel regulatory network involving REDD1, which collectively exert a pro-inflammatory effect within gastric microenvironment. Efforts to inhibit this REDD1-dependent pathway may prove valuable strategies in treating of H. pylori-associated gastritis.
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Affiliation(s)
- Zong-Bao Yan
- Department of General Surgery and Center of Minimal Invasive Gastrointestinal Surgery, Southwest Hospital, Third Military Medical University, Chongqing, China
| | - Jin-Yu Zhang
- National Engineering Research Center of Immunological Products, Department of Microbiology and Biochemical Pharmacy, College of Pharmacy and Laboratory Medicine, Third Military Medical University, Chongqing, China
| | - Yi-Pin Lv
- Department of Digestive Diseases, General Hospital of Western Theater Command, Chengdu, Sichuan, China
| | - Wen-Qing Tian
- Department of Endocrinology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Zhi-Guo Shan
- Department of General Surgery and Center of Minimal Invasive Gastrointestinal Surgery, Southwest Hospital, Third Military Medical University, Chongqing, China
| | - Fang-Yuan Mao
- National Engineering Research Center of Immunological Products, Department of Microbiology and Biochemical Pharmacy, College of Pharmacy and Laboratory Medicine, Third Military Medical University, Chongqing, China
| | - Yu-Gang Liu
- National Engineering Research Center of Immunological Products, Department of Microbiology and Biochemical Pharmacy, College of Pharmacy and Laboratory Medicine, Third Military Medical University, Chongqing, China
| | - Wan-Yan Chen
- National Engineering Research Center of Immunological Products, Department of Microbiology and Biochemical Pharmacy, College of Pharmacy and Laboratory Medicine, Third Military Medical University, Chongqing, China
| | - Pan Wang
- National Engineering Research Center of Immunological Products, Department of Microbiology and Biochemical Pharmacy, College of Pharmacy and Laboratory Medicine, Third Military Medical University, Chongqing, China
| | - Yun Yang
- National Engineering Research Center of Immunological Products, Department of Microbiology and Biochemical Pharmacy, College of Pharmacy and Laboratory Medicine, Third Military Medical University, Chongqing, China
| | - Ping Cheng
- National Engineering Research Center of Immunological Products, Department of Microbiology and Biochemical Pharmacy, College of Pharmacy and Laboratory Medicine, Third Military Medical University, Chongqing, China
| | - Liu-Sheng Peng
- National Engineering Research Center of Immunological Products, Department of Microbiology and Biochemical Pharmacy, College of Pharmacy and Laboratory Medicine, Third Military Medical University, Chongqing, China
| | - Ya-Ling Liao
- National Engineering Research Center of Immunological Products, Department of Microbiology and Biochemical Pharmacy, College of Pharmacy and Laboratory Medicine, Third Military Medical University, Chongqing, China
| | - Geng-Yu Yue
- Department of Gastroenterology, The Affiliated Hospital of Zunyi Medical University, Zunyi, Guizhou, China
| | - Xiao-Lin Xu
- Department of Gastroenterology, The Affiliated Hospital of Zunyi Medical University, Zunyi, Guizhou, China
| | - Yong-Liang Zhao
- Department of General Surgery and Center of Minimal Invasive Gastrointestinal Surgery, Southwest Hospital, Third Military Medical University, Chongqing, China
| | | | - Yuan Zhuang
- National Engineering Research Center of Immunological Products, Department of Microbiology and Biochemical Pharmacy, College of Pharmacy and Laboratory Medicine, Third Military Medical University, Chongqing, China
- Department of Gastroenterology, The Affiliated Hospital of Zunyi Medical University, Zunyi, Guizhou, China
- Department of Gastroenterology, Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan, China
- Department of Gastroenterology, Southwest Hospital, Third Military Medical University, Chongqing, China
- Jiangsu Key Laboratory of Medical Science and Laboratory Medicine, School of Medicine, Jiangsu University, Jiangsu, China
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14
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Chen LJ, Zhi X, Zhang KK, Wang LB, Li JH, Liu JL, Xu LL, Yoshida JS, Xie XL, Wang Q. Escalating dose-multiple binge methamphetamine treatment elicits neurotoxicity, altering gut microbiota and fecal metabolites in mice. Food Chem Toxicol 2021; 148:111946. [PMID: 33359793 DOI: 10.1016/j.fct.2020.111946] [Citation(s) in RCA: 44] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2020] [Revised: 11/30/2020] [Accepted: 12/18/2020] [Indexed: 02/06/2023]
Abstract
Methamphetamine (METH) is an addictive and illegal psychostimulant drug that can cause multiple organ dysfunction, especially in the central nervous system (CNS). Gut microbiota have been implicated in development of various CNS-related diseases, via the gut-brain axis (GBA). However, effect of METH in the alteration of gut microbiota and fecal metabolites is unclear, whereas the relationship with METH-induced neurotoxicity remains unknown. In the current study, we investigated effect of METH on neurotoxicity in striatum and colonic damage by exposing BALB/c mice to an escalating dose-multiple binge regimen, and then analyzed protein expression using Western blot analysis. We further detected and sequenced the 16 S rRNA gene in fecal samples, and performed ultra-high-performance liquid chromatography-mass spectrometry (UHPLC-MS)-based metabolomics to analyze gut microbes and fecal metabolites. Exposure to METH significantly downregulated tyrosine hydroxylase (TH) proteins, but upregulated MAOA, Beclin1, Atg5, and LC3-Ⅱ. METH up-regulated inflammation-related factors, such as caspase1, TNF-α and IL-18, by activating the toll-like receptors 4 (TLR4)/myeloid differentiation factor 88 (Myd88)/nuclear factor κB (NF-κB) pathway and reduced occludin protein expression. In addition, METH exposure changed α and β diversities of gut microbiota. Specifically, METH exposure elevated relative abundances of pathogenic bacteria, but reduced those of probiotics. Metabolomics, combined with enrichment analyses revealed that METH exposure altered fecal metabolites. Our findings suggest that METH exposure induced autophagy in the CNS, elevated intestinal autophagy flora, leading to accumulation of fecal metabolites in the autophagy pathway, and causing enteritis. Moreover, METH promoted intestinal inflammation by increasing the relative abundance of the pathogenic bacteria in the intestinal tract, and reduced intestinal TJ protein expression.
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Affiliation(s)
- Li-Jian Chen
- Department of Forensic Pathology, School of Forensic Medicine, Southern Medical University, Guangzhou, China
| | - Xu Zhi
- Center for Reproductive Medicine, Department of Obstetrics and Gynecology, Peking University Third Hospital, Beijing, China
| | - Kai-Kai Zhang
- Department of Forensic Pathology, School of Forensic Medicine, Southern Medical University, Guangzhou, China
| | - Li-Bin Wang
- Department of Toxicology, School of Public Health, Southern Medical University, Guangzhou, China
| | - Jia-Hao Li
- Department of Forensic Pathology, School of Forensic Medicine, Southern Medical University, Guangzhou, China
| | - Jia-Li Liu
- Department of Forensic Pathology, School of Forensic Medicine, Southern Medical University, Guangzhou, China
| | - Ling-Ling Xu
- Department of Toxicology, School of Public Health, Southern Medical University, Guangzhou, China
| | | | - Xiao-Li Xie
- Department of Toxicology, School of Public Health, Southern Medical University, Guangzhou, China.
| | - Qi Wang
- Department of Forensic Pathology, School of Forensic Medicine, Southern Medical University, Guangzhou, China.
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15
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Andrade WA, Zamboni DS. NLRC4 biology in immunity and inflammation. J Leukoc Biol 2020; 108:1117-1127. [PMID: 32531834 DOI: 10.1002/jlb.3mr0420-573r] [Citation(s) in RCA: 21] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2020] [Revised: 04/29/2020] [Accepted: 05/05/2020] [Indexed: 12/14/2022] Open
Abstract
Inflammasomes are cytosolic multiprotein complexes that sense microbial infections or host cell damage, triggering cytokine production and a proinflammatory form of cell death, called pyroptosis. Whereas pyroptosis and cytokine production may often promote host resistance to infections, uncontrolled inflammasome activation leads to autoinflammatory diseases in humans. Among the multiple inflammasomes described, the neuronal apoptosis inhibitory protein/nucleotide-binding domain leucine-rich repeat-containing protein family caspase activation and recruitment domain-containing protein 4 (NLRC4) inflammasome emerged as a critical component for the restriction of bacterial infections. Accordingly, our understanding of this inflammasome advanced remarkably over the last 10 yr, expanding our knowledge about ligand-receptor interaction; cryo-EM structure; and downstream effectors and substrates, such as gasdermin-D, caspase-1, caspase-8, and caspase-7. In this review, we discuss recent advances on the biology of the NLRC4 inflammasome, in terms of structure and activation mechanisms, importance in bacterial and nonbacterial diseases, and the identification of NLRC4 gain-of-function mutations leading to NLRC4-associated autoinflammatory diseases in humans.
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Affiliation(s)
- Warrison A Andrade
- Department of Cell Biology, School of Medicine of Ribeirão Preto, University of São Paulo, Ribeirão Preto, Ribeirão Preto, São Paulo, Brazil
| | - Dario S Zamboni
- Department of Cell Biology, School of Medicine of Ribeirão Preto, University of São Paulo, Ribeirão Preto, Ribeirão Preto, São Paulo, Brazil
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16
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Semper RP, Vieth M, Gerhard M, Mejías-Luque R. Helicobacter pylori Exploits the NLRC4 Inflammasome to Dampen Host Defenses. THE JOURNAL OF IMMUNOLOGY 2019; 203:2183-2193. [PMID: 31511355 DOI: 10.4049/jimmunol.1900351] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/26/2019] [Accepted: 08/07/2019] [Indexed: 02/06/2023]
Abstract
Helicobacter pylori colonizes the stomach of around 50% of humans. This chronic infection can lead to gastric pathologic conditions such as gastric ulcers and gastric adenocarcinomas. The strong inflammatory response elicited by H. pylori is characterized by the induction of the expression of several cytokines. Among those, IL-18 is found highly upregulated in infected individuals, and its expression correlates with the severity of gastric inflammation. IL-18 is produced as inactive proform and has to be cleaved by the multiprotein complex inflammasome to be active. In immune cells, the NLRC4 inflammasome, which is activated by flagellin or bacterial secretion systems, was shown to be dispensable for H. pylori-induced inflammasome activation. However, apart from immune cells, gastric epithelial cells can also produce IL-18. In this study, we analyzed the role of the NLRC4 inflammasome during H. pylori infection. Our results indicate that NLRC4 and a functional type IV secretion system are crucial for the production of IL-18 from human and murine gastric epithelial cells. In vivo, Nlrc4-/- mice failed to produce gastric IL-18 upon H. pylori infection. Compared with wild type mice, Nlrc4-/- mice controlled H. pylori better without showing strong inflammation. Moreover, H. pylori-induced IL-18 inhibits β-defensin 1 expression in a NF-κB-dependent manner, resulting in higher bacterial colonization. At the same time, inflammasome activation enhances neutrophil infiltration, resulting in inflammation. Thus, NLRC4 inflammasome activation and subsequent IL-18 production favors bacterial persistence by inhibiting antimicrobial peptide production and, at the same time, contributes to gastric inflammation.
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Affiliation(s)
- Raphaela P Semper
- Institut für Medizinische Mikrobiologie, Immunologie und Hygiene, Fakultät für Medizin, Technische Universität München, 81675 Munich, Germany; and
| | - Michael Vieth
- Institut für Pathologie, Klinikum Bayreuth, 95445 Bayreuth, Germany
| | - Markus Gerhard
- Institut für Medizinische Mikrobiologie, Immunologie und Hygiene, Fakultät für Medizin, Technische Universität München, 81675 Munich, Germany; and
| | - Raquel Mejías-Luque
- Institut für Medizinische Mikrobiologie, Immunologie und Hygiene, Fakultät für Medizin, Technische Universität München, 81675 Munich, Germany; and
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17
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Gao Q, Zhu H. The Overexpression of Sirtuin1 (SIRT1) Alleviated Lipopolysaccharide (LPS)-Induced Acute Kidney Injury (AKI) via Inhibiting the Activation of Nucleotide-Binding Oligomerization Domain-Like Receptors (NLR) Family Pyrin Domain Containing 3 (NLRP3) Inflammasome. Med Sci Monit 2019; 25:2718-2726. [PMID: 30980521 PMCID: PMC6476233 DOI: 10.12659/msm.913146] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022] Open
Abstract
Background Sepsis-induced acute kidney injury (AKI) is threatening the patients with sepsis, and nucleotide-binding oligomerization domain-like receptors (NLR) family pyrin domain containing 3 (NLRP3) inflammasome is considered to play a critical role in this complication of sepsis and might be regulated by sirtuin1 (SIRT1). Thus, we explored the roles of NLRP3 and SIRT1 in the lipopolysaccharide (LPS)-induced AKI in the HK-2 cell line. Material/Methods Cell viability was assessed by Cell Counting Kit-8 (CCK-8). Apoptosis rate was measured by flow cytometry. Protein levels of interleukin (IL)-1β and IL-18 were tested by enzyme-linked immunosorbent assay (ELISA) and NLRP3, cleaved caspase-1, caspase-1 were tested by western blot. The mRNA levels of IL-1β, IL-18, and SIRT1 were quantified by qPCR. Results LPS could decrease cell viability and the expression of SIRT1 and elevate the expressions of IL-1β, IL-18, NLRP3, and cleaved caspase-1. However, the overexpression of SIRT1 could upregulate cell viability and expression of caspase-1 and downregulate apoptosis rate, expressions of NLRP3, IL-1β, IL-18, and cleaved caspase-1. Conclusions NLRP3 inflammasome could act as a critical regulator promoting the process of AKI induced by LPS, and the overexpression of SIRT1 might be able to suppress the activation of NLRP3 and therefore resist the kidney injury, showing promise to be used as a target in the treatment of sepsis-induced AKI.
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Affiliation(s)
- Qiufang Gao
- Department of Critical Care Medicine, Jining No. 1 People's Hospital, Jining, Shandong, China (mainland)
| | - Hengting Zhu
- Department of Critical Care Medicine, Jining No. 1 People's Hospital, Jining, Shandong, China (mainland)
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18
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Induction of TNF, CXCL8 and IL-1β in macrophages by Helicobacter pylori secreted protein HP1173 occurs via MAP-kinases, NF-κB and AP-1 signaling pathways. Microb Pathog 2018; 125:295-305. [DOI: 10.1016/j.micpath.2018.09.037] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2018] [Revised: 09/06/2018] [Accepted: 09/24/2018] [Indexed: 02/07/2023]
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19
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Nguyen PM, Putoczki TL. Could the inhibition of IL-17 or IL-18 be a potential therapeutic opportunity for gastric cancer? Cytokine 2018; 118:8-18. [PMID: 29396054 DOI: 10.1016/j.cyto.2018.01.008] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/27/2017] [Revised: 01/08/2018] [Accepted: 01/08/2018] [Indexed: 02/07/2023]
Abstract
Chronic inflammation is recognized as a key tumor-promoting factor in a number of epithelial cancers, including gastric cancer (GC). The production of pro-inflammatory cytokines in the tumor microenvironment by both the innate and the adaptive immune response can activate signaling pathways that are associated with increased cell survival and proliferation of cancer cells. Among the cytokines that have most commonly been linked to inflammation-associated cancers, are the Th17 cell-associated cytokines IL-17A, IL-23, IL-22, and the IL-1 family members IL-1β and IL-18. However, whether their contribution to inflammation-associated cancers is universal, or specific to individual types of cancers, remains to be elucidated. This review will explore our current understanding of the known roles of these cytokines in gastritis and discuss how their therapeutic inhibition may be useful for GC.
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Affiliation(s)
- Paul M Nguyen
- Walter and Eliza Hall Institute of Medical Research, Victoria 3052, Australia; Department of Medical Biology, University of Melbourne, Victoria 3052, Australia
| | - Tracy L Putoczki
- Walter and Eliza Hall Institute of Medical Research, Victoria 3052, Australia; Department of Medical Biology, University of Melbourne, Victoria 3052, Australia.
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20
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Jafarzadeh A, Larussa T, Nemati M, Jalapour S. T cell subsets play an important role in the determination of the clinical outcome of Helicobacter pylori infection. Microb Pathog 2018; 116:227-236. [PMID: 29407232 DOI: 10.1016/j.micpath.2018.01.040] [Citation(s) in RCA: 74] [Impact Index Per Article: 10.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2016] [Revised: 01/20/2018] [Accepted: 01/26/2018] [Indexed: 12/12/2022]
Abstract
Helicobacter pylori (H. pylori) is one of the most prevalent human pathogen and a persistent infection with this bacterium causes common pathologies, such as gastritis or peptic ulcers, and also less common but more serious pathologies, such as gastric cancer or gastric mucosa-associated lymphoid tissue (MALT) lymphoma. The clinical outcome of gastrointestinal infection sustained by H. pylori is determined by the reciprocal interactions between virulence factors of the bacterium and host factors, including immune response genes. Although H. pylori induces a strong immune response, the bacterium is not eliminated. The eradication failure could be attributed to the bacterial capability to regulate helper T (Th) cell-related responses. H. pylori specific CD4+ T cells play a fundamental role in regulating host immunity and immunopathologic events. It has been documented that Th1, Th2, Th9, Th17, Th22 and T regulatory (Treg) cells, separately or in coordination with each other, can affect the outcome of the infection sustained by of H. pylori. Some studies indicated that both Th1 and Th17 cells may be protective or pathogenic, whereas Treg and Th2 cells perform anti-inflammatory impacts during H. pylori infection. This review gathers recent information regarding the association of the CD4+ T cells-mediated immunological responses and the clinical consequence of H. pylori infection.
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Affiliation(s)
- Abdollah Jafarzadeh
- Immunology of Infectious Diseases Research Center, Rafsanjan University of Medical Sciences, Rafsanjan, Iran; Department of Immunology, School of Medicine, Rafsanjan University of Medical Sciences, Rafsanjan, Iran; Department of Immunology, School of Medicine, Kerman University of Medical Sciences, Kerman, Iran.
| | - Tiziana Larussa
- Department of Health Science, University of Catanzaro "Magna Graecia", 88100 Catanzaro, Italy
| | - Maryam Nemati
- Department of Laboratory Sciences, School of Para-Medicine, Kerman University of Medical Sciences, Kerman, Iran
| | - Shila Jalapour
- Molecular Medicine Research Center, Rafsanjan University of Medical Sciences, Rafsanjan, Iran.
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21
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Tran LS, Chonwerawong M, Ferrero RL. Regulation and functions of inflammasome-mediated cytokines in Helicobacter pylori infection. Microbes Infect 2017; 19:449-458. [PMID: 28690082 DOI: 10.1016/j.micinf.2017.06.005] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2017] [Accepted: 06/22/2017] [Indexed: 02/08/2023]
Abstract
Persistent stomach infection with Helicobacter pylori causes chronic mucosal inflammation (gastritis), which is widely recognized as an essential precursor to gastric cancer. The IL-1 interleukin family cytokines IL-1β and IL-18 have emerged as central mediators of mucosal inflammation. Here, we review the regulation and functions of these cytokines in H. pylori-induced inflammation and carcinogenesis.
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Affiliation(s)
- Le Son Tran
- Centre for Innate Immunity and Infectious Diseases, The Hudson Institute of Medical Research, Monash University, 27-31 Wright Street, Clayton, Victoria, Australia
| | - Michelle Chonwerawong
- Centre for Innate Immunity and Infectious Diseases, The Hudson Institute of Medical Research, Monash University, 27-31 Wright Street, Clayton, Victoria, Australia
| | - Richard L Ferrero
- Centre for Innate Immunity and Infectious Diseases, The Hudson Institute of Medical Research, Monash University, 27-31 Wright Street, Clayton, Victoria, Australia; Biomedicine Discovery Institute, Department of Microbiology, Monash University, Wellington Road, Clayton, Victoria, Australia.
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22
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Pachathundikandi SK, Müller A, Backert S. Inflammasome Activation by Helicobacter pylori and Its Implications for Persistence and Immunity. Curr Top Microbiol Immunol 2016; 397:117-31. [DOI: 10.1007/978-3-319-41171-2_6] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
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23
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Stubljar D, Skvarc M. Helicobacter pylori vs immune system or antibiotics. World J Immunol 2015; 5:142-151. [DOI: 10.5411/wji.v5.i3.142] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/28/2015] [Revised: 06/18/2015] [Accepted: 07/27/2015] [Indexed: 02/05/2023] Open
Abstract
Helicobacter pylori (H. pylori) infection has often no clinical signs and is one of the most common bacterial infections. All infected subjects have histology of active chronic gastritis. In some cases patients develop peptic ulcer and minority of them develop gastric cancer. Gastric cancer is multifactorial disease, thus various progressions of H. pylori infection and disease are dependent on the host genetic factors, the characteristics of the individual’s immune response, environmental factors, and different bacterial virulence factors of the individual bacterial strains. Eradication of the bacteria plays a crucial role in the treatment of these cases however antibiotic therapy does not always help. Bacteria often develop resistance to antibiotics so we recommend that not only screening for H. pylori also the strain determination should have some diagnostic value, especially in the patients who already developed gastritis. Furthermore, for such patients assessment of disease progression (atrophic or metaplastic gastritis) could be followed by polymorphism determination. Until now we cannot predict the disease based only on single polymorphism. Bacteria successfully neutralize the responses of the immune systems using different enzymes or even components of the host immune response. However, the influence of immune system and its components could represent new ways of treatments and could help to eradicate the infection.
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24
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Myung DS, Lee WS, Park YL, Kim N, Oh HH, Kim MY, Oak CY, Chung CY, Park HC, Kim JS, Cho SB, Kweon SS, Joo YE. Association between interleukin-18 gene polymorphism and Helicobacter pylori infection in the Korean population. Sci Rep 2015; 5:11535. [PMID: 26096341 PMCID: PMC4476145 DOI: 10.1038/srep11535] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2014] [Accepted: 05/07/2015] [Indexed: 12/13/2022] Open
Abstract
Interleukin-18 (IL-18) is a pleiotropic, pro-inflammatory cytokine that is capable of promoting the Th1 response. A predominant Th1 response induces chronic and persistent inflammatory changes in the gastric mucosa in response to Helicobacter pylori (H. pylori) infection. The aim of this study was to investigate the potential association between IL-18 gene polymorphisms and susceptibility to H. pylori infection in the Korean population. A total of 678 subjects who underwent a routine health check-up were enrolled. The IL-18 gene polymorphisms at positions −656, −607, −137, +113, and +127 were genotyped. H. pylori positivity was demonstrated in 456 subjects (67.3%). The allele frequencies of IL-18 gene polymorphisms at position −137 (rs187238) were different based on the status of H. pylori infection (G vs. C, adjusted OR 0.64 CI: 0.47–0.87, P = 0.005). The results indicate that the genetic variants in the IL-18 gene may be associated with susceptibility to H. pylori infection in the Korean population, suggesting that IL-18 plays a role in the pathogenesis of H. pylori-associated diseases. However, this finding requires further replication and validation.
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Affiliation(s)
- Dae-Seong Myung
- Department of Internal Medicine, Chonnam National University Medical School, Gwangju, Korea
| | - Wan-Sik Lee
- Department of Internal Medicine, Chonnam National University Medical School, Gwangju, Korea
| | - Young-Lan Park
- Department of Internal Medicine, Chonnam National University Medical School, Gwangju, Korea
| | - Nuri Kim
- Department of Internal Medicine, Chonnam National University Medical School, Gwangju, Korea
| | - Hyung-Hoon Oh
- Department of Internal Medicine, Chonnam National University Medical School, Gwangju, Korea
| | - Mi-Young Kim
- Department of Internal Medicine, Chonnam National University Medical School, Gwangju, Korea
| | - Chan-Young Oak
- Department of Internal Medicine, Chonnam National University Medical School, Gwangju, Korea
| | - Cho-Yun Chung
- Department of Internal Medicine, Chonnam National University Medical School, Gwangju, Korea
| | - Hyung-Chul Park
- Department of Internal Medicine, Chonnam National University Medical School, Gwangju, Korea
| | - Jong-Sun Kim
- Department of Internal Medicine, Chonnam National University Medical School, Gwangju, Korea
| | - Sung-Bum Cho
- Department of Internal Medicine, Chonnam National University Medical School, Gwangju, Korea
| | - Sun-Seog Kweon
- Department of Preventive Medicine, Chonnam National University Medical School, Gwangju, Korea
| | - Young-Eun Joo
- Department of Internal Medicine, Chonnam National University Medical School, Gwangju, Korea
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25
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Li X, Liu S, Luo J, Liu A, Tang S, Liu S, Yu M, Zhang Y. Helicobacter pylori induces IL-1β and IL-18 production in human monocytic cell line through activation of NLRP3 inflammasome via ROS signaling pathway. Pathog Dis 2015; 73:ftu024. [DOI: 10.1093/femspd/ftu024] [Citation(s) in RCA: 38] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 12/23/2014] [Indexed: 12/21/2022] Open
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26
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He C, Yang Z, Lu NH. Helicobacter pylori-an infectious risk factor for atherosclerosis? J Atheroscler Thromb 2014; 21:1229-42. [PMID: 25342566 DOI: 10.5551/jat.25775] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/11/2022] Open
Abstract
Accumulating evidence implicates Helicobacter pylori (H. pylori) infection in the pathogenesis of certain diseases localized outside the stomach, particularly those characterized by persistent and low-grade systematic inflammation. Recently, the role of H. pylori infection in the development of atherosclerosis and its clinical complications has received attention. Atherosclerosis is a high-cost disease, and acute events resulting from this condition rank first among morbidity and mortality statistics in most industrialized countries. Atherosclerosis is a multifactorial disorder, and traditional risk factors explain only 50% of its etiology. Therefore, identifying new risk factors for atherosclerosis is necessary. Serological studies indicate that chronic H. pylori infection, especially that with more virulent strains, may predispose patients to the onset of atherosclerosis and related adverse clinical events, and PCR studies have detected H. pylori DNA in atherosclerotic plaques, although this finding remains controversial. If this association were to be confirmed, its importance to public health would be substantial, as the eradication of H. pylori is more straightforward and less costly than the long-term treatment of other risk factors. This review investigates the potential relationship between H. pylori infection and atherosclerosis from both epidemiological and pathogenic perspectives and characterizes the potential mechanisms underlying this correlation.
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Affiliation(s)
- Cong He
- Department of Gastroenterology, The First Affiliated Hospital of Nanchang University
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27
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Gobert AP, Verriere T, Asim M, Barry DP, Piazuelo MB, de Sablet T, Delgado AG, Bravo LE, Correa P, Peek RM, Chaturvedi R, Wilson KT. Heme oxygenase-1 dysregulates macrophage polarization and the immune response to Helicobacter pylori. THE JOURNAL OF IMMUNOLOGY 2014; 193:3013-22. [PMID: 25108023 DOI: 10.4049/jimmunol.1401075] [Citation(s) in RCA: 61] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/29/2022]
Abstract
Helicobacter pylori incites a futile inflammatory response, which is the key feature of its immunopathogenesis. This leads to the ability of this bacterial pathogen to survive in the stomach and cause peptic ulcers and gastric cancer. Myeloid cells recruited to the gastric mucosa during H. pylori infection have been directly implicated in the modulation of host defense against the bacterium and gastric inflammation. Heme oxygenase-1 (HO-1) is an inducible enzyme that exhibits anti-inflammatory functions. Our aim was to analyze the induction and role of HO-1 in macrophages during H. pylori infection. We now show that phosphorylation of the H. pylori virulence factor cytotoxin-associated gene A (CagA) in macrophages results in expression of hmox-1, the gene encoding HO-1, through p38/NF (erythroid-derived 2)-like 2 signaling. Blocking phagocytosis prevented CagA phosphorylation and HO-1 induction. The expression of HO-1 was also increased in gastric mononuclear cells of human patients and macrophages of mice infected with cagA(+) H. pylori strains. Genetic ablation of hmox-1 in H. pylori-infected mice increased histologic gastritis, which was associated with enhanced M1/Th1/Th17 responses, decreased regulatory macrophage (Mreg) response, and reduced H. pylori colonization. Gastric macrophages of H. pylori-infected mice and macrophages infected in vitro with this bacterium showed an M1/Mreg mixed polarization type; deletion of hmox-1 or inhibition of HO-1 in macrophages caused an increased M1 and a decrease of Mreg phenotype. These data highlight a mechanism by which H. pylori impairs the immune response and favors its own survival via activation of macrophage HO-1.
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Affiliation(s)
- Alain P Gobert
- Division of Gastroenterology, Hepatology, and Nutrition, Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN 37232; Institut National de la Recherche Agronomique, Unité de Recherche Microbiologie (UR454), 63122 Saint-Genès-Champanelle, France
| | - Thomas Verriere
- Division of Gastroenterology, Hepatology, and Nutrition, Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN 37232
| | - Mohammad Asim
- Division of Gastroenterology, Hepatology, and Nutrition, Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN 37232
| | - Daniel P Barry
- Division of Gastroenterology, Hepatology, and Nutrition, Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN 37232
| | - M Blanca Piazuelo
- Division of Gastroenterology, Hepatology, and Nutrition, Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN 37232
| | - Thibaut de Sablet
- Division of Gastroenterology, Hepatology, and Nutrition, Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN 37232
| | - Alberto G Delgado
- Division of Gastroenterology, Hepatology, and Nutrition, Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN 37232
| | - Luis E Bravo
- Departamento de Patología, Escuela de Medicina, Universidad del Valle, Cali, Colombia
| | - Pelayo Correa
- Division of Gastroenterology, Hepatology, and Nutrition, Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN 37232
| | - Richard M Peek
- Division of Gastroenterology, Hepatology, and Nutrition, Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN 37232; Department of Cancer Biology, Vanderbilt University School of Medicine, Nashville, TN 37232; Veterans Affairs Tennessee Valley Healthcare System, Nashville, TN 37212; and
| | - Rupesh Chaturvedi
- Division of Gastroenterology, Hepatology, and Nutrition, Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN 37232
| | - Keith T Wilson
- Division of Gastroenterology, Hepatology, and Nutrition, Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN 37232; Department of Cancer Biology, Vanderbilt University School of Medicine, Nashville, TN 37232; Veterans Affairs Tennessee Valley Healthcare System, Nashville, TN 37212; and Department of Pathology, Microbiology and Immunology, Vanderbilt University School of Medicine, Nashville, TN 37232
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28
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Nagata N, Akiyama J, Marusawa H, Shimbo T, Liu Y, Igari T, Nakashima R, Watanabe H, Uemura N, Chiba T. Enhanced expression of activation-induced cytidine deaminase in human gastric mucosa infected by Helicobacter pylori and its decrease following eradication. J Gastroenterol 2014; 49:427-35. [PMID: 23591766 DOI: 10.1007/s00535-013-0808-z] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/04/2013] [Accepted: 04/02/2013] [Indexed: 02/04/2023]
Abstract
BACKGROUND Recent studies have shown important roles for activation-induced cytidine deaminase (AID), an intrinsic genome mutator, in H. pylori-associated gastric cancer development. Here, we evaluated the relationship between H. pylori-induced gastritis and AID expression from human biopsy specimens. METHODS In 109 patients with dyspeptic symptoms who had undergone endoscopy and received biopsy of the antrum, angulus, and corpus, H. pylori infection was diagnosed by serologic test, (13)C urea breath test, and histological examination. Histological scores of H. pylori, neutrophils, mononuclear cells, atrophy, and intestinal metaplasia (IM) were assessed using the updated Sydney system (USS). Immunohistochemical AID expression of the biopsy specimens was scored. RESULTS Sixty of 109 (55.0 %) patients were positive for H. pylori and eradication was successful in 48 patients. AID expression in H. pylori-infected mucosa was significantly higher (p < 0.01) than in non-infected mucosa. AID expression was highest in the antrum and was significantly (p < 0.01) reduced toward the proximal portion of the stomach. For USS, multivariate analysis using linear regression revealed that mononuclear cell infiltration (p < 0.01) and IM (p < 0.05) correlated independently with AID expression. After eradication of H. pylori, AID expression was significantly decreased (p < 0.01), but was still higher than that in H. pylori-negative patients in all sites of the stomach. CONCLUSIONS AID expression is elevated in H. pylori-positive patients and is reduced following H. pylori eradication. Moreover, AID expression is highest in the antrum and correlated with severity of chronic inflammation and IM, suggesting an important role for AID in gastric cancer development through gastritis.
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Affiliation(s)
- Naoyoshi Nagata
- Department of Gastroenterology and Hepatology, National Center for Global Health and Medicine (NCGM), 1-21-1 Toyama, Shinjuku-ku, Tokyo, 162-8655, Japan,
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29
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Bagheri N, Taghikhani A, Rahimian G, Salimzadeh L, Azadegan Dehkordi F, Zandi F, Chaleshtori MH, Rafieian-Kopaei M, Shirzad H. Association between virulence factors of helicobacter pylori and gastric mucosal interleukin-18 mRNA expression in dyspeptic patients. Microb Pathog 2013; 65:7-13. [DOI: 10.1016/j.micpath.2013.08.005] [Citation(s) in RCA: 45] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2013] [Revised: 08/17/2013] [Accepted: 08/30/2013] [Indexed: 12/30/2022]
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30
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Pachathundikandi SK, Tegtmeyer N, Backert S. Signal transduction of Helicobacter pylori during interaction with host cell protein receptors of epithelial and immune cells. Gut Microbes 2013; 4:454-74. [PMID: 24280762 PMCID: PMC3928158 DOI: 10.4161/gmic.27001] [Citation(s) in RCA: 60] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/03/2023] Open
Abstract
Helicobacter pylori infections can induce pathologies ranging from chronic gastritis, peptic ulceration to gastric cancer. Bacterial isolates harbor numerous well-known adhesins, vacuolating cytotoxin VacA, protease HtrA, urease, peptidoglycan, and type IV secretion systems (T4SS). It appears that H. pylori targets more than 40 known host protein receptors on epithelial or immune cells. A series of T4SS components such as CagL, CagI, CagY, and CagA can bind to the integrin α 5β 1 receptor. Other targeted membrane-based receptors include the integrins αvβ 3, αvβ 5, and β 2 (CD18), RPTP-α/β, GP130, E-cadherin, fibronectin, laminin, CD46, CD74, ICAM1/LFA1, T-cell receptor, Toll-like receptors, and receptor tyrosine kinases EGFR, ErbB2, ErbB3, and c-Met. In addition, H. pylori is able to activate the intracellular receptors NOD1, NOD2, and NLRP3 with important roles in innate immunity. Here we review the interplay of various bacterial factors with host protein receptors. The contribution of these interactions to signal transduction and pathogenesis is discussed.
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31
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Pathak SK, Tavares R, de Klerk N, Spetz AL, Jonsson AB. Helicobacter pylori protein JHP0290 binds to multiple cell types and induces macrophage apoptosis via tumor necrosis factor (TNF)-dependent and independent pathways. PLoS One 2013; 8:e77872. [PMID: 24223737 PMCID: PMC3815203 DOI: 10.1371/journal.pone.0077872] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2013] [Accepted: 09/09/2013] [Indexed: 01/03/2023] Open
Abstract
Activated macrophages at the sub-mucosal space play a major role in generating innate immune responses during H. pylori infection. Final disease outcome largely depends on how H. pylori and bacterium-derived products modulate macrophage responses. Here, we report that JHP0290, a functionally unknown protein from H. pylori, regulates macrophage functions. Recombinant purified JHP0290 (rJHP0290) had the ability to bind to several cell types including macrophages, human gastric epithelial cell lines, human monocyte-derived dendritic cells (MoDC) and human neutrophils. Exposure to rJHP0290 induced apoptosis in macrophages concurrent with release of proinflammatory cytokine tumor necrosis factor (TNF). A mutant strain of H. pylori disrupted in the jhp0290 gene was significantly impaired in its ability to induce apoptosis and TNF in macrophages confirming the role of endogenous protein in regulating macrophage responses. Intracellular signaling involving Src family of tyrosine kinases (SFKs) and ERK MAPK were required for rJHP0290-induced TNF release and apoptosis in macrophages. Furthermore, rJHP0290-induced TNF release was partly dependent on activation of nuclear transcription factor-κB (NF-κB). Neutralizing antibodies against TNF partially blocked rJHP0290-induced macrophage apoptosis indicating TNF-independent pathways were also involved. These results provide mechanistic insight into the potential role of the protein JHP0290 during H. pylori-associated disease development. By virtue of its ability to induce TNF, an acid suppressive proinflammatory cytokine and induction of macrophage apoptosis, JHP0290 possibly helps in persistent survival of the bacterium inside the stomach.
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Affiliation(s)
- Sushil Kumar Pathak
- Department of Molecular Biosciences, The Wenner-Gren Institute, Stockholm University, Stockholm, Sweden
| | - Raquel Tavares
- Department of Molecular Biosciences, The Wenner-Gren Institute, Stockholm University, Stockholm, Sweden
| | - Nele de Klerk
- Department of Molecular Biosciences, The Wenner-Gren Institute, Stockholm University, Stockholm, Sweden
| | - Anna-Lena Spetz
- Department of Medicine, Center for Infectious Medicine, Karolinska Institutet, Karolinska University Hospital Huddinge, Stockholm, Sweden
| | - Ann-Beth Jonsson
- Department of Molecular Biosciences, The Wenner-Gren Institute, Stockholm University, Stockholm, Sweden
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Rezaeifar A, Eskandari-Nasab E, Moghadampour M, Kharazi-Nejad E, Hasani SSA, Asadi-Saghandi A, Hadadi-Fishani M, Sepanjnia A, Sadeghi-Kalani B. The association of interleukin-18 promoter polymorphisms and serum levels with duodenal ulcer, and their correlations with bacterial CagA and VacA virulence factors. ACTA ACUST UNITED AC 2013; 45:584-92. [PMID: 23746337 DOI: 10.3109/00365548.2013.794301] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/01/2023]
Abstract
BACKGROUND We analyzed the impact of interleukin (IL)-18 promoter polymorphisms on IL-18 serum levels in Helicobacter pylori-infected duodenal ulcer (DU) patients and healthy asymptomatic (AS) carriers. We also aimed to determine the association of the H. pylori virulence factors CagA and VacA antibodies with serum concentrations of IL-18 in order to elucidate any correlation between them. METHODS Three groups of patients were enrolled: DU patients (67 individuals), AS carriers (48 individuals), and H. pylori-negative subjects (26 individuals). Serum concentrations of IL-18 were determined by ELISA. Patient sera were tested by Western blot method to determine the presence of serum antibodies to bacterial CagA and VacA. Genotyping of IL-18 promoter polymorphisms at positions - 137G/C and - 607C/A were performed by allele-specific primer PCR protocol. RESULTS Our study revealed that serum IL-18 levels are positively influenced by CagA-positive H. pylori strains, so that maximum levels of IL-18 were detected in DU patients with the CagA(+) phenotype, regardless of the presence of the anti-VacA antibody. Regarding IL-18 promoter polymorphisms, the AA genotype and A allele at position - 607C/A were found to be significantly lower in DU patients than in AS carriers and H. pylori-negative subjects (p = 0.032 and 0.043, respectively). CONCLUSIONS The IL-18 - 607C variant was associated with higher levels of serum IL-18 and an increased risk of DU. Moreover, our findings indicated that serum concentrations of IL-18 were influenced by CagA factor, irrespective of the VacA status, suggesting that high levels of IL-18 in CagA-positive subjects predisposes to susceptibility to DU.
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Affiliation(s)
- Alireza Rezaeifar
- Department of Clinical Biochemistry, School of Medicine, Zabol University of Medical Sciences, Zabol, Iran
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Chen BF, Xu X, Deng Y, Ma SC, Tang LQ, Zhang SB, Chen ZF. Relationship between Helicobacter pylori infection and serum interleukin-18 in patients with carotid atherosclerosis. Helicobacter 2013; 18:124-8. [PMID: 23121308 DOI: 10.1111/hel.12014] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
BACKGROUND Helicobacter pylori (H. pylori) infection stimulates the production of proinflammatory cytokines associated with the development of atherosclerosis. Levels of circulating interleukin-18 (IL-18) have been positively correlated with carotid intima-media thickness (IMT) and coronary plaque area and have identified IL-18 levels as important predictors of coronary events and cardiovascular mortality. This study aimed to examine the relationship between serum IL-18 and H. pylori-IgG antibody as a sign of H. pylori infection in patients with carotid atherosclerosis. METHODS The carotid IMT, traditional atherosclerotic risk factors, levels of serum H. pylori-IgG and IL-18 were measured in 573 health checkup examinees. RESULTS Serum IL-18 and H. pylori-IgG levels were significantly increased in subjects with increased IMT in comparison with those with normal IMT. In subjects with increased IMT, serum H. pylori-IgG was positively correlated with serum IL-18 (r = .402, p = .002), and the association was independent of traditional atherosclerotic risk factors (β = 0.310, p < .001). CONCLUSIONS In health checkup examinees with increased IMT, serum IL-18 and H. pylori-IgG were independently correlated and were significantly higher than in subjects with normal IMT.
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Affiliation(s)
- Bao-Feng Chen
- Department of Cardiovasology, Yue Bei People's Hospital, Huimin South Road, Shaoguan, 512026, Guangdong Province, China
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TLR2 and Nod2 mediate resistance or susceptibility to fatal intracellular Ehrlichia infection in murine models of ehrlichiosis. PLoS One 2013; 8:e58514. [PMID: 23526993 PMCID: PMC3602367 DOI: 10.1371/journal.pone.0058514] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2012] [Accepted: 02/05/2013] [Indexed: 01/23/2023] Open
Abstract
Our murine models of human monocytic ehrlichiosis (HME) have shown that severe and fatal ehrlichiosis is due to generation of pathogenic T cell responses causing immunopathology and multi-organ failure. However, the early events in the liver, the main site of infection, are not well understood. In this study, we examined the liver transcriptome during the course of lethal and nonlethal infections caused by Ixodes ovatus Ehrlichia and Ehrlichia muris, respectively. On day 3 post-infection (p.i.), although most host genes were down regulated in the two groups of infected mice compared to naïve counterparts, lethal infection induced significantly higher expression of caspase 1, caspase 4, nucleotide binding oligomerization domain-containing proteins (Nod1), tumor necrosis factor-alpha, interleukin 10, and CCL7 compared to nonlethal infection. On day 7 p.i., lethal infection induced highly significant upregulation of type-1 interferon, several inflammatory cytokines and chemokines, which was associated with increased expression levels of Toll-like receptor-2 (TLR2), Nod2, MyD88, nuclear factor-kappa B (NF-kB), Caspase 4, NLRP1, NLRP12, Pycard, and IL-1β, suggesting enhanced TLR signals and inflammasomes activation. We next evaluated the participation of TLR2 and Nod2 in the host response during lethal Ehrlichia infection. Although lack of TLR2 impaired bacterial elimination and increased tissue necrosis, Nod2 deficiency attenuated pathology and enhanced bacterial clearance, which correlated with increased interferon-γ and interleukin-10 levels and a decreased frequency of pathogenic CD8(+) T cells in response to lethal infection. Thus, these data indicate that Nod2, but not TLR2, contributes to susceptibility to severe Ehrlichia-induced shock. Together, our studies provide, for the first time, insight into the diversity of host factors and novel molecular pathogenic mechanisms that may contribute to severe HME.
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Flahou B, Deun KV, Pasmans F, Smet A, Volf J, Rychlik I, Ducatelle R, Haesebrouck F. The local immune response of mice after Helicobacter suis infection: strain differences and distinction with Helicobacter pylori. Vet Res 2012; 43:75. [PMID: 23107128 PMCID: PMC3537685 DOI: 10.1186/1297-9716-43-75] [Citation(s) in RCA: 37] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2012] [Accepted: 10/11/2012] [Indexed: 12/11/2022] Open
Abstract
Helicobacter (H.) suis colonizes the stomach of pigs and is the most prevalent gastric non-H. pylori Helicobacter species in humans. Limited information is available on host immune responses after infection with this agent and it is unknown if variation in virulence exists between different H. suis strains. Therefore, BALB/c and C57BL/6 mice were used to compare colonization ability and gene expression of various inflammatory cytokines, as determined by real-time PCR, after experimental infection with 9 different H. suis strains. All strains were able to persist in the stomach of mice, but the number of colonizing bacteria at 59 days post inoculation was higher in stomachs of C57BL/6 mice compared to BALB/c mice. All H. suis strains caused an upregulation of interleukin (IL)-17, which was more pronounced in BALB/c mice. This upregulation was inversely correlated with the number of colonizing bacteria. Most strains also caused an upregulation of regulatory IL-10, positively correlating with colonization in BALB/c mice. Only in C57BL/6 mice, upregulation of IL-1β was observed. Increased levels of IFN-γ mRNA were never detected, whereas most H. suis strains caused an upregulation of the Th2 signature cytokine IL-4, mainly in BALB/c mice. In conclusion, the genetic background of the murine strain has a clear impact on the colonization ability of different H. suis strains and the immune response they evoke. A predominant Th17 response was observed, accompanied by a mild Th2 response, which is different from the Th17/Th1 response evoked by H. pylori infection.
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Affiliation(s)
- Bram Flahou
- Department of Pathology, Bacteriology and Avian Diseases, Faculty of Veterinary Medicine, Ghent University, Salisburylaan 133, Merelbeke, 9820, Belgium.
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Serelli-Lee V, Ling KL, Ho C, Yeong LH, Lim GK, Ho B, Wong SBJ. Persistent Helicobacter pylori specific Th17 responses in patients with past H. pylori infection are associated with elevated gastric mucosal IL-1β. PLoS One 2012; 7:e39199. [PMID: 22761739 PMCID: PMC3382622 DOI: 10.1371/journal.pone.0039199] [Citation(s) in RCA: 36] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2012] [Accepted: 05/16/2012] [Indexed: 12/16/2022] Open
Abstract
BACKGROUND Ongoing Helicobacter pylori (HP) infection triggers a chronic active gastritis. Eradicating HP reduces gastric inflammation, but does not eliminate it. We sought to characterize this persistent gastritis, and demonstrate the persistence of HP-specific Th17 responses in individuals previously infected with HP but who no longer had evidence of ongoing infection. METHODOLOGY/PRINCIPAL FINDINGS Study subjects were divided into 3 groups 55 individuals had active HP infection (group A), 41 were diagnosed with previous HP infection (group P), and 59 were naïve to HP (group N). Blood and gastric tissue were obtained with written informed consent from all subjects, and immune responses were evaluated using flow cytometry, semi-quantitative real time PCR, immunofluorescent staining, ELISA, and multiplex cytometric bead array for cytokine quantification. Elevated IL-17A responses were observed in patients from group A compared to group N. Interestingly, IL-17A responses remained persistently elevated in the blood and gastric mucosa of individuals from group P, despite the absence of ongoing HP infection. Using purified CD4(+) T cells as effectors and antibodies that blocked antigen presentation by MHC Class II, we showed that these persistent IL-17A responses were mediated primarily by HP-specific Th17 cells, rather than other immune cells that have also been described to secrete IL-17A. Gastric mucosal IL-1β levels were also persistently elevated in group P, and neutralisation of IL-1β reduced the HP-specific IL-17A response of purified CD4(+) T cells to autologous HP-pulsed antigen presenting cells in vitro, suggesting a functional association between IL-1β and the persistent Th17 response in group P patients. CONCLUSIONS/SIGNIFICANCE Despite lack of ongoing HP infection, HP-specific Th17 cells persist in the blood and gastric mucosa of individuals with past HP infection. We speculate that this persistent inflammation might contribute to gastric mucosal pathology, for example, persistent increased gastric cancer risk despite eradication of HP.
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Affiliation(s)
- Victoria Serelli-Lee
- Department of Microbiology, National University of Singapore, Singapore, Republic of Singapore
| | - Khoon Lin Ling
- Department of Gastroenterology and Hepatology, Singapore General Hospital, Singapore, Republic of Singapore
| | - Cassandra Ho
- Department of Microbiology, National University of Singapore, Singapore, Republic of Singapore
| | - Lai Han Yeong
- Department of Microbiology, National University of Singapore, Singapore, Republic of Singapore
| | - Gek Keow Lim
- Department of Gastroenterology and Hepatology, Singapore General Hospital, Singapore, Republic of Singapore
| | - Bow Ho
- Department of Microbiology, National University of Singapore, Singapore, Republic of Singapore
| | - Soon Boon Justin Wong
- Department of Microbiology, National University of Singapore, Singapore, Republic of Singapore
- Immunology Programme, National University of Singapore, Singapore, Republic of Singapore
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Shimoyama A, Saeki A, Tanimura N, Tsutsui H, Miyake K, Suda Y, Fujimoto Y, Fukase K. Chemical synthesis of Helicobacter pylori lipopolysaccharide partial structures and their selective proinflammatory responses. Chemistry 2011; 17:14464-74. [PMID: 22095469 DOI: 10.1002/chem.201003581] [Citation(s) in RCA: 53] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2010] [Revised: 07/27/2011] [Indexed: 12/23/2022]
Abstract
Helicobacter pylori is a common cause of gastroduodenal inflammatory diseases such as chronic gastritis and peptic ulcers and also an important factor in gastric carcinogenesis. Recent reports have demonstrated that bacterial inflammatory processes, such as stimulation with H. pylori lipopolysaccharide (LPS), initiate atherosclerosis. To establish the structures responsible for the inflammatory response of H. pylori LPS, we synthesized various kinds of lipid A structures (i.e., triacylated lipid A and Kdo-lipid A compounds), with or without the ethanolamine group at the 1-phosphate moiety, by a new divergent synthetic route. Stereoselective α-glycosylation of Kdo N-phenyltrifluoroacetimidate was achieved by use of microfluidic methods. None of the lipid A and Kdo-lipid A compounds were a strong inducer of IL-1β, IL-6, or IL-8, suggesting that H. pylori LPS is unable to induce acute inflammation. In fact, the lipid A and Kdo-lipid A compounds showed antagonistic activity against cytokine induction by E. coli LPS, except for the lipid A compound with the ethanolamine group, which showed very weak agonistic activity. On the other hand, these H. pylori LPS partial structures showed potent IL-18- and IL-12-inducing activities. IL-18 has been shown to correlate with chronic inflammation, so H. pylori LPS might be implicated in the chronic inflammatory responses induced by H. pylori. These results also indicated that H. pylori LPS can modulate the immune response: NF-κB activation through hTLR4/MD-2 was suppressed, whereas production of IL-18 and IL-12 was promoted.
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Affiliation(s)
- Atsushi Shimoyama
- Department of Chemistry, Graduate School of Science, Osaka University, Toyonaka, Osaka 560-0043, Japan
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Chaturvedi R, de Sablet T, Coburn LA, Gobert AP, Wilson KT. Arginine and polyamines in Helicobacter pylori-induced immune dysregulation and gastric carcinogenesis. Amino Acids 2011; 42:627-40. [PMID: 21874531 DOI: 10.1007/s00726-011-1038-4] [Citation(s) in RCA: 45] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2011] [Accepted: 06/13/2011] [Indexed: 02/07/2023]
Abstract
L-arginine (L-Arg) is metabolized by nitric oxide synthase and arginase enzymes. The gastric pathogen Helicobacter pylori causes peptic ulcer disease and gastric cancer. We have shown that alterations in L-Arg availability and metabolism into polyamines contribute significantly to the dysregulation of the host immune response to this infection. Nitric oxide (NO) derived from inducible NO synthase (iNOS) can kill H. pylori. There are multiple mechanisms leading to failure of this process, including competition for L-Arg substrate by H. pylori arginase, and induction of host macrophage arginase II (Arg2) and ornithine decarboxylase (ODC). Generation of spermine by ODC inhibits iNOS translation and NO-mediated H. pylori killing. Expression of ODC is dependent on formation of a unique AP-1 complex, leading to upregulation of c-Myc as a transcriptional enhancer. Macrophage apoptosis is mediated by oxidation of spermine via the enzyme spermine oxidase (SMO) that generates hydrogen peroxide (H(2)O(2)), and thus oxidative stress-induced mitochondrial membrane polarization. Our studies have demonstrated that apoptosis occurs through a pERK → pc-Fos/c-Jun → c-Myc → ODC → SMO pathway. In gastric epithelial cells, activation of oxidative stress by H. pylori is dependent on SMO induction and results in both apoptosis and DNA damage, such that inhibition or knockdown of SMO markedly attenuates these events. In summary, L-Arg metabolism by the arginase-ODC pathway and the activation of SMO leads to H. pylori-induced DNA damage and immune dysregulation through polyamine-mediated oxidative stress and impairment of antimicrobial NO synthesis. Our studies indicate novel targets for therapeutic intervention in H. pylori-associated diseases, including gastritis, ulcer disease, and gastric cancer.
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Affiliation(s)
- Rupesh Chaturvedi
- Division of Gastroenterology, Department of Medicine, Vanderbilt University School of Medicine, 1030C MRBIV, 2215 Garland Avenue, Nashville, TN 37232, USA
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Ghose P, Ali AQ, Fang R, Forbes D, Ballard B, Ismail N. The interaction between IL-18 and IL-18 receptor limits the magnitude of protective immunity and enhances pathogenic responses following infection with intracellular bacteria. THE JOURNAL OF IMMUNOLOGY 2011; 187:1333-46. [PMID: 21715688 DOI: 10.4049/jimmunol.1100092] [Citation(s) in RCA: 34] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
The binding of IL-18 to IL-18Rα induces both proinflammatory and protective functions during infection, depending on the context in which it occurs. IL-18 is highly expressed in the liver of wild-type (WT) C57BL/6 mice following lethal infection with highly virulent Ixodes ovatus ehrlichia (IOE), an obligate intracellular bacterium that causes acute fatal toxic shock-like syndrome. In this study, we found that IOE infection of IL-18Rα(-/-) mice resulted in significantly less host cell apoptosis, decreased hepatic leukocyte recruitment, enhanced bacterial clearance, and prolonged survival compared with infected WT mice, suggesting a pathogenic role for IL-18/IL-18Rα in Ehrlichia-induced toxic shock. Although lack of IL-18R decreased the magnitude of IFN-γ producing type-1 immune response, enhanced resistance of IL-18Rα(-/-) mice against Ehrlichia correlated with increased proinflammatory cytokines at sites of infection, decreased systemic IL-10 production, increased frequency of protective NKT cells producing TNF-α and IFN-γ, and decreased frequency of pathogenic TNF-α-producing CD8(+) T cells. Adoptive transfer of immune WT CD8(+) T cells increased bacterial burden in IL-18Rα(-/-) mice following IOE infection. Furthermore, rIL-18 treatment of WT mice infected with mildly virulent Ehrlichia muris impaired bacterial clearance and enhanced liver injury. Finally, lack of IL-18R signal reduced dendritic cell maturation and their TNF-α production, suggesting that IL-18 might promote the adaptive pathogenic immune responses against Ehrlichia by influencing T cell priming functions of dendritic cells. Together, these results suggested that the presence or absence of IL-18R signals governs the pathogenic versus protective immunity in a model of Ehrlichia-induced immunopathology.
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Affiliation(s)
- Purnima Ghose
- Department of Pathology, Meharry Medical College, Nashville, TN 37028, USA
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40
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Lin HY, Tang CH, Chen JH, Chuang JY, Huang SM, Tan TW, Lai CH, Lu DY. Peptidoglycan induces interleukin-6 expression through the TLR2 receptor, JNK, c-Jun, and AP-1 pathways in microglia. J Cell Physiol 2011; 226:1573-82. [DOI: 10.1002/jcp.22489] [Citation(s) in RCA: 54] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
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Sundquist M, Quiding-Järbrink M. Helicobacter pylori and its effect on innate and adaptive immunity: new insights and vaccination strategies. Expert Rev Gastroenterol Hepatol 2010; 4:733-44. [PMID: 21108593 DOI: 10.1586/egh.10.71] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Infection with the gastric bacterium Helicobacter pylori invariably leads to active chronic gastritis, and is strongly correlated to peptic ulcer disease, gastric adenocarcinoma and mucosa-associated lymphoid tissue lymphoma. The infection leads to local accumulation of inflammatory cells and strong activation of B- and T-cell immunity. Still, the immune response can not eliminate the bacteria, and unless antibiotic treatment is used, the infection is usually lifelong. During the last few years, several immunomodulatory properties of H. pylori have been described, which probably contribute to the inability of the immune system to eradicate the bacterium. Another factor promoting bacterial persistence is probably the induction of a substantial regulatory T-cell response by the infection. Several different immunization schedules have resulted in protective immunity in animal models, while in humans no reliable vaccine is available as yet. In this article, we describe the innate and adaptive immune responses to H. pylori, and the attempts to create an effective vaccine.
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Affiliation(s)
- Malin Sundquist
- Department of Microbiology and Immunology, The Sahlgrenska Academy at the University of Gothenburg, P.O. Box 435, 405 30 Göteborg, Sweden
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Asim M, Chaturvedi R, Hoge S, Lewis ND, Singh K, Barry DP, Algood HS, de Sablet T, Gobert AP, Wilson KT. Helicobacter pylori induces ERK-dependent formation of a phospho-c-Fos c-Jun activator protein-1 complex that causes apoptosis in macrophages. J Biol Chem 2010; 285:20343-57. [PMID: 20410304 DOI: 10.1074/jbc.m110.116988] [Citation(s) in RCA: 67] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022] Open
Abstract
Macrophages are essential components of innate immunity, and apoptosis of these cells impairs mucosal defense to microbes. Helicobacter pylori is a gastric pathogen that infects half of the world population and causes peptic ulcer disease and gastric cancer. The host inflammatory response fails to eradicate the organism. We have reported that H. pylori induces apoptosis of macrophages by generation of polyamines from ornithine decarboxylase (ODC), which is dependent on c-Myc as a transcriptional enhancer. We have now demonstrated that expression of c-Myc requires phosphorylation and nuclear translocation of ERK, which results in phosphorylation of c-Fos and formation of a specific activator protein (AP)-1 complex. Electromobility shift assay and immunoprecipitation revealed a previously unrecognized complex of phospho-c-Fos (pc-Fos) and c-Jun in the nucleus. Fluorescence resonance energy transfer demonstrated the interaction of pc-Fos and c-Jun. The capacity of this AP-1 complex to bind to putative AP-1 sequences was demonstrated by oligonucleotide pulldown and fluorescence polarization. Binding of the pc-Fos.c-Jun complex to the c-Myc promoter was demonstrated by chromatin immunoprecipitation. A dominant-negative c-Fos inhibited H. pylori-induced expression of c-Myc and ODC and apoptosis. H. pylori infection of mice induced a rapid infiltration of macrophages into the stomach. Concomitant apoptosis depleted these cells, and this was associated with formation of a pc-Fos.c-Jun complex. Treatment of mice with an inhibitor of ERK phosphorylation attenuated phosphorylation of c-Fos, expression of ODC, and apoptosis in gastric macrophages. A unique AP-1 complex in gastric macrophages contributes to the immune escape of H. pylori.
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Affiliation(s)
- Mohammad Asim
- Division of Gastroenterology, Vanderbilt University Medical Center, Nashville, Tennessee 37232, USA
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Sugimoto M, Ohno T, Graham DY, Yamaoka Y. Gastric mucosal interleukin-17 and -18 mRNA expression in Helicobacter pylori-induced Mongolian gerbils. Cancer Sci 2009; 100:2152-2159. [PMID: 19694753 PMCID: PMC3128813 DOI: 10.1111/j.1349-7006.2009.01291.x] [Citation(s) in RCA: 53] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2009] [Revised: 07/09/2009] [Accepted: 07/15/2009] [Indexed: 12/12/2022] Open
Abstract
Helicobacter pylori infection causes characteristic mucosal infiltration of inflammatory cells, resulting in the development of peptic ulcers and gastric cancer in approximately 10% of cases. Different clinical expressions of the infection may reflect different patterns of cytokine expression. Interleukin (IL)-1ss, tumor necrosis factor (TNF)-alpha, IL-17, and IL-18 have been reported to be involved in H. pylori-induced gastric mucosal inflammation, but the details and relation to different patterns of inflammation remain unclear. Moreover, the proinflammatory virulence factor outer inflammatory protein (OipA) was reported to be associated with gastric mucosal inflammatory cytokine levels. To clarify these findings, Mongolian gerbils were infected for up to 12 months with wild-type H. pylori 7.13 or with isogenic oipA mutants for 3 months, and mucosal cytokines (IL-1ss, IL-17, IL-18, and TNF-alpha) mRNA levels were then assessed using real-time RT-PCR. Antral mucosal IL-1beta and IL-18 mRNA levels peaked 1 month after infection, whereas the peak of TNF-alpha mRNA was at 6-12 months; IL-17 levels peaked at 12 months. The inflammatory cell infiltration and mRNA levels of all cytokines studied were significantly lower in oipA mutants than in wild-type-infected gerbils. Mucosal IL-1ss, IL-17, and TNF-alpha expression, but not that of IL-18, were significantly associated with the grade of inflammatory cell infiltration. The pattern of increased inflammatory cytokines differed relative to the phase of the infection and pattern of inflammation. OipA appears to play a role in IL-1ss, IL-17, and TNF-alpha expression and the resulting inflammation.
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Affiliation(s)
- Mitsushige Sugimoto
- Department of Medicine - Gastroenterology, Michael E. DeBakey Veterans Affairs Medical Center and Baylor College of Medicine, Houston, TX, USA
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Romero-Adrián TB, Leal-Montiel J, Monsalve-Castillo F, Mengual-Moreno E, McGregor EG, Perini L, Antúnez A. Helicobacter pylori: Bacterial Factors and the Role of Cytokines in the Immune Response. Curr Microbiol 2009; 60:143-55. [DOI: 10.1007/s00284-009-9518-4] [Citation(s) in RCA: 27] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2009] [Accepted: 09/25/2009] [Indexed: 12/26/2022]
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Abstract
Helicobacter pylori infects almost half of the population worldwide and represents the major cause of gastroduodenal diseases, such as duodenal and gastric ulcer, gastric adenocarcinoma, autoimmune gastritis, and B-cell lymphoma of mucosa-associated lymphoid tissue. Helicobacter pylori induces the activation of a complex and fascinating cytokine and chemokine network in the gastric mucosa. Different bacterial and environmental factors, other concomitant infections, and host genetics may influence the balance between mucosal tolerance and inflammation in the course of H. pylori infection. An inverse association between H. pylori prevalence and the frequencies of asthma and allergies was demonstrated, and the neutrophil activating protein of H. pylori was shown to inhibit the allergic inflammation of bronchial asthma. During the last year, significant progress was made on the road to the first efficient vaccine for H. pylori that will represent a novel and very important bullet against both infection and gastric cancer.
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Affiliation(s)
- Mario M D'Elios
- Department of Internal Medicine, University of Florence, Viale Morgagni 85, Florence, Italy.
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Alsaleh G, Suffert G, Semaan N, Juncker T, Frenzel L, Gottenberg JE, Sibilia J, Pfeffer S, Wachsmann D. Bruton's tyrosine kinase is involved in miR-346-related regulation of IL-18 release by lipopolysaccharide-activated rheumatoid fibroblast-like synoviocytes. THE JOURNAL OF IMMUNOLOGY 2009; 182:5088-97. [PMID: 19342689 DOI: 10.4049/jimmunol.0801613] [Citation(s) in RCA: 118] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/08/2023]
Abstract
MicroRNAs (miRNAs) have emerged as key players in the regulation of expression of target mRNAs expression. They have been associated with diverse biological processes, and recent studies have demonstrated that miRNAs play a role in inflammatory responses. We reported previously that LPS-activated fibroblast-like synoviocytes (FLS) isolated from rheumatoid arthritis (RA) patients express IL-18 mRNA but they do not release IL-18. Based on the observation that this inhibition was due to a rapid degradation of IL-18 mRNA, our group has conducted a study to identify miRNAs that could play a role in the "antiinflammatory" response of LPS-activated RA FLS. LPS challenge modulated the expression of 63 miRNAs as assessed by microarray analysis. Fifteen miRNAs were up-regulated, including miR-346, for which overexpression upon LPS treatment was validated by quantitative RT-PCR. We then transfected FLS with an antisense oligonucleotide targeting miR-346 and found that, in these conditions, IL-18 release could be measured upon LPS activation of FLS. Moreover, we also demonstrated that miR-346 indirectly regulated IL-18 release by indirectly inhibiting LPS-induced Bruton's tyrosine kinase expression in LPS-activated RA FLS. These findings suggest that miRNAs function as regulators that help to fine-tune the inflammatory response in RA.
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Affiliation(s)
- Ghada Alsaleh
- Laboratoire Physiopathologie des Arthrites, EA3432, Université Louis Pasteur de Strasbourg, Unité de Formation et de Recherche Sciences Pharmaceutiques, Illkirch, France
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Benoit BN, Kobayashi M, Kawakubo M, Takeoka M, Sano K, Zou J, Itano N, Tsutsui H, Noda T, Fukuda M, Nakayama J, Taniguchi S. Role of ASC in the mouse model of Helicobacter pylori infection. J Histochem Cytochem 2008; 57:327-38. [PMID: 19064716 DOI: 10.1369/jhc.2008.952366] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/10/2023] Open
Abstract
Apoptosis-associated speck-like protein containing a C-terminal caspase recruitment domain (ASC) is an adaptor molecule activating caspase-1 that stimulates pro-interleukin-1beta (pro-IL-1beta) and pro-IL-18, two pro-inflammatory cytokines with critical functions in host defense against a variety of pathogens. In this study, we investigated the role of ASC in the host defense against Helicobacter pylori utilizing ASC-deficient mice. Mice were orally inoculated with H. pylori; bacterial load, degree of gastritis, and mucosal levels of inflammatory cytokines were analyzed and compared with those obtained from wild-type mice. We found more prominent H. pylori colonization in ASC-deficient mice, as revealed by colony-forming unit counts. Both groups of mice developed gastritis; however, ASC-deficient mice showed significant attenuation of inflammation despite high H. pylori colonization. ELISA, immunohistochemistry, and quantitative RT-PCR analyses revealed complete suppression of IL-1beta and IL-18, and substantial reduction of interferon-gamma (IFN-gamma) expression, in ASC-deficient mice without apparent upregulation of other cytokines, including IL-10 and tumor necrosis factor-alpha. These results as a whole indicate that ASC exerts considerable influence on the host defense, acting through IL-1beta/IL-18 and subsequent IFN-gamma production, which in turn contributes to continuous chronic inflammatory response and consequent reduction of H. pylori colonization.
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Affiliation(s)
- Bekale N Benoit
- Department of Molecular Oncology, Institute on Aging and Adaptation, Shinshu University Graduate School of Medicine, 3-1-1 Asahi, Matsumoto, Nagano 390-8621, Japan
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Abstract
Helicobacter pylori infection causes chronic gastritis, peptic ulcer, and gastric cancer. Colonization of H. pylori in the stomach activates Toll-like and Nod-like receptors to induce not only innate immunity but also adaptive Th1 responses against this organism. Adaptive Th1 response is not sufficient to clear this organism and, as a result, the infection persists. Insufficient adaptive immunity can be explained by poor activation of Toll-like receptors, suppressive effects of bacterial factors, and induction of regulatory T-cell responses. Significant progress in the understanding of innate and adaptive immunity against H. pylori was made during the past year. Recent findings in the fields of vaccines for H. pylori are also reviewed.
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Affiliation(s)
- Tamara Vorobjova
- Department of Immunology, Institute of General and Molecular Pathology, University of Tartu, Tartu, Estonia.
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Yamaoka Y, Kato M, Asaka M. Geographic differences in gastric cancer incidence can be explained by differences between Helicobacter pylori strains. Intern Med 2008; 47:1077-83. [PMID: 18552463 PMCID: PMC3732488 DOI: 10.2169/internalmedicine.47.0975] [Citation(s) in RCA: 167] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
Certain populations with high incidences of Helicobacter pylori infection, such as those in East Asian countries, have high incidences of gastric cancer, while other highly infected populations, such as those in Africa and South Asia, do not. The various rates of gastric cancer associated with different geographic areas can be explained, at least in part, by the differences in the genotypes of H. pylori cagA and vacA. Populations expressing a high incidence of gastric cancer are mostly identical with regions where East Asian type CagA is predominant. In contrast, incidence of gastric cancer is low in Africa, South Asia, and Europe, where strains typically possess Western type CagA. Within East Asia, strains from northern parts, where the incidence of gastric cancer is high, predominantly possess the vacA m1 genotype, whereas the m2 genotype is predominant in southern parts where the gastric cancer incidence is low.
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Affiliation(s)
- Yoshio Yamaoka
- Department of Medicine-Gastroenterology, Michael E. DeBakey Veterans Affairs Medical Center and Baylor College of Medicine, Texas, USA.
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