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Gong Y, Lou Y, Han X, Chen K, Zhao Y, Zhang H, Zhang J, Xiong Y, Fu W, Ding S. Serum proteomic profiling of precancerous gastric lesions and early gastric cancer reveals signatures associated with systemic inflammatory response and metaplastic differentiation. Front Mol Biosci 2024; 11:1252058. [PMID: 38584705 PMCID: PMC10995311 DOI: 10.3389/fmolb.2024.1252058] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2023] [Accepted: 03/11/2024] [Indexed: 04/09/2024] Open
Abstract
The noninvasive detection technique using serum for large-scale screening is useful for the early diagnosis of gastric cancer (GC). Herein, we employed liquid chromatography mass spectrometry to determine the serum proteome signatures and related pathways in individuals with gastric precancerous (pre-GC) lesions and GC and explore the effect of Helicobacter pylori (H. pylori) infection. Differentially expressed proteins in GC and pre-GC compared with non-atrophic gastritis (NAG) group were identified. APOA4, a protein associated with metaplastic differentiation, and COMP, an extracellular matrix protein, were increased in the serum of patients with pre-GC lesions and GC. In addition, several inflammation-associated proteins, such as component C3, were decreased in the GC and pre-GC groups, which highlight a tendency for the inflammatory response to converge at the gastric lesion site during the GC cascade. Moreover, the abundance of proteins associated with oxidant detoxification was higher in the GC group compared with that in the NAG group, and these proteins were also increased in the serum of the H. pylori-positive GC group compared with that in the H. pylori-negative GC patients, reflecting the importance of oxidative stress pathways in H. pylori infection. Collectively, the findings of this study highlight pathways that play important roles in GC progression, and may provide potential diagnostic biomarkers for the detection of pre-GC lesions.
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Affiliation(s)
- Yueqing Gong
- Department of Gastroenterology, Peking University Third Hospital, Beijing, China
- Beijing Key Laboratory for Helicobacter Pylori Infection and Upper Gastrointestinal Diseases (BZ0371), Beijing, China
| | - Yaxin Lou
- Medical and Health Analytical Center, Peking University, Beijing, China
| | - Xiurui Han
- Department of Gastroenterology, Peking University Third Hospital, Beijing, China
- Beijing Key Laboratory for Helicobacter Pylori Infection and Upper Gastrointestinal Diseases (BZ0371), Beijing, China
| | - Keyan Chen
- Department of Gastroenterology, Peking University Third Hospital, Beijing, China
- Beijing Key Laboratory for Helicobacter Pylori Infection and Upper Gastrointestinal Diseases (BZ0371), Beijing, China
| | - Yang Zhao
- Department of Laboratory Medicine, Peking University Third Hospital, Beijing, China
| | - Hejun Zhang
- Department of Gastroenterology, Peking University Third Hospital, Beijing, China
- Beijing Key Laboratory for Helicobacter Pylori Infection and Upper Gastrointestinal Diseases (BZ0371), Beijing, China
| | - Jing Zhang
- Department of Gastroenterology, Peking University Third Hospital, Beijing, China
- Beijing Key Laboratory for Helicobacter Pylori Infection and Upper Gastrointestinal Diseases (BZ0371), Beijing, China
| | - Ying Xiong
- Department of Gastroenterology, Peking University Third Hospital, Beijing, China
- Beijing Key Laboratory for Helicobacter Pylori Infection and Upper Gastrointestinal Diseases (BZ0371), Beijing, China
| | - Weiwei Fu
- Department of Gastroenterology, Peking University Third Hospital, Beijing, China
- Beijing Key Laboratory for Helicobacter Pylori Infection and Upper Gastrointestinal Diseases (BZ0371), Beijing, China
| | - Shigang Ding
- Department of Gastroenterology, Peking University Third Hospital, Beijing, China
- Beijing Key Laboratory for Helicobacter Pylori Infection and Upper Gastrointestinal Diseases (BZ0371), Beijing, China
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Yoon K. Gastric Cancer: H. pylori and Macrophage Migration Inhibitory Factor. HELICOBACTER PYLORI 2023:321-326. [DOI: 10.1007/978-981-97-0013-4_25] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/04/2025]
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Increased Glycated Hemoglobin but Decreased Cholesterol after a Loss of Helicobacter pylori Infection: A Community-Based Longitudinal Metabolic Parameters Follow-Up Study. J Pers Med 2021; 11:jpm11100997. [PMID: 34683138 PMCID: PMC8538159 DOI: 10.3390/jpm11100997] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2021] [Revised: 09/25/2021] [Accepted: 09/28/2021] [Indexed: 11/16/2022] Open
Abstract
This study aimed to evaluate the impact of Helicobacter pylori (H. pylori) infection on metabolic parameters in a longitudinal follow-up manner. From August 2013 to August 2019, a community-based prospective study of H. pylori and metabolic syndrome (MetS) was performed in the northeastern region of Taiwan. A total of 1865 subjects were divided into four groups according to the serial results of urea breath test (UBT): new H. pylori infection (group 1, n = 41), null H. pylori infection (group 2, n = 897), loss of H. pylori infection (group 3, n = 369), and persistent H. pylori infection (group 4, n = 558). When comparing the subjects between groups 1 and 2, HBA1c was associated with a new H. pylori infection. Body mass index (BMI) was associated with a loss of H. pylori when comparing subjects between groups 3 and 4. Elevated HBA1c and high-density lipoprotein (HDL) levels but lower values of cholesterol and white blood cells (WBCs) were found during serial analyses within group 3. Conclusively, HBA1c was associated with a new H. pylori infection. BMI was associated with H. pylori loss. Increased HBA1c and HDL values but decreased values of cholesterol and WBC were associated with a loss of H. pylori infection.
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Abstract
Helicobacter pylori (H. pylori) represents one of the most widespread bacterial infections globally. Infection causes chronic gastritis and increases the risk of peptic ulcer disease, gastric adenocarcinoma, and mucosa-associated lymphoid tissue lymphoma. The pioneering discovery of H. pylori by Marshall and Warren in the early 1980s has initiated fervent research into H. pylori as a pathogen ever since. This chapter aims to provide an overview of our understanding of H. pylori infection and its management, with a focus on current options for diagnosis, the challenges associated with H. pylori eradication, and the need for alternative therapeutic strategies based on furthering our understanding of host: H. pylori interactions.
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Affiliation(s)
| | - Sinéad M Smith
- Department of Clinical Medicine, School of Medicine, Trinity College Dublin, Dublin 2, Ireland.
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Szulc-Dąbrowska L, Bossowska-Nowicka M, Struzik J, Toka FN. Cathepsins in Bacteria-Macrophage Interaction: Defenders or Victims of Circumstance? Front Cell Infect Microbiol 2020; 10:601072. [PMID: 33344265 PMCID: PMC7746538 DOI: 10.3389/fcimb.2020.601072] [Citation(s) in RCA: 42] [Impact Index Per Article: 8.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2020] [Accepted: 11/05/2020] [Indexed: 02/06/2023] Open
Abstract
Macrophages are the first encounters of invading bacteria and are responsible for engulfing and digesting pathogens through phagocytosis leading to initiation of the innate inflammatory response. Intracellular digestion occurs through a close relationship between phagocytic/endocytic and lysosomal pathways, in which proteolytic enzymes, such as cathepsins, are involved. The presence of cathepsins in the endo-lysosomal compartment permits direct interaction with and killing of bacteria, and may contribute to processing of bacterial antigens for presentation, an event necessary for the induction of antibacterial adaptive immune response. Therefore, it is not surprising that bacteria can control the expression and proteolytic activity of cathepsins, including their inhibitors – cystatins, to favor their own intracellular survival in macrophages. In this review, we summarize recent developments in defining the role of cathepsins in bacteria-macrophage interaction and describe important strategies engaged by bacteria to manipulate cathepsin expression and activity in macrophages. Particularly, we focus on specific bacterial species due to their clinical relevance to humans and animal health, i.e., Mycobacterium, Mycoplasma, Staphylococcus, Streptococcus, Salmonella, Shigella, Francisella, Chlamydia, Listeria, Brucella, Helicobacter, Neisseria, and other genera.
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Affiliation(s)
- Lidia Szulc-Dąbrowska
- Division of Immunology, Department of Preclinical Sciences, Institute of Veterinary Medicine, Warsaw University of Life Sciences-Szkoła Główna Gospodarstwa Wejskiego, Warsaw, Poland
| | - Magdalena Bossowska-Nowicka
- Division of Immunology, Department of Preclinical Sciences, Institute of Veterinary Medicine, Warsaw University of Life Sciences-Szkoła Główna Gospodarstwa Wejskiego, Warsaw, Poland
| | - Justyna Struzik
- Division of Immunology, Department of Preclinical Sciences, Institute of Veterinary Medicine, Warsaw University of Life Sciences-Szkoła Główna Gospodarstwa Wejskiego, Warsaw, Poland
| | - Felix N Toka
- Division of Immunology, Department of Preclinical Sciences, Institute of Veterinary Medicine, Warsaw University of Life Sciences-Szkoła Główna Gospodarstwa Wejskiego, Warsaw, Poland.,Center for Integrative Mammalian Research, Ross University School of Veterinary Medicine, Basseterre, Saint Kitts and Nevis
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Role of Host and Parasite MIF Cytokines during Leishmania Infection. Trop Med Infect Dis 2020; 5:tropicalmed5010046. [PMID: 32244916 PMCID: PMC7157535 DOI: 10.3390/tropicalmed5010046] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2019] [Revised: 11/18/2019] [Accepted: 12/06/2019] [Indexed: 12/28/2022] Open
Abstract
Macrophage migration inhibitory factor (MIF) is an immunoregulatory cytokine that has been extensively characterized in human disease and in mouse models. Its pro-inflammatory functions in mammals includes the retention of tissue macrophages and a unique ability to counteract the immunosuppressive activity of glucocorticoids. MIF also acts as a survival factor by preventing activation-induced apoptosis and by promoting sustained expression of inflammatory factors such as TNF-α and nitric oxide. The pro-inflammatory activity of MIF has been shown to be protective against Leishmania major infection in mouse models of cutaneous disease, however the precise role of this cytokine in human infections is less clear. Moreover, various species of Leishmania produce their own MIF orthologs, and there is evidence that these may drive an inflammatory environment that is detrimental to the host response. Herein the immune response to Leishmania in mouse models and humans will be reviewed, and the properties and activities of mammalian and Leishmania MIF will be integrated into the current understandings in this field. Furthermore, the prospect of targeting Leishmania MIF for therapeutic purposes will be discussed.
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Noto JM, Rose KL, Hachey AJ, Delgado AG, Romero-Gallo J, Wroblewski LE, Schneider BG, Shah SC, Cover TL, Wilson KT, Israel DA, Roa JC, Schey KL, Zavros Y, Piazuelo MB, Peek RM. Carcinogenic Helicobacter pylori Strains Selectively Dysregulate the In Vivo Gastric Proteome, Which May Be Associated with Stomach Cancer Progression. Mol Cell Proteomics 2019; 18:352-371. [PMID: 30455363 PMCID: PMC6356085 DOI: 10.1074/mcp.ra118.001181] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2018] [Indexed: 12/11/2022] Open
Abstract
Helicobacter pylori is the strongest risk factor for gastric cancer. Initial interactions between H. pylori and its host originate at the microbial-gastric epithelial cell interface, and contact between H. pylori and gastric epithelium activates signaling pathways that drive oncogenesis. One microbial constituent that increases gastric cancer risk is the cag pathogenicity island, which encodes a type IV secretion system that translocates the effector protein, CagA, into host cells. We previously demonstrated that infection of Mongolian gerbils with a carcinogenic cag+H. pylori strain, 7.13, recapitulates many features of H. pylori-induced gastric cancer in humans. Therefore, we sought to define gastric proteomic changes induced by H. pylori that are critical for initiation of the gastric carcinogenic cascade. Gastric cell scrapings were harvested from H. pylori-infected and uninfected gerbils for quantitative proteomic analyses using isobaric tags for relative and absolute quantitation (iTRAQ). Quantitative proteomic analysis of samples from two biological replicate experiments quantified a total of 2764 proteins, 166 of which were significantly altered in abundance by H. pylori infection. Pathway mapping identified significantly altered inflammatory and cancer-signaling pathways that included Rab/Ras signaling proteins. Consistent with the iTRAQ results, RABEP2 and G3BP2 were significantly up-regulated in vitro, ex vivo in primary human gastric monolayers, and in vivo in gerbil gastric epithelium following infection with H. pylori strain 7.13 in a cag-dependent manner. Within human stomachs, RABEP2 and G3BP2 expression in gastric epithelium increased in parallel with the severity of premalignant and malignant lesions and was significantly elevated in intestinal metaplasia and dysplasia, as well as gastric adenocarcinoma, compared with gastritis alone. These results indicate that carcinogenic strains of H. pylori induce dramatic and specific changes within the gastric proteome in vivo and that a subset of altered proteins within pathways with oncogenic potential may facilitate the progression of gastric carcinogenesis in humans.
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Affiliation(s)
- Jennifer M Noto
- Division of Gastroenterology, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee
| | - Kristie L Rose
- Department of Biochemistry, Mass Spectrometry Research Center, Vanderbilt University Medical Center, Nashville, Tennessee
| | - Amanda J Hachey
- Department of Biochemistry, Mass Spectrometry Research Center, Vanderbilt University Medical Center, Nashville, Tennessee
| | - Alberto G Delgado
- Division of Gastroenterology, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee
| | - Judith Romero-Gallo
- Division of Gastroenterology, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee
| | - Lydia E Wroblewski
- Division of Gastroenterology, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee
| | - Barbara G Schneider
- Division of Gastroenterology, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee
| | - Shailja C Shah
- Division of Gastroenterology, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee
| | - Timothy L Cover
- Division of Infectious Diseases, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee;; Department of Veterans Affairs, Tennessee Valley Healthcare System, Nashville, Tennessee;; Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, Tennessee
| | - Keith T Wilson
- Division of Gastroenterology, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee;; Department of Veterans Affairs, Tennessee Valley Healthcare System, Nashville, Tennessee;; Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, Tennessee
| | - Dawn A Israel
- Division of Gastroenterology, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee
| | - Juan Carlos Roa
- Department of Pathology, Pontificia Universidad Catolica de Chile, Santiago, Chile
| | - Kevin L Schey
- Department of Biochemistry, Mass Spectrometry Research Center, Vanderbilt University Medical Center, Nashville, Tennessee
| | - Yana Zavros
- Department of Pharmacology and System Physiology, University of Cincinnati, Cincinnati, Ohio
| | - M Blanca Piazuelo
- Division of Gastroenterology, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee
| | - Richard M Peek
- Division of Gastroenterology, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee;; Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, Tennessee;.
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Raza Y, Khan A, Khan AI, Khan S, Akhter S, Mubarak M, Ahmed A, Kazmi SU. Combination of Interleukin 1 Polymorphism and Helicobacter pylori Infection: an Increased Risk of Gastric Cancer in Pakistani Population. Pathol Oncol Res 2017; 23:873-880. [PMID: 28110439 DOI: 10.1007/s12253-017-0191-9] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/15/2016] [Accepted: 01/09/2017] [Indexed: 02/07/2023]
Abstract
Helicobacter pylori is one of the major risk factors involved in the development ofgastritis and gastric cancer (GC). H. pylori infection leads to increased production of pro-inflammatory cytokines by the host. Carriage of specific polymorphisms in cytokine genes may be associated with host susceptibility to the development of GC. We investigated the role of host genetic factors including polymorphisms of IL-1B and IL-1RN in correlation with gastritis and GC in H. pylori infected Pakistani population. A total of 230 gastritis cases and 100 GC cases were genotyped for IL 1B-511 and IL-1RN penta-allelic variable number of tandem repeats (VNTRs). A combination of IL-1B-511*T and IL-1RN*2 alleles (OR 19.064; 95% CI 2.319-156.7; p = 0.001) in H. pylori infected individuals had markedly increased risk of GC development. In Pakistani population, an increased risk of GC development is associated with the carriage of IL-1B-511*T and IL-1RN*2 alleles. Synergistic effect of H. pylori infection and IL-1B-511*T/IL-1RN*2 genotypes was also observed in association with significantly higher risk of developing GC. Further prospective and large scale studies are needed to establish the clinical impact of these findings.
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Affiliation(s)
- Yasir Raza
- Stem Cell Research Laboratory, Sindh Institute of Urology and Transplantation, Deewan Farooq Medical Complex, Chand Bibi Road, Karachi, Pakistan.
- Immunology and Infectious Diseases Research Laboratory, Department of Microbiology, University of Karachi, Karachi, Pakistan.
| | - Adnan Khan
- Immunology and Infectious Diseases Research Laboratory, Department of Microbiology, University of Karachi, Karachi, Pakistan
| | - Asif Iqbal Khan
- Department of Molecular Pathology, Dow University of Health and Sciences, Karachi, Pakistan
| | - Saeed Khan
- Department of Molecular Pathology, Dow University of Health and Sciences, Karachi, Pakistan
| | - Shakeel Akhter
- Department of Surgery and Medicine, Civil Hospital Karachi, Karachi, Pakistan
| | - Muhammad Mubarak
- Department of Histopathology, Sindh Institute of Urology and Transplantation, Karachi, Pakistan
| | - Ayaz Ahmed
- Dr. Panjwani Center For Molecular Medicine And Drug Research, Karachi, Pakistan
| | - Shahana Urooj Kazmi
- Immunology and Infectious Diseases Research Laboratory, Department of Microbiology, University of Karachi, Karachi, Pakistan
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Triantafyllou K, Kourikou A, Gazouli M, Karamanolis GP, Dimitriadis GD. Functional dyspepsia susceptibility is related to CD14, GNB3, MIF, and TRPV1 gene polymorphisms in the Greek population. Neurogastroenterol Motil 2017; 29. [PMID: 27430937 DOI: 10.1111/nmo.12913] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/09/2016] [Accepted: 06/27/2016] [Indexed: 02/08/2023]
Abstract
BACKGROUND Functional dyspepsia (FD) susceptibility might be influenced by polymorphisms of genes related to inflammation (CD14, macrophage migration inhibitory factor [MIF]), motor (GNB3), and sensory dysfunction (GNB3, TRPV1). We examined the association between CD14 rs2569190, GNB3 rs5443, MIF rs222747, and TRPV1 rs755622 gene polymorphisms with FD (Rome III criteria) in the Greek population. METHODS We genotyped 174 dyspeptics (115 with epigastric pain syndrome; 41% Helicobacter pylori positive) and 181 controls using polymerase chain reaction-based methods and we measured disease symptoms' burden with a modified Gastrointestinal Symptoms Related Scale. KEY RESULTS Homozygous for the TT genotype and the T allele of the CD14 gene were significantly associated (OR [95% CI]) with FD (2.65 [1.42-4.94] and 1.67 [1.23-2.26], respectively). The CT, TT genotypes, and T allele frequencies of GNB3 showed also significant association with FD (2.18 [1.35-3.54], 3.46 [1.30-9.23], and 2.18 [1.48-3.19]). While heterozygous GC MIF genotype was more common in dyspeptics (1.67 [1.07-2.60]), homozygous CC genotype and the C allele of TRPV1 gene were more prevalent in controls (0.47 [0.25-0.87] and 0.69 [0.51-0.92], respectively). None of the gene polymorphism was related either to dyspepsia clinical syndrome type or to the H. pylori infection. Among dyspeptics, CD14 TT genotype was related to lower epigastric pain burden score (p<.011); CD14 CT genotype was related to higher epigastric burning and nausea burden scores (p<.04) while belching score was lower (p=.027) in MIF CG dyspeptics. CONCLUSION & INFERENCES Functional dyspepsia susceptibility is related to CD14, GNB3, MIF, and TRPV1 gene polymorphisms, while CD14 and MIF gene variants are also associated with dyspepsia symptoms burden.
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Affiliation(s)
- K Triantafyllou
- Hepatogastroenterology Unit, Second Department of Internal Medicine, Research institute and Diabetes Center, Attikon University General Hospital, Medical School, National and Kapodistrian University, Athens, Greece
| | - A Kourikou
- Hepatogastroenterology Unit, Second Department of Internal Medicine, Research institute and Diabetes Center, Attikon University General Hospital, Medical School, National and Kapodistrian University, Athens, Greece
| | - M Gazouli
- Laboratory of Biology, Medical School, National and Kapodistrian University, Athens, Greece
| | - G P Karamanolis
- Academic Department of Gastroenterology, Laiko General Hospital, Medical School, National and Kapodistrian University, Athens, Greece
| | - G D Dimitriadis
- Hepatogastroenterology Unit, Second Department of Internal Medicine, Research institute and Diabetes Center, Attikon University General Hospital, Medical School, National and Kapodistrian University, Athens, Greece
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Yoon K. Gastric Cancer: H. pylori and Macrophage Migration Inhibitory Factor. HELICOBACTER PYLORI 2016:269-274. [DOI: 10.1007/978-981-287-706-2_24] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/04/2025]
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He LJ, Xie D, Hu PJ, Liao YJ, Deng HX, Kung HF, Zhu SL. Macrophage migration inhibitory factor as a potential prognostic factor in gastric cancer. World J Gastroenterol 2015; 21:9916-9926. [PMID: 26379396 PMCID: PMC4566384 DOI: 10.3748/wjg.v21.i34.9916] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/23/2015] [Revised: 04/13/2015] [Accepted: 07/15/2015] [Indexed: 02/06/2023] Open
Abstract
AIM: To investigate macrophage migration inhibitory factor (MIF) expression and its clinical relevance in gastric cancer, and effects of MIF knockdown on proliferation of gastric cancer cells.
METHODS: Tissue microarray containing 117 samples of gastric cancer and adjacent non-cancer normal tissues was studied for MIF expression by immunohistochemistry (IHC) semiquantitatively, and the association of MIF expression with clinical parameters was analyzed. MIF expression in gastric cancer cell lines was detected by reverse transcription-polymerase chain reaction (RT-PCR) and Western blot. Two pairs of siRNA targeting the MIF gene (MIF si-1 and MIF si-2) and one pair of scrambled siRNA as a negative control (NC) were designed and chemically synthesized. All siRNAs were transiently transfected in AGS cells with OligofectamineTM to knock down the MIF expression, with the NC group and mock group (OligofectamineTM alone) as controls. At 24, 48, and 72 h after transfection, MIF mRNA was analyzed by RT-PCR, and MIF and proliferating cell nuclear antigen (PCNA) proteins were detected by Western blot. The proliferative rate of AGS cells was assessed by methylthiazolyl tetrazolium (MTT) assay and colony forming assay.
RESULTS: The tissue microarray was informative for IHC staining, in which the MIF expression in gastric cancer tissues was higher than that in adjacent non-cancer normal tissues (P < 0.001), and high level of MIF was related to poor tumor differentiation, advanced T stage, advanced tumor stage, lymph node metastasis, and poor patient survival (P < 0.05 for all). After siRNA transfection, MIF mRNA was measured by real-time PCR, and MIF protein and PCNA were assessed by Western blot analysis. We found that compared to the NC group and mock group, MIF expression was knocked down successfully in gastric cancer cells, and PCNA expression was downregulated with MIF knockdown as well. The cell counts and the doubling times were assayed by MTT 4 d after transfection, and colonies formed were assayed by colony forming assay 10 d after transfection; all these showed significant changes in gastric cancer cells transfected with specific siRNA compared with the control siRNA and mock groups (P < 0.001 for all).
CONCLUSION: MIF could be of prognostic value in gastric cancer and might be a potential target for small-molecule therapy.
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12
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Kourikou A, Karamanolis GP, Dimitriadis GD, Triantafyllou K. Gene polymorphisms associated with functional dyspepsia. World J Gastroenterol 2015; 21:7672-7682. [PMID: 26167069 PMCID: PMC4491956 DOI: 10.3748/wjg.v21.i25.7672] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/23/2015] [Revised: 04/07/2015] [Accepted: 05/21/2015] [Indexed: 02/06/2023] Open
Abstract
Functional dyspepsia (FD) is a constellation of functional upper abdominal complaints with poorly elucidated pathophysiology. However, there is increasing evidence that susceptibility to FD is influenced by hereditary factors. Genetic association studies in FD have examined genotypes related to gastrointestinal motility or sensation, as well as those related to inflammation or immune response. G-protein b3 subunit gene polymorphisms were first reported as being associated with FD. Thereafter, several gene polymorphisms including serotonin transporter promoter, interlukin-17F, migration inhibitory factor, cholecystocynine-1 intron 1, cyclooxygenase-1, catechol-o-methyltransferase, transient receptor potential vanilloid 1 receptor, regulated upon activation normal T cell expressed and secreted, p22PHOX, Toll like receptor 2, SCN10A, CD14 and adrenoreceptors have been investigated in relation to FD; however, the results are contradictory. Several limitations underscore the value of current studies. Among others, inconsistencies in the definitions of FD and controls, subject composition differences regarding FD subtypes, inadequate samples, geographical and ethnical differences, as well as unadjusted environmental factors. Further well-designed studies are necessary to determine how targeted genes polymorphisms, influence the clinical manifestations and potentially the therapeutic response in FD.
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Nalbantoglu S, Tabel Y, Mir S, Berdeli A. Lack of association between macrophage migration inhibitory factor gene promoter (-173 G/C) polymorphism and childhood Henoch-Schönlein purpura in Turkish patients. Cytokine 2013; 62:160-4. [PMID: 23523092 DOI: 10.1016/j.cyto.2013.02.024] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2012] [Revised: 01/31/2013] [Accepted: 02/21/2013] [Indexed: 11/26/2022]
Abstract
Henoch-Schönlein purpura (HSP) is a small-vessel vasculitis of autoimmune hypersensitivity with rash, arthritis, abdominal pain and renal involvements. Macrophage migration inhibitory factor (MIF) is a immunoregulatory proinflammatory cytokine, and a major mediator at the inflammatory sites. The pathogenesis of HSP has not been fully elucidated. Here we aimed to assess the influence of macrophage migration inhibitory factor gene (-173 G/C) polymorphism in the susceptibility and clinical expression of patients with Henoch-Schönlein purpura (HSP). HSP patients (n:139) and ethnically matched healthy controls (n:100) were genotyped by PCR-RFLP. Genotype analysis of both polymorphisms did not reveal a significant deviation from Hardy-Weinberg equilibrium in any group (p > 0.05). No significant difference was obtained in genotype distribution (p > 0.05) and allele frequencies (p > 0.05) between patients and controls. A statistically significant genotype-phenotype correlation was not obtained when HSP patients were stratified by the presence of certain systemic complications and the macrophage migration inhibitory factor gene (-173 G/C) polymorphism (p > 0.05). A significant risk was not observed in the subjects both with the GC+CC genotype (p = 0.06, OR: 0.5538, 95% CI: 0.2985-1.0274) and C allele (odds ratio: C vs. G: 1.799, 95% CI: 1.002-3.23, p = 0.05). Our findings suggest that MIF gene -173 G/C polymorphism is not associated with HSP in the present Turkish population.
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Affiliation(s)
- Sinem Nalbantoglu
- Ege University, School of Medicine, Children's Hospital, Molecular Medicine Laboratory, Bornova, Izmir, Turkey.
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14
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Li X, Lan HY, Huang XR, Zhang C, Jin LJ. Expression profile of macrophage migration-inhibitory factor in human gingiva and reconstituted human gingival epithelia stimulated by Porphyromonas gingivalis lipopolysaccharide. J Periodontal Res 2013; 48:527-32. [PMID: 23298274 DOI: 10.1111/jre.12035] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 10/30/2012] [Indexed: 11/29/2022]
Abstract
BACKGROUND AND OBJECTIVE Macrophage migration-inhibitory factor (MIF) plays crucial roles in the recruitment and activation of macrophages as well as in helping to kill bacteria. This study investigated the expression profile of MIF in human gingiva under different periodontal conditions and its expression patterns induced by Porphyromonas gingivalis lipopolysaccharide (LPS) in gingival epithelia. MATERIAL AND METHODS Gingival tissue samples were collected from deep pockets and clinically healthy sites of 22 nonsmoking subjects with chronic periodontitis. The expression of MIF mRNA and protein was evaluated using real-time PCR and immunohistochemistry, respectively. The in vitro study analyzed the effects of P. gingivalis LPS on the expression of MIF in a reconstituted human gingival epithelia (RHGE) model. RESULTS In gingival epithelia, MIF protein was diffusely expressed from the basal layer to the granular and spinous layers; whereas, in the underlying connective tissues, MIF was observed around the dilated blood vessels in the deep-pocket tissues. A significantly lower level of expression of MIF mRNA and an increased level of expression of MIF protein were found in deep-pocket tissues compared with clinically healthy tissues. Expression of MIF mRNA in the RHGE model was significantly down-regulated by P. gingivalis LPS. CONCLUSION The present study suggests that MIF expression may be related to periodontal conditions and that its expression profile could be modulated by P. gingivalis LPS. MIF may play a role in periodontal pathogenesis.
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Affiliation(s)
- X Li
- Faculty of Dentistry, The University of Hong Kong, Hong Kong SAR, China
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15
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Li H, Zang J, Wang P, Dai L, Zhang J, Wang K. Gastric cancer susceptibility in gastric cancer relatives: attributable risks of Macrophage migration inhibitory factor promoter polymorphism and Helicobacter pylori. Cytokine 2012; 60:346-351. [PMID: 22892326 DOI: 10.1016/j.cyto.2012.07.015] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2011] [Revised: 06/20/2012] [Accepted: 07/12/2012] [Indexed: 01/30/2023]
Abstract
The purpose of this study is to assess attributable effects of Macrophage migration inhibitory factor (MIF) promoter region polymorphisms and Helicobacter pylori infection to the susceptibility to gastric cancer. 296 individuals from non-cardia gastric cancer case families and 319 individuals from control families were obtained from Henan Province, China. The results showed the frequencies of MIF (-173 C/C and -794 non-CATT(5)carrier) genotypes were significantly higher in the family members of gastric cancer cases than that in the controls family (-173: OR=2.59; -794: OR=2.65), and the ORs reduced with decreasing relative degrees. Multivariate analysis showed that MIF-173 C and -794 non-CATT(5) alleles synergized with H. pylori for the risk of gastric cancer (OR=14.64). The attributable risk percent (ARP) and the population attributable risk percent (PARP) attributed to interaction of MIF-173 C/C and MIF-794 non-CATT(5)carrier were 72.3% and 4.7%, respectively. The MIF risk genotypes and H. pylori conferred a joint ARP of 93.2% to gastric cancer. In summary, Possession of -173 G→C substitution and -794 non-CATT(5)carrier in the MIF promoter region are associated with increased susceptibility to non-cardia gastric cancer. H. pylori infection increases the risks of MIF polymorphisms for susceptibility with gastric cancer.
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Affiliation(s)
- Haixia Li
- Department of Epidemiology, College of Public Health, Zhengzhou University, No. 100, Science Ave., Zhengzhou 450001, China
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16
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Fehlings M, Drobbe L, Moos V, Renner Viveros P, Hagen J, Beigier-Bompadre M, Pang E, Belogolova E, Churin Y, Schneider T, Meyer TF, Aebischer T, Ignatius R. Comparative analysis of the interaction of Helicobacter pylori with human dendritic cells, macrophages, and monocytes. Infect Immun 2012; 80:2724-34. [PMID: 22615251 PMCID: PMC3434561 DOI: 10.1128/iai.00381-12] [Citation(s) in RCA: 79] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2012] [Accepted: 05/14/2012] [Indexed: 12/15/2022] Open
Abstract
Helicobacter pylori may cause chronic gastritis, gastric cancer, or lymphoma. Myeloid antigen-presenting cells (APCs) are most likely involved in the induction and expression of the underlying inflammatory responses. To study the interaction of human APC subsets with H. pylori, we infected monocytes, monocyte-derived dendritic cells (DCs), and monocyte-derived (classically activated; M1) macrophages with H. pylori and analyzed phenotypic alterations, cytokine secretion, phagocytosis, and immunostimulation. Since we detected CD163(+) (alternatively activated; M2) macrophages in gastric biopsy specimens from H. pylori-positive patients, we also included monocyte-derived M2 macrophages in the study. Upon H. pylori infection, monocytes secreted interleukin-1β (IL-1β), IL-6, IL-10, and IL-12p40 (partially secreted as IL-23) but not IL-12p70. Infected DCs became activated, as shown by the enhanced expression of CD25, CD80, CD83, PDL-1, and CCR7, and secreted IL-1β, IL-6, IL-10, IL-12p40, IL-12p70, and IL-23. However, infection led to significantly downregulated CD209 and suppressed the constitutive secretion of macrophage migration inhibitory factor (MIF). H. pylori-infected M1 macrophages upregulated CD14 and CD32, downregulated CD11b and HLA-DR, and secreted mainly IL-1β, IL-6, IL-10, IL-12p40, and IL-23. Activation of DCs and M1 macrophages correlated with increased capacity to induce T-cell proliferation and decreased phagocytosis of dextran. M2 macrophages upregulated CD14 and CD206 and secreted IL-10 but produced less of the proinflammatory cytokines than M1 macrophages. Thus, H. pylori affects the functions of human APC subsets differently, which may influence the course and the outcome of H. pylori infection. The suppression of MIF in DCs constitutes a novel immune evasion mechanism exploited by H. pylori.
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Affiliation(s)
- Michael Fehlings
- Institute of Tropical Medicine and International Health, Charité-Universitätsmedizin Berlin, Berlin, Germany
- Department of Molecular Biology, Max Planck Institute for Infection Biology, Berlin, Germany
| | - Lea Drobbe
- Department of Molecular Biology, Max Planck Institute for Infection Biology, Berlin, Germany
| | - Verena Moos
- Medical Clinic I, Charité-Universitätsmedizin Berlin, Berlin, Germany
| | - Pablo Renner Viveros
- Institute of Tropical Medicine and International Health, Charité-Universitätsmedizin Berlin, Berlin, Germany
| | - Jana Hagen
- Institute of Tropical Medicine and International Health, Charité-Universitätsmedizin Berlin, Berlin, Germany
- Department of Molecular Biology, Max Planck Institute for Infection Biology, Berlin, Germany
| | | | - Ervinna Pang
- Department of Molecular Biology, Max Planck Institute for Infection Biology, Berlin, Germany
| | - Elena Belogolova
- Department of Molecular Biology, Max Planck Institute for Infection Biology, Berlin, Germany
| | - Yuri Churin
- Department of Molecular Biology, Max Planck Institute for Infection Biology, Berlin, Germany
| | - Thomas Schneider
- Medical Clinic I, Charité-Universitätsmedizin Berlin, Berlin, Germany
| | - Thomas F. Meyer
- Department of Molecular Biology, Max Planck Institute for Infection Biology, Berlin, Germany
| | - Toni Aebischer
- Department of Molecular Biology, Max Planck Institute for Infection Biology, Berlin, Germany
- Robert Koch Institute, Berlin, Germany
| | - Ralf Ignatius
- Institute of Tropical Medicine and International Health, Charité-Universitätsmedizin Berlin, Berlin, Germany
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Ohkawara T, Takeda H, Ohnishi S, Kato M, Nishihira J, Asaka M. Macrophage migration inhibitory factor contributes to development of nonsteroidal anti-inflammatory drugs-induced gastric injury in mice. Int Immunopharmacol 2010; 11:418-23. [PMID: 21185918 DOI: 10.1016/j.intimp.2010.12.009] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2010] [Revised: 12/09/2010] [Accepted: 12/10/2010] [Indexed: 01/06/2023]
Abstract
Macrophage migration inhibitory factor (MIF) plays an important role in the development of inflammation. In this study, we evaluated the role of MIF in gastric injury induced by non-steroidal anti-inflammatory drugs (NSAIDs) in mice. To induce gastric injury, mice were intraperitnoneally injected with 35 mg/kg of indomethacin. The level of MIF protein was up-regulated and severe gastric injury with inflammatory infiltrate was observed in the stomach of wild-type (WT) mice treated with indomethacin. The severity of gastric injury in MIF-deficient mice was less than that in WT mice. Increase in TNF-α in gastric tissue of mice treated with indomethacin was suppressed in MIF-deficient mice. The expression of HSP70, which has a cytoprotective role, was remarkably up-regulated in the stomach of MIF-deficient mice compared with WT mice after indomethacin treatment. Our results suggest that MIF is essential for the development of gastric injury-induced by NSAIDs.
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Affiliation(s)
- Tatsuya Ohkawara
- Department of Gastroenterology and Hematology, Hokkaido University Graduate School of Medicine, Kita 15, Nishi 7, Sapporo 060-8638, Japan.
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18
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Li ZW, Wu Y, Sun Y, Liu LY, Tian MM, Feng GS, You WC, Li JY. Inflammatory cytokine gene polymorphisms increase the risk of atrophic gastritis and intestinal metaplasia. World J Gastroenterol 2010; 16:1788-94. [PMID: 20380014 PMCID: PMC2852830 DOI: 10.3748/wjg.v16.i14.1788] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To investigate the effects of interleukin-8 (IL-8), macrophage migration inhibitory factor (MIF) gene polymorphisms, Helicobacter pylori (H. pylori) infection, on the risk of developing severe chronic atrophic gastritis (SCAG) and intestinal metaplasia (IM).
METHODS: A total of 372 cases were selected from a cohort study in Linqu County, a high risk area for gastric cancer (GC) in northern China. To obtain a sufficient group size, patients with normal or superficial gastritis were included. Based on an average follow-up period of 56 mo, the 372 cases were divided into no progression group (no histological progression from normal or superficial gastritis, n = 137), group I (progressed from normal or superficial gastritis to SCAG, n = 134) and group II (progressed from normal or superficial gastritis to IM, n = 101). IL-8, MIF gene polymorphisms were detected by polymerase chain reaction-based denaturing high-performance liquid chromatography analysis and DNA sequencing.
RESULTS: An increased risk of SCAG was found in subjects with IL-8-251 AA genotype [odds ratio (OR) = 2.62, 95% CI: 1.23-5.72] or IL-8-251 A allele carriers (AA + AT) (OR = 1.81, 95% CI: 1.06-3.09). An elevated risk of IM was found in subjects with IL-8-251 AT genotype (OR = 2.27, 95% CI: 1.25-4.14) or IL-8-251 A allele carriers (OR = 2.07, 95% CI: 1.16-3.69). An increased risk of SCAG was found in subjects with MIF-173 GC genotype (OR = 2.36, 95% CI: 1.38-4.02) or MIF-173 C allele carriers (GC + CC) (OR = 2.07, 95% CI: 1.21-3.55). An elevated risk of IM was found in subjects with MIF-173 CC genotype (OR = 2.27, 95% CI: 1.16-4.46) or MIF-173 C allele carriers (OR = 3.84, 95% CI: 1.58-9.34). The risk of SCAG and IM was more evident in subjects carrying IL-8-251 A allele (OR = 6.70, 95% CI: 1.29-9.78) or MIF-173 C allele (OR = 6.54, 95% CI: 2.97-14.20) and positive for H. pylori infection.
CONCLUSION: IL-8-251 and MIF-173 gene polymorphisms are significantly associated with the risk of SCAG and IM in a population with a high risk of GC in Linqu County, Shandong Province, China.
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19
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Xia HHX, Yang Y, Chu KM, Gu Q, Zhang YY, He H, Wong WM, Leung SY, Yuen ST, Yuen MF, Chan AOO, Wong BCY. Serum macrophage migration-inhibitory factor as a diagnostic and prognostic biomarker for gastric cancer. Cancer 2009; 115:5441-5449. [PMID: 19685530 DOI: 10.1002/cncr.24609] [Citation(s) in RCA: 41] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/05/2023]
Abstract
BACKGROUND This study aimed to determine the potential diagnostic value of migration-inhibitory factor (MIF) for gastric cancer in patients presenting with dyspepsia and its prognostic value for gastric cancer. METHODS A cohort of 97 patients with histologically confirmed gastric adenocarcinoma and 222 patients with dyspepsia were recruited. Enzyme-linked immunosorbent assay was used to measure serum MIF and carcinoembryonic antigen (CEA). RESULTS The serum MIF concentrations were 6554.0 +/- 204.1 pg/mL and 1453.7 +/- 79.9 pg/mL, respectively, in gastric cancer patients and dyspeptic patients (P < .001). Serum MIF levels increased with the advancing gastric pathologies (P < .001). With the cutoff value of 3230 pg/mL, serum MIF had sensitivity, specificity, and accuracy of 83.5%, 92.3%, and 89.7%, respectively, in diagnosing gastric cancer, whereas the rates were 60.8%, 83.3%, and 76.5%, respectively, for serum CEA. Gastric cancer patients with serum MIF levels above 6600 pg/mL had a lower 5-year survival rate than those with serum MIF level below that level (P = .012). Higher serum CEA levels were also associated with poor survival. The prediction for 5-year survival was even better (P = .0001), using a combination of serum MIF and CEA. CONCLUSIONS Serum MIF level, which correlates with gastric MIF expression, is a better molecular marker than CEA in diagnosing gastric cancer in patients presenting with dyspepsia. A combination of serum MIF and CEA predicts 5-year survival better than the individual test.
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20
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Wong BLW, Zhu SL, Huang XR, Ma J, Xia HHX, Bucala R, Wong BCY, Lan HY. Essential role for macrophage migration inhibitory factor in gastritis induced by Helicobacter pylori. THE AMERICAN JOURNAL OF PATHOLOGY 2009; 174:1319-1328. [PMID: 19286569 PMCID: PMC2671363 DOI: 10.2353/ajpath.2009.080708] [Citation(s) in RCA: 26] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Accepted: 12/22/2008] [Indexed: 02/05/2023]
Abstract
Macrophage migration inhibitory factor (MIF) is an upstream regulator of immune and inflammatory responses; however, its role in Helicobacter pylori (HP)-associated gastritis remains unknown. We infected MIF knockout (KO) and wild-type mice with SS1 HP and found that 2 weeks after infection, MIF and its receptor CD74 were markedly up-regulated in wild-type mice. This up-regulation preceded the up-regulation of both tumor necrosis factor-alpha and intercellular adhesion molecule-1, as well as the development of moderate gastritis at 8 weeks, as determined by a significant infiltration of neutrophils, T cells, and macrophages. In contrast, KO mice were protected against HP-induced gastritis by preventing the up-regulation of CD74 and Th1-mediated immune injury, including a reduction in the Th1 transcriptional factor T-bet and the expression of interferon-gamma. Additionally, inhibition of skin delayed type hypersensitivity reactions to HP antigens in KO mice also suggested a critical role for MIF in cell-mediated injury. A regulatory role for MIF in Th1-immune responses was further demonstrated by the finding that antigen-primed CD4(+) T cells lacking MIF failed to differentiate into the Th1 phenotype; these cells were instead promoted to Th2 differentiation after challenge with HP antigen in vitro. Results from this study indicated that inhibition of HP-induced innate immune responses and Th1-mediated immune injury may be the key mechanisms by which KO mice failed to develop gastritis after HP infection.
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Affiliation(s)
- Benny L W Wong
- Department of Medicine, The University of Hong Kong, Pokfulam, Hong Kong
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21
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Kariya S, Okano M, Fukushima K, Nomiya S, Kataoka Y, Nomiya R, Akagi H, Nishizaki K. Expression of inflammatory mediators in the otitis media induced by Helicobacter pylori antigen in mice. Clin Exp Immunol 2008; 154:134-40. [PMID: 18727622 DOI: 10.1111/j.1365-2249.2008.03740.x] [Citation(s) in RCA: 15] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023] Open
Abstract
Helicobacter pylori is a Gram-negative bacterium that is recognized as one of the key factors in gastric diseases such as gastritis, peptic ulcer and gastric cancer. Recent studies have shown relationships between H. pylori and extra-digestive diseases, and the presence of H. pylori in the middle ear and upper respiratory tract has been reported. However, the role of H. pylori in middle ear disease remains unclear. The present study demonstrated that H. pylori whole-cell protein directly induces macrophage migration inhibitory factor, macrophage inflammatory protein 2, interleukin 1 beta and tumor necrosis factor alpha in middle ear epithelium in mice, and severe proliferation of inflammatory cells was observed in middle ear cavity inoculated with H. pylori whole-cell protein. In addition, trans-tympanic injection of macrophage migration inhibitory factor up-regulated expression of macrophage inflammatory protein 2 in the middle ear. These findings indicate that H. pylori infection causes immunological inflammation in middle ear epithelium, and H. pylori may play a significant role in otitis media.
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Affiliation(s)
- S Kariya
- Department of Otolaryngology-Head and Neck Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan.
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22
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Ohkawara T, Nishihira J, Kato M, Takeda H, Sugiyama T, Asaka M. Serum level of macrophage migration inhibitory factor in Helicobacter pylori-infected patients. Intern Med 2007; 46:789-90. [PMID: 17541237 DOI: 10.2169/internalmedicine.46.6242] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/06/2022] Open
Affiliation(s)
- Tatsuya Ohkawara
- Department of Medical Information, Hokkaido Information University, Ebetsu.
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23
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Lebiedz P, Heidemann J, Lugering A, Riedel S, Herbst H, Domschke W, Kucharzik T, Maaser C. Gastric epithelial expression of macrophage migration inhibitory factor is not altered by Helicobacter pylori infection in humans. Helicobacter 2006; 11:258-65. [PMID: 16882329 DOI: 10.1111/j.1523-5378.2006.00411.x] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
BACKGROUND Recent reports have shown an upregulation of macrophage migration inhibitory factor (MIF) during gastric ulcer development in a rat model and elevated counts of MIF-positive cells in biopsies from Helicobacter pylori-infected patients. H. pylori infection is a proven cofactor in humans causing gastritis and gastric ulcers. The aim of this study was to characterize MIF expression in human gastric epithelial cells in response to H. pylori. METHODS MIF mRNA and MIF protein expression was detected in human gastric epithelial cell lines after stimulation with proinflammatory cytokines or infection with H. pylori (cagA+/vacA+) using real-time reverse transcriptase-polymerase and enzyme-linked immunosorbent assay. Interleukin-8 secretion was measured as positive control. MIF mRNA and MIF protein expression was assessed in H. pylori-positive and -negative human gastric biopsy samples. RESULTS While interleukin-8 mRNA expression and interleukin-8 secretion were upregulated in gastric epithelial cells in vitro after H. pylori infection, no changes in MIF mRNA expression and MIF secretion could be detected. We found no significant differences in MIF expression in total RNA extracted from gastric biopsy tissue when comparing H. pylori-positive to control patients. Likewise, MIF protein expression in gastric epithelium was unaffected by H. pylori infection as compared to uninfected tissue. CONCLUSIONS While an increased MIF expression and positive effects of MIF blockade in ulcer healing have been shown in a rodent model and elevated numbers of MIF-positive cells have been found in H. pylori-infected human tissue, we herein could not confirm any differences in human gastric epithelial MIF expression and secretion after H. pylori infection in vitro and in vivo.
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Affiliation(s)
- Pia Lebiedz
- Department of Medicine B, University of Muenster, Albert-Schweitzer-Strasse 33, D-48129 Muenster, Germany.
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24
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Schaefer TM, Fahey JV, Wright JA, Wira CR. Migration inhibitory factor secretion by polarized uterine epithelial cells is enhanced in response to the TLR3 agonist poly (I:C). Am J Reprod Immunol 2006; 54:193-202. [PMID: 16135010 DOI: 10.1111/j.1600-0897.2005.00298.x] [Citation(s) in RCA: 17] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/26/2023] Open
Abstract
PROBLEM Uterine epithelial cells produce cytokines that stimulate leukocytes in response to a microbial insult. The goals of this study were to determine if uterine epithelial cells produce the pro-inflammatory cytokine macrophage migration inhibitory factor (MIF), and to see if toll-like receptor (TLR) agonists stimulate MIF secretion. METHODS OF STUDY Human uterine epithelial cells were isolated and grown in cell culture inserts. Levels of MIF secretion were examined by ELISA and MIF messenger RNA (mRNA) expression was examined using real time RT-PCR. RESULTS Uterine epithelial cells constitutively secrete MIF and exposure to the TLR3 agonist poly (I:C) resulted in enhanced apical secretion of MIF. MIF secretion appeared to be from pre-formed intracellular stores, since exposure of epithelial cells to poly (I:C) had little effect on the expression of MIF-mRNA. CONCLUSIONS These results demonstrate that uterine epithelial cells constitutively produce MIF and stimulation with poly (I:C) results in enhanced MIF production. This suggests that MIF secretion by uterine epithelial cells may play a critical role in innate immune responses against viral pathogens mediated through TLR3.
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Affiliation(s)
- Todd M Schaefer
- Department of Physiology, Dartmouth Medical School, 710W Borwell, 1 Medical Center Drive, Lebanon, NH 03756, USA.
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Abstract
Pro-inflammatory cytokines such as IL-18, IFN-gamma, and IL-1beta play a significant role in the inflammation induced by Helicobacter. During the recent years of H. pylori research, the main focus has been on development of vaccines for therapeutic or prophylactic use against the infection. Both bacterial components of H. pylori as well as engineered vaccines have been tested as well as different forms of administration including systemic and oral/intranasal pathways.
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Affiliation(s)
- Henrik Permin
- Department of Internal Medicine, Bispebjerg Hospital, DK-2400 Copenhagen NV, Denmark.
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26
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Barrera CA, Beswick EJ, Sierra JC, Bland D, Espejo R, Mifflin R, Adegboyega P, Crowe SE, Ernst PB, Reyes VE. Polarized expression of CD74 by gastric epithelial cells. J Histochem Cytochem 2005; 53:1481-9. [PMID: 15923369 PMCID: PMC3957538 DOI: 10.1369/jhc.4a6552.2005] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
CD74 is known as the major histocompatibility complex (MHC) class II-associated invariant chain (Ii) that regulates the cell biology and functions of MHC class II molecules. Class II MHC and Ii expression was believed to be restricted to classical antigen-presenting cells (APC); however, during inflammation, other cell types, including mucosal epithelial cells, have also been reported to express class II MHC molecules. Given the importance of Ii in the biology of class II MHC, we sought to examine the expression of Ii by gastric epithelial cells (GEC) to determine whether class II MHC molecules in these nonconventional APC cells were under the control of Ii and to further support the role that these cells may play in local immune and inflammatory responses during Helicobacter pylori infection. Thus we examined the expression of Ii on GEC from human biopsy samples and then confirmed this observation using independent methods on several GEC lines. The mRNA for Ii was detected by RT-PCR, and the various protein isoforms were also detected. Interestingly, these cells have a high level expression of surface Ii, which is polarized to the apical surface. These studies are the first to demonstrate the constitutive expression of Ii by human GEC.
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Affiliation(s)
- Carlos A. Barrera
- Department of Pathology (CAB, PA), University of Texas Medical Branch, Galveston, Texas
| | - Ellen J. Beswick
- Department of Pediatrics (EJB, JCS, RE, VER), University of Texas Medical Branch, Galveston, Texas
| | - Johanna C. Sierra
- Department of Pediatrics (EJB, JCS, RE, VER), University of Texas Medical Branch, Galveston, Texas
| | - David Bland
- Department of Microbiology and Immunology (DB, VER), University of Texas Medical Branch, Galveston, Texas
| | - Rosario Espejo
- Department of Pediatrics (EJB, JCS, RE, VER), University of Texas Medical Branch, Galveston, Texas
| | - Randy Mifflin
- Department of Internal Medicine (RM), University of Texas Medical Branch, Galveston, Texas
| | - Patrick Adegboyega
- Department of Pathology (CAB, PA), University of Texas Medical Branch, Galveston, Texas
| | - Sheila E. Crowe
- Digestive Health Center, Department of Internal Medicine, University of Virginia, Charlottesville, Virginia (SEC, PBE)
| | - Peter B. Ernst
- Digestive Health Center, Department of Internal Medicine, University of Virginia, Charlottesville, Virginia (SEC, PBE)
| | - Victor E. Reyes
- Department of Pediatrics (EJB, JCS, RE, VER), University of Texas Medical Branch, Galveston, Texas
- Department of Microbiology and Immunology (DB, VER), University of Texas Medical Branch, Galveston, Texas
- Correspondence to: Dr. Victor E. Reyes, Route 0366, Children's Hospital, 301 University Boulevard, UTMB, Galveston, TX 77555-0366. E-mail:
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27
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Xia HHX, Lam SK, Chan AOO, Lin MCM, Kung HF, Ogura K, Berg DE, Wong BCY. Macrophage migration inhibitory factor stimulated by Helicobacter pylori increases proliferation of gastric epithelial cells. World J Gastroenterol 2005; 11:1946-1950. [PMID: 15800984 PMCID: PMC4305715 DOI: 10.3748/wjg.v11.i13.1946] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/15/2004] [Revised: 09/16/2004] [Accepted: 11/29/2004] [Indexed: 02/06/2023] Open
Abstract
AIM Helicobacter pylori (H pylori) is associated with increased gastric inflammatory and epithelial expression of macrophage migration inhibitory factor (MIF) and gastric epithelial cell proliferation. This study aimed at determining whether H pylori directly stimulates release of MIF in monocytes, whether the cag pathogenicity island (PAI) is involved for this function, and whether MIF stimulated by H pylori increases gastric epithelial cell proliferation in vitro. METHODS A cytotoxic wild-type H pylori strain (TN2), its three isogenic mutants (TN2Deltacag, TN2DeltacagA and TN2DeltacagE) were co-cultured with cells of a human monocyte cell line, THP-1, for 24 h at different organism/cell ratios. MIF in the supernatants was measured by an ELISA. Cells of a human gastric cancer cell line, MKN45, were then co-cultured with the supernatants, with and without monoclonal anti-MIF antibody for 24 h. The cells were further incubated for 12 h after addition of 3H-thymidine, and the levels of incorporation of 3H-thymidine were measured with a liquid scintillation counter. RESULTS The wild-type strain and the isogenic mutants, TN2DeltacagA and TN2 DeltacagE, increased MIF release at organism/cell ratios of 200/1 and 400/1, but not at the ratios of 50/1 and 100/1. However, the mutant TN2delta cag did not increase the release of MIF at any of the four ratios. 3H-thymidine readings for MKN-45 cells were significantly increased with supernatants derived from the wild-type strain and the mutants TN2DeltacagA and TN2DeltacagE, but not from the mutant TN2Deltacag. Moreover, in the presence of monoclonal anti-MIF antibody, the stimulatory effects of the wild-type strain on cell proliferation disappeared. CONCLUSION H pylori stimulates MIF release in monocytes, likely through its cag PAI, but not related to cagA or cagE. H pylori-stimulated monocyte culture supernatant increases gastric cell proliferation, which is blocked by anti-MIF antibody, suggesting that MIF plays an important role in H pylori-induced gastric epithelial cell proliferation.
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Affiliation(s)
- Harry Hua-Xiang Xia
- Department of Medicine, The University of Hong Kong, Queen Mary Hospital, Hong Kong, China
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