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1
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Song C, Chai Z, Chen S, Zhang H, Zhang X, Zhou Y. Intestinal mucus components and secretion mechanisms: what we do and do not know. Exp Mol Med 2023; 55:681-691. [PMID: 37009791 PMCID: PMC10167328 DOI: 10.1038/s12276-023-00960-y] [Citation(s) in RCA: 85] [Impact Index Per Article: 42.5] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2022] [Accepted: 12/26/2022] [Indexed: 04/04/2023] Open
Abstract
Damage to the colon mucus barrier, the first line of defense against microorganisms, is an important determinant of intestinal diseases such as inflammatory bowel disease and colorectal cancer, and disorder in extraintestinal organs. The mucus layer has attracted the attention of the scientific community in recent years, and with the discovery of new mucosal components, it has become increasingly clear that the mucosal barrier is a complex system composed of many components. Moreover, certain components are jointly involved in regulating the structure and function of the mucus barrier. Therefore, a comprehensive and systematic understanding of the functional components of the mucus layer is clearly warranted. In this review, we summarize the various functional components of the mucus layer identified thus far and describe their unique roles in shaping mucosal structure and function. Furthermore, we detail the mechanisms underlying mucus secretion, including baseline and stimulated secretion. In our opinion, baseline secretion can be categorized into spontaneous Ca2+ oscillation-mediated slow and continuous secretion and stimulated secretion, which is mediated by massive Ca2+ influx induced by exogenous stimuli. This review extends the current understanding of the intestinal mucus barrier, with an emphasis on host defense strategies based on fortification of the mucus layer.
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Affiliation(s)
- Chunyan Song
- Department of Preventive Medicine, Health Science Center, Ningbo University, Zhejiang Key Laboratory of Pathophysiology, Ningbo, Zhejiang, 315211, China
| | - Zhenglong Chai
- Department of Preventive Medicine, Health Science Center, Ningbo University, Zhejiang Key Laboratory of Pathophysiology, Ningbo, Zhejiang, 315211, China
| | - Si Chen
- Department of Preventive Medicine, Health Science Center, Ningbo University, Zhejiang Key Laboratory of Pathophysiology, Ningbo, Zhejiang, 315211, China
| | - Hui Zhang
- Department of Preventive Medicine, Health Science Center, Ningbo University, Zhejiang Key Laboratory of Pathophysiology, Ningbo, Zhejiang, 315211, China
| | - Xiaohong Zhang
- Department of Preventive Medicine, Health Science Center, Ningbo University, Zhejiang Key Laboratory of Pathophysiology, Ningbo, Zhejiang, 315211, China.
- The Affiliated Hospital of Medical School, Ningbo University, Institute of Digestive Disease of Ningbo University, Ningbo, Zhejiang, 315020, China.
| | - Yuping Zhou
- The Affiliated Hospital of Medical School, Ningbo University, Institute of Digestive Disease of Ningbo University, Ningbo, Zhejiang, 315020, China.
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2
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Thomas-Dupont P, Velázquez-Soto H, Izaguirre-Hernández IY, Amieva-Balmori M, Triana-Romero A, Islas-Vázquez L, Jiménez-Martínez MDC, Remes-Troche JM. Obesity Contributes to Inflammation in Patients with IBS via Complement Component 3 and C-Reactive Protein. Nutrients 2022; 14:nu14245227. [PMID: 36558394 PMCID: PMC9781895 DOI: 10.3390/nu14245227] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2022] [Revised: 11/24/2022] [Accepted: 12/01/2022] [Indexed: 12/13/2022] Open
Abstract
Irritable Bowel Syndrome (IBS) is usually a lifelong state that disturbs the digestive system. IBS has been linked to low-grade inflammation and the release of inflammatory mediators into the bloodstream. This could be associated with the degree of obesity presented by patients with IBS. Reports imply that IBS is more frequent in obese patients than in the overall population, with a prevalence of up to 31%. Here, we evaluated the serum levels of immunological and inflammation molecules and their correlation with Body Mass Index in IBS patients and the healthy control (HC). Seventy-nine serum samples of the IBS patients and thirty-five of the HC group were analyzed to determine the levels of each molecule and compare them with their BMI. Serum levels of C3 and C4 were significantly increased in IBS patients. C3 and C4 levels were higher in IBS-M and IBS-D subtypes compared with the HC group. When patients were grouped by BMI, a positive correlation between serum C3 (r = 0.49, p < 0.0001) and CRP (r = 0.40, p < 0.001) levels was found. Our results show, for the first time, a correlation between immunological molecules and BMI in IBS patients, suggesting that the inflammatory nature of obesity could contribute to the development of the symptoms in IBS through the stimulation and release of proteins as complement components and CRP.
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Affiliation(s)
- Pablo Thomas-Dupont
- Instituto de Investigaciones Médico-Biológicas, Universidad Veracruzana, Veracruz 91700, Mexico
| | - Henry Velázquez-Soto
- Departamento de Inmunología y Unidad de Investigación, Instituto de Oftalmología “Conde de Valencia”, Ciudad de México 06800, Mexico
| | | | - Mercedes Amieva-Balmori
- Instituto de Investigaciones Médico-Biológicas, Universidad Veracruzana, Veracruz 91700, Mexico
| | - Arturo Triana-Romero
- Instituto de Investigaciones Médico-Biológicas, Universidad Veracruzana, Veracruz 91700, Mexico
| | - Lorenzo Islas-Vázquez
- Departamento de Inmunología y Unidad de Investigación, Instituto de Oftalmología “Conde de Valencia”, Ciudad de México 06800, Mexico
| | - María del Carmen Jiménez-Martínez
- Departamento de Inmunología y Unidad de Investigación, Instituto de Oftalmología “Conde de Valencia”, Ciudad de México 06800, Mexico
- Departamento de Bioquímica, Facultad de Medicina, Universidad Nacional Autónoma de México, Ciudad de México 04510, Mexico
| | - José María Remes-Troche
- Instituto de Investigaciones Médico-Biológicas, Universidad Veracruzana, Veracruz 91700, Mexico
- Correspondence: ; Tel.: +52-228-842-17-00 (ext. 26421)
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Signore MA, De Pascali C, Giampetruzzi L, Siciliano PA, Francioso L. Gut-on-Chip microphysiological systems: Latest advances in the integration of sensing strategies and adoption of mature detection mechanisms. SENSING AND BIO-SENSING RESEARCH 2021. [DOI: 10.1016/j.sbsr.2021.100443] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/09/2023] Open
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Chulanetra M, Chaicumpa W. Revisiting the Mechanisms of Immune Evasion Employed by Human Parasites. Front Cell Infect Microbiol 2021; 11:702125. [PMID: 34395313 PMCID: PMC8358743 DOI: 10.3389/fcimb.2021.702125] [Citation(s) in RCA: 29] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2021] [Accepted: 06/25/2021] [Indexed: 12/14/2022] Open
Abstract
For the establishment of a successful infection, i.e., long-term parasitism and a complete life cycle, parasites use various diverse mechanisms and factors, which they may be inherently bestowed with, or may acquire from the natural vector biting the host at the infection prelude, or may take over from the infecting host, to outmaneuver, evade, overcome, and/or suppress the host immunity, both innately and adaptively. This narrative review summarizes the up-to-date strategies exploited by a number of representative human parasites (protozoa and helminths) to counteract the target host immune defense. The revisited information should be useful for designing diagnostics and therapeutics as well as vaccines against the respective parasitic infections.
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Affiliation(s)
- Monrat Chulanetra
- Center of Research Excellence on Therapeutic Proteins and Antibody Engineering, Department of Parasitology, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand
| | - Wanpen Chaicumpa
- Center of Research Excellence on Therapeutic Proteins and Antibody Engineering, Department of Parasitology, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand
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Noel G, In JG, Lemme-Dumit JM, DeVine LR, Cole RN, Guerrerio AL, Campbell JD, Kovbasnjuk O, Pasetti MF. Human Breast Milk Enhances Intestinal Mucosal Barrier Function and Innate Immunity in a Healthy Pediatric Human Enteroid Model. Front Cell Dev Biol 2021; 9:685171. [PMID: 34327199 PMCID: PMC8313895 DOI: 10.3389/fcell.2021.685171] [Citation(s) in RCA: 27] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2021] [Accepted: 06/18/2021] [Indexed: 12/20/2022] Open
Abstract
Breastfeeding has been associated with long lasting health benefits. Nutrients and bioactive components of human breast milk promote cell growth, immune development, and shield the infant gut from insults and microbial threats. The molecular and cellular events involved in these processes are ill defined. We have established human pediatric enteroids and interrogated maternal milk's impact on epithelial cell maturation and function in comparison with commercial infant formula. Colostrum applied apically to pediatric enteroid monolayers reduced ion permeability, stimulated epithelial cell differentiation, and enhanced tight junction function by upregulating occludin. Breast milk heightened the production of antimicrobial peptide α-defensin 5 by goblet and Paneth cells, and modulated cytokine production, which abolished apical release of pro-inflammatory GM-CSF. These attributes were not found in commercial infant formula. Epithelial cells exposed to breast milk elevated apical and intracellular pIgR and enabled maternal IgA translocation. Proteomic data revealed a breast milk-induced molecular pattern associated with tissue remodeling and homeostasis. Using a novel ex vivo pediatric enteroid model, we have identified distinct cellular and molecular events involved in human milk-mediated improvement of human intestinal physiology and immunity.
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Affiliation(s)
- Gaelle Noel
- Department of Pediatrics, Center for Vaccine Development and Global Health, University of Maryland School of Medicine, Baltimore, MD, United States
| | - Julie G. In
- Department of Internal Medicine, Division of Gastroenterology and Hepatology, University of New Mexico Health Science Center, Albuquerque, NM, United States
- Department of Medicine, Division of Gastroenterology and Hepatology, Johns Hopkins University School of Medicine, Baltimore, MD, United States
| | - Jose M. Lemme-Dumit
- Department of Pediatrics, Center for Vaccine Development and Global Health, University of Maryland School of Medicine, Baltimore, MD, United States
| | - Lauren R. DeVine
- Department of Biological Chemistry, Johns Hopkins Mass Spectrometry and Proteomics Facility, Johns Hopkins University School of Medicine, Baltimore, MD, United States
| | - Robert N. Cole
- Department of Biological Chemistry, Johns Hopkins Mass Spectrometry and Proteomics Facility, Johns Hopkins University School of Medicine, Baltimore, MD, United States
| | - Anthony L. Guerrerio
- Department of Pediatrics, Division of Pediatric Gastroenterology, Hepatology and Nutrition, Johns Hopkins University School of Medicine, Baltimore, MD, United States
| | - James D. Campbell
- Department of Pediatrics, Center for Vaccine Development and Global Health, University of Maryland School of Medicine, Baltimore, MD, United States
| | - Olga Kovbasnjuk
- Department of Internal Medicine, Division of Gastroenterology and Hepatology, University of New Mexico Health Science Center, Albuquerque, NM, United States
- Department of Medicine, Division of Gastroenterology and Hepatology, Johns Hopkins University School of Medicine, Baltimore, MD, United States
| | - Marcela F. Pasetti
- Department of Pediatrics, Center for Vaccine Development and Global Health, University of Maryland School of Medicine, Baltimore, MD, United States
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Zhou Y, Zhang Y, Wang J. Trefoil Factor 2 Regulates Proliferation and Apoptosis of Pancreatic Cancer Cells and LPS-Induced Normal Pancreatic Duct Cells by β-Catenin Pathway. Cancer Manag Res 2020; 12:10705-10713. [PMID: 33149677 PMCID: PMC7605628 DOI: 10.2147/cmar.s274578] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2020] [Accepted: 09/11/2020] [Indexed: 01/13/2023] Open
Abstract
Introduction Pancreatic cancer (PC) is a malignant tumor with poor prognosis. This study aimed to determine the role of trefoil factor 2 (TFF2) in the proliferation and apoptosis of LPS-induced normal pancreatic duct cells and pancreatic cancer cells through β-catenin pathway. Methods TFF2 expression in normal pancreatic duct cells, pancreatic cancer cells and LPS-induced normal pancreatic duct cells was detected by RT-qPCR analysis and Western blot analysis. The transfection effects in pancreatic cancer cells and LPS-induced normal pancreatic duct cells were analyzed by RT-qPCR analysis. After indicated transfection, proliferation, apoptosis and inflammation of these cells were respectively detected by CCK-8 assay, TUNEL assay and certain ELISA kits. Expression of β-catenin pathway-related proteins was analyzed by Western blot analysis. Co-immunoprecipitation assay determined the combination of TFF2 and β-catenin. Results TFF2 expression was increased in pancreatic cancer cells and LPS-induced HPDE cells compared with HPDE cells. According to TFF2 expression in these cells, PanC-1 cells and 5 μg/mL LPS were selected. In addition, TFF2 interference decreased the proliferation and promoted the apoptosis of PanC-1 cells and LPS-induced HPDE cells. However, TFF2 interference did not obviously change the levels of TNF-α, IL-1β and IL-6 in PanC-1 cells and LPS-induced HPDE cells. Furthermore, TFF2 interference suppressed the expression of β-catenin, c-Myc, Cyclin D1 and BIRC5 in PanC-1 cells and LPS-induced HPDE cells. TFF2 was demonstrated to combine with β-catenin. Discussion TFF2 interference inhibits proliferation and promotes apoptosis of PanC-1 cells and LPS-induced HPDE cells by suppressing β-catenin pathway.
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Affiliation(s)
- Yun Zhou
- Department of Clinical Laboratory Medicine, Shanghai Tenth People's Hospital of Tongji University, Shanghai 200072, People's Republic of China
| | - Yan Zhang
- Department of Clinical Laboratory Medicine, Shanghai Tenth People's Hospital of Tongji University, Shanghai 200072, People's Republic of China
| | - Jia Wang
- Department of Clinical Laboratory Medicine, Shanghai Tenth People's Hospital of Tongji University, Shanghai 200072, People's Republic of China
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7
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Nguyen H, Alawieh A, Bastian D, Kuril S, Dai M, Daenthanasanmak A, Zhang M, Iamsawat S, Schutt SD, Wu Y, Sleiman MM, Shetty A, Atkinson C, Sun S, Varela JC, Tomlinson S, Yu XZ. Targeting the Complement Alternative Pathway Permits Graft Versus Leukemia Activity while Preventing Graft Versus Host Disease. Clin Cancer Res 2020; 26:3481-3490. [PMID: 31919135 PMCID: PMC7334060 DOI: 10.1158/1078-0432.ccr-19-1717] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2019] [Revised: 10/03/2019] [Accepted: 12/20/2019] [Indexed: 12/12/2022]
Abstract
PURPOSE Application of allogeneic hematopoietic cell transplantation (allo-HCT) for patients with hematologic disorders is limited by the development of GVHD. Separation of GVHD and graft-versus-leukemia (GVL) remains a great challenge in the field. We investigated the contribution of individual pathways involved in the complement cascade in GVH and GVL responses to identify specific targets by which to separate these two processes. EXPERIMENTAL DESIGN We used multiple preclinical murine and human-to-mouse xenograft models involving allo-HCT recipients lacking components of the alternative pathway (AP) or classical pathway (CP)/lectin pathway (LP) to dissect the role of each individual pathway in GVHD pathogenesis and the GVL effect. For translational purposes, we used the AP-specific complement inhibitor, CR2-fH, which localizes in injured target organs to allow specific blockade of complement activation at sites of inflammation. RESULTS Complement deposition was evident in intestines of mice and patients with GVHD. In a preclinical setting, ablation of the AP, but not the CP/LP, significantly improved GVHD outcomes. Complement activation through the AP in host hematopoietic cells, and specifically dendritic cells (DC), was required for GVHD progression. AP deficiency in recipients decreased donor T-cell migration and Th1/Th2 differentiation, while increasing the generation of regulatory T cells. This was because of decreased activation and stimulatory activity of recipient DCs in GVHD target organs. Treatment with CR2-fH effectively prevented GVHD while preserving GVL activity. CONCLUSIONS This study highlights the AP as a new therapeutic target to prevent GVHD and tumor relapse after allo-HCT. Targeting the AP by CR2-fH represents a promising therapeutic approach for GVHD treatment.
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Affiliation(s)
- Hung Nguyen
- Department of Microbiology and Immunology, Medical University of South Carolina, Charleston, South Carolina.
| | - Ali Alawieh
- Department of Microbiology and Immunology, Medical University of South Carolina, Charleston, South Carolina
- Medical Scientist Training Program, College of Medicine, Medical University of South Carolina, Charleston, South Carolina
| | - David Bastian
- Department of Microbiology and Immunology, Medical University of South Carolina, Charleston, South Carolina
| | - Sandeepkumar Kuril
- Department of Pediatric, Medical University of South Carolina, Charleston, South Carolina
| | - Min Dai
- Department of Microbiology and Immunology, Medical University of South Carolina, Charleston, South Carolina
| | - Anusara Daenthanasanmak
- Department of Microbiology and Immunology, Medical University of South Carolina, Charleston, South Carolina
| | - Mengmeng Zhang
- Department of Microbiology and Immunology, Medical University of South Carolina, Charleston, South Carolina
| | - Supinya Iamsawat
- Department of Microbiology and Immunology, Medical University of South Carolina, Charleston, South Carolina
| | - Steven D Schutt
- Department of Microbiology and Immunology, Medical University of South Carolina, Charleston, South Carolina
| | - Yongxia Wu
- Department of Microbiology and Immunology, Medical University of South Carolina, Charleston, South Carolina
| | - M Mahdi Sleiman
- Department of Microbiology and Immunology, Medical University of South Carolina, Charleston, South Carolina
| | - Akshay Shetty
- Department of Pathology, Medical University of South Carolina, Charleston, South Carolina
| | - Carl Atkinson
- Department of Microbiology and Immunology, Medical University of South Carolina, Charleston, South Carolina
- Department of Surgery, Medical University of South Carolina, Charleston, South Carolina
| | - Shaoli Sun
- Department of Pathology, Medical University of South Carolina, Charleston, South Carolina
| | - Juan Carlos Varela
- Department of Microbiology and Immunology, Medical University of South Carolina, Charleston, South Carolina
| | - Stephen Tomlinson
- Department of Microbiology and Immunology, Medical University of South Carolina, Charleston, South Carolina
- Ralph H. Johnson Veterans Affairs Medical Center, Medical University of South Carolina, Charleston, South Carolina
| | - Xue-Zhong Yu
- Department of Microbiology and Immunology, Medical University of South Carolina, Charleston, South Carolina.
- Department of Medicine, Medical University of South Carolina, Charleston, South Carolina
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8
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Braga Emidio N, Brierley SM, Schroeder CI, Muttenthaler M. Structure, Function, and Therapeutic Potential of the Trefoil Factor Family in the Gastrointestinal Tract. ACS Pharmacol Transl Sci 2020; 3:583-597. [PMID: 32832864 DOI: 10.1021/acsptsci.0c00023] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2020] [Indexed: 12/20/2022]
Abstract
Trefoil factor family peptides (TFF1, TFF2, and TFF3) are key players in protecting, maintaining, and repairing the gastrointestinal tract. Accordingly, they have the therapeutic potential to treat and prevent a variety of gastrointestinal disorders associated with mucosal damage. TFF peptides share a conserved motif, including three disulfide bonds that stabilize a well-defined three-loop-structure reminiscent of a trefoil. Although multiple functions have been described for TFF peptides, their mechanisms at the molecular level remain poorly understood. This review presents the status quo of TFF research relating to gastrointestinal disorders. Putative TFF receptors and protein partners are described and critically evaluated. The therapeutic potential of these peptides in gastrointestinal disorders where altered mucosal biology plays a crucial role in the underlying etiology is discussed. Finally, areas of investigation that require further research are addressed. Thus, this review provides a comprehensive update on TFF literature as well as guidance toward future research to better understand this peptide family and its therapeutic potential for the treatment of gastrointestinal disorders.
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Affiliation(s)
- Nayara Braga Emidio
- Institute for Molecular Bioscience, The University of Queensland, Brisbane, Queensland 4072, Australia
| | - Stuart M Brierley
- Visceral Pain Research Group, College of Medicine and Public Health, Flinders Health and Medicial Research Insittitue (FHMRI), Flinders University, Bedford Park, South Australia 5042, Australia.,Hopwood Centre for Neurobiology, Lifelong Health Theme, South Australian Health and Medical Research Institute (SAHMRI), North Terrace, Adelaide, South Australia 5000, Australia.,Discipline of Medicine, University of Adelaide, Adelaide, South Australia 5000, Australia
| | - Christina I Schroeder
- Institute for Molecular Bioscience, The University of Queensland, Brisbane, Queensland 4072, Australia.,National Cancer Institute, National Institutes of Health, Frederick, Maryland 21702, United States
| | - Markus Muttenthaler
- Institute of Biological Chemistry, Faculty of Chemistry, University of Vienna, 1090 Vienna, Austria.,Institute for Molecular Bioscience, The University of Queensland, Brisbane, Queensland 4072, Australia
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Ponce de León-Rodríguez MDC, Guyot JP, Laurent-Babot C. Intestinal in vitro cell culture models and their potential to study the effect of food components on intestinal inflammation. Crit Rev Food Sci Nutr 2018; 59:3648-3666. [DOI: 10.1080/10408398.2018.1506734] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Affiliation(s)
| | - Jean-Pierre Guyot
- NUTRIPASS—University of Montpellier, IRD, Montpellier SupAgro, Montpellier, France
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Huang S, Park J, Qiu C, Chung KW, Li SY, Sirin Y, Han SH, Taylor V, Zimber-Strobl U, Susztak K. Jagged1/Notch2 controls kidney fibrosis via Tfam-mediated metabolic reprogramming. PLoS Biol 2018; 16:e2005233. [PMID: 30226866 PMCID: PMC6161902 DOI: 10.1371/journal.pbio.2005233] [Citation(s) in RCA: 53] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2018] [Revised: 09/28/2018] [Accepted: 09/03/2018] [Indexed: 12/14/2022] Open
Abstract
While Notch signaling has been proposed to play a key role in fibrosis, the direct molecular pathways targeted by Notch signaling and the precise ligand and receptor pair that are responsible for kidney disease remain poorly defined. In this study, we found that JAG1 and NOTCH2 showed the strongest correlation with the degree of interstitial fibrosis in a genome-wide expression analysis of a large cohort of human kidney samples. Transcript analysis of mouse kidney disease models, including folic-acid (FA)-induced nephropathy, unilateral ureteral obstruction (UUO), or apolipoprotein L1 (APOL1)-associated kidney disease, indicated that Jag1 and Notch2 levels were higher in all analyzed kidney fibrosis models. Mice with tubule-specific deletion of Jag1 or Notch2 (Kspcre/Jag1flox/flox and Kspcre/Notch2flox/flox) had no kidney-specific alterations at baseline but showed protection from FA-induced kidney fibrosis. Tubule-specific genetic deletion of Notch1 and global knockout of Notch3 had no effect on fibrosis. In vitro chromatin immunoprecipitation experiments and genome-wide expression studies identified the mitochondrial transcription factor A (Tfam) as a direct Notch target. Re-expression of Tfam in tubule cells prevented Notch-induced metabolic and profibrotic reprogramming. Tubule-specific deletion of Tfam resulted in fibrosis. In summary, Jag1 and Notch2 play a key role in kidney fibrosis development by regulating Tfam expression and metabolic reprogramming.
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Affiliation(s)
- Shizheng Huang
- Renal Electrolyte and Hypertension Division, Department of Medicine, Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America
| | - Jihwan Park
- Renal Electrolyte and Hypertension Division, Department of Medicine, Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America
| | - Chengxiang Qiu
- Renal Electrolyte and Hypertension Division, Department of Medicine, Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America
| | - Ki Wung Chung
- Renal Electrolyte and Hypertension Division, Department of Medicine, Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America
| | - Szu-yuan Li
- Renal Electrolyte and Hypertension Division, Department of Medicine, Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America
| | - Yasemin Sirin
- Renal Electrolyte and Hypertension Division, Department of Medicine, Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America
| | - Seung Hyeok Han
- Renal Electrolyte and Hypertension Division, Department of Medicine, Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America
| | - Verdon Taylor
- Department of Biomedicine, University of Basel, Basel, Switzerland
| | - Ursula Zimber-Strobl
- Research Unit Gene Vectors, Helmholtz Zentrum München, German Research Center for Environment and Health, Munich, Germany
| | - Katalin Susztak
- Renal Electrolyte and Hypertension Division, Department of Medicine, Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America
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11
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Urine Trefoil Factors as Prognostic Biomarkers in Chronic Kidney Disease. BIOMED RESEARCH INTERNATIONAL 2018; 2018:3024698. [PMID: 29850501 PMCID: PMC5903307 DOI: 10.1155/2018/3024698] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/03/2017] [Accepted: 03/01/2018] [Indexed: 12/18/2022]
Abstract
Introduction Trefoil factor family (TFF) peptides are increased in serum and urine in patients with chronic kidney disease (CKD). However, whether the levels of TFF predict the progression of CKD remains to be elucidated. Methods We determined the TFF levels using peptide-specific ELISA in spot urine samples and performed a prospective cohort study. The association between the levels of urine TFFs and other urine biomarkers as well as the renal prognosis was analyzed in 216 CKD patients (mean age: 53.7 years, 47.7% female, 56.9% with chronic glomerulonephritis, and mean eGFR: 58.5 ml/min/1.73 m2). Results The urine TFF1 and TFF3 levels significantly increased with the progression of CKD stages, but not the urine TFF2 levels. The TFF1 and TFF3 peptide levels predicted the progression of CKD ≥ stage 3b by ROC analysis (AUC 0.750 and 0.879, resp.); however, TFF3 alone predicted CKD progression in a multivariate logistic regression analysis (odds ratio 3.854, 95% confidence interval 1.316–11.55). The Kaplan-Meier survival curves demonstrated that patients with a higher TFF1 and TFF3 alone, or in combination with macroalbuminuria, had a significantly worse renal prognosis. Conclusion The data suggested that urine TFF peptides are associated with renal progression and the outcomes in patients with CKD.
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12
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Kopp ZA, Jain U, Van Limbergen J, Stadnyk AW. Do antimicrobial peptides and complement collaborate in the intestinal mucosa? Front Immunol 2015; 6:17. [PMID: 25688244 PMCID: PMC4311685 DOI: 10.3389/fimmu.2015.00017] [Citation(s) in RCA: 38] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2014] [Accepted: 01/08/2015] [Indexed: 12/13/2022] Open
Abstract
It is well understood that multiple antimicrobial peptides (AMPs) are constitutively deployed by the epithelium to bolster the innate defenses along the entire length of the intestines. In addition to this constitutive/homeostatic production, AMPs may be inducible and levels changed during disease. In contrast to this level of knowledge on AMP sources and roles in the intestines, our understanding of the complement cascade in the healthy and diseased intestines is rudimentary. Epithelial cells make many complement proteins and there is compelling evidence that complement becomes activated in the lumen. With the common goal of defending the host against microbes, the opportunities for cross-talk between these two processes is great, both in terms of actions on the target microbes but also on regulating the synthesis and secretion of the alternate family of molecules. This possibility is beginning to become apparent with the finding that colonic epithelial cells possess anaphylatoxin receptors. There still remains much to be learned about the possible points of collaboration between AMPs and complement, for example, whether there is reciprocal control over expression in the intestinal mucosa in homeostasis and restoring the balance following infection and inflammation.
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Affiliation(s)
- Zoë A Kopp
- Department of Microbiology and Immunology, Faculty of Medicine, Dalhousie University , Halifax, NS , Canada
| | - Umang Jain
- Department of Microbiology and Immunology, Faculty of Medicine, Dalhousie University , Halifax, NS , Canada
| | - Johan Van Limbergen
- Department of Microbiology and Immunology, Faculty of Medicine, Dalhousie University , Halifax, NS , Canada ; Department of Pediatrics, Faculty of Medicine, Dalhousie University , Halifax, NS , Canada
| | - Andrew W Stadnyk
- Department of Microbiology and Immunology, Faculty of Medicine, Dalhousie University , Halifax, NS , Canada ; Department of Pediatrics, Faculty of Medicine, Dalhousie University , Halifax, NS , Canada
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13
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Abstract
Complement is well appreciated to be a potent innate immune defense against microbes and is important in the housekeeping act of removal of apoptotic and effete cells. It is also understood that hyperactivation of complement, or the lack of regulators, may underlie chronic inflammatory diseases. A pipeline of products to intervene in complement activation, some already in clinical use, is being studied in various chronic inflammatory diseases. To date, the role of complement in inflammatory bowel disease has not received a lot of research interest. Novel genetically modified laboratory animals and experiments using antagonists to complement effector molecules have kindled important research observations implicating the complement system in inflammatory bowel disease pathogenesis. We review the evidence base for the role and potential therapeutic manipulation of the complement cascade in inflammatory bowel disease.
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14
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A tandem repeat in decay accelerating factor 1 is associated with severity of murine mercury-induced autoimmunity. Autoimmune Dis 2014; 2014:260613. [PMID: 24818014 PMCID: PMC4003777 DOI: 10.1155/2014/260613] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2014] [Accepted: 02/21/2014] [Indexed: 11/17/2022] Open
Abstract
Decay accelerating factor (DAF), a complement-regulatory protein, protects cells from bystander complement-mediated lysis and negatively regulates T cells. Reduced expression of DAF occurs in several systemic autoimmune diseases including systemic lupus erythematosus, and DAF deficiency exacerbates disease in several autoimmune models, including murine mercury-induced autoimmunity (mHgIA). Daf1, located within Hmr1, a chromosome 1 locus associated in DBA/2 mice with resistance to mHgIA, could be a candidate. Here we show that reduced Daf1 transcription in lupus-prone mice was not associated with a reduction in the Daf1 transcription factor SP1. Studies of NZB mice congenic for the mHgIA-resistant DBA/2 Hmr1 locus suggested that Daf1 expression was controlled by the host genome and not the Hmr1 locus. A unique pentanucleotide repeat variant in the second intron of Daf1 in DBA/2 mice was identified and shown in F2 intercrosses to be associated with less severe disease; however, analysis of Hmr1 congenics indicated that this most likely reflected the presence of autoimmunity-predisposing genetic variants within the Hmr1 locus or that Daf1 expression is mediated by the tandem repeat in epistasis with other genetic variants present in autoimmune-prone mice. These studies argue that the effect of DAF on autoimmunity is complex and may require multiple genetic elements.
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15
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Narayanan GA, Murray IA, Krishnegowda G, Amin S, Perdew GH. Selective aryl hydrocarbon receptor modulator-mediated repression of CD55 expression induced by cytokine exposure. J Pharmacol Exp Ther 2012; 342:345-55. [PMID: 22553215 PMCID: PMC3400802 DOI: 10.1124/jpet.112.193482] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2012] [Accepted: 05/01/2012] [Indexed: 01/14/2023] Open
Abstract
Modulation of aryl hydrocarbon receptor (AHR) activity by a class of ligands termed selective AHR modulators (SAhRMs) has been demonstrated to attenuate proinflammatory gene expression and signaling, including repression of cytokine-mediated induction of acute-phase genes (e.g., Saa1). These effects are observed to occur through an AHR-dependent mechanism that does not require canonical signaling through dioxin response elements. Previously, we have demonstrated that the SAhRM 3',4'-dimethoxy-α-naphthoflavone (DiMNF) can repress the cytokine-mediated induction of complement factor genes. Here, we report that the activation of the AHR with DiMNF can suppress cytokine-mediated induction of the membrane complement regulatory protein CD55. When CD55 is expressed on host cells, it facilitates the decay of the complement component 3 (C3) convertase, thereby protecting the cell from complement-mediated lysis. Tumor cells often exhibit elevated CD55 expression on the cell surface in the inflammatory microenvironment of the tumor, and such enhanced expression could represent a means of escaping immune surveillance. DiMNF can repress the cytokine-mediated induction of CD55 mRNA and protein. Luciferase reporter analysis has identified possible response elements on the CD55 promoter, which may be targets for this repression. A C3 deposition assay with [(125)I]C3 revealed that repression of cytokine-mediated CD55 expression by DiMNF led to an increase of C3 deposition on the surface of Huh7 cells, which would likely stimulate the formation of the membrane attack complex. These results suggest that SAhRMs such as DiMNF have therapeutic potential in regulating the immune response to tumor formation.
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Affiliation(s)
- Gitanjali A Narayanan
- Center for Molecular Toxicology and Carcinogenesis, Department of Veterinary Sciences, Pennsylvania State University, 309A Life Sciences Building, University Park, PA 16802, USA
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16
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Bourgine J, Billaut-Laden I, Happillon M, Lo-Guidice JM, Maunoury V, Imbenotte M, Broly F. Gene expression profiling of systems involved in the metabolism and the disposition of xenobiotics: comparison between human intestinal biopsy samples and colon cell lines. Drug Metab Dispos 2012; 40:694-705. [PMID: 22217464 DOI: 10.1124/dmd.111.042465] [Citation(s) in RCA: 61] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/12/2023] Open
Abstract
Intestinal cell lines are used as in vitro models for pharmacological and toxicological studies. However, a general report of the gene expression spectrum of proteins that are involved in the metabolism and the disposition of xenobiotics in these in vitro systems is not currently available. To fill this information gap, we systematically characterized the expression profile of 377 genes encoding xenobiotic-metabolizing enzymes, transporters, and nuclear receptors and transcription factors in intestinal mucosa (ileum, ascending colon, transverse colon, descending colon, and rectum) from five healthy subjects and in five commonly used intestinal cell lines (Caco-2, C2BBe1, HT29, T84, and FHC). For this, we performed a quantitative real-time reverse transcription-polymerase chain reaction analysis using TaqMan low-density arrays and analyzed the results by different statistical approaches: Spearman correlation coefficients, hierarchical clustering, and principal component analysis (PCA). A large variation in gene expression spectra was observed between intestinal cell lines and intestinal tissues. Both hierarchical clustering and PCA showed that two distinct clusters are visible, of which one corresponds to all cultured cell lines and the other to all intestinal biopsies. The best agreement between human tissue and the representative cell line was observed for human colonic tissues and HT29 and T84 cell lines. Altogether, these data demonstrated that gene expression profiling represents a new valuable tool for investigating in vitro and in vivo expression level correlation. This study has pointed out interesting expression profiles for various colon cell lines, which will be useful for choosing the appropriate in vitro model for pharmacological and toxicological studies.
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Affiliation(s)
- Joanna Bourgine
- Equipe d'Accueil 4483, Faculté de Médecine Pôle Recherche, Université Lille Nord de France, Lille, France.
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17
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Fusobacterium nucleatum infection of colonic cells stimulates MUC2 mucin and tumor necrosis factor alpha. Infect Immun 2011; 79:2597-607. [PMID: 21536792 DOI: 10.1128/iai.05118-11] [Citation(s) in RCA: 108] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
The etiology of inflammatory bowel disease is not completely known, but it is influenced by the presence of normal gut microflora as well as yet-unrecognized pathogens. The anaerobic, Gram-negative bacterial species Fusobacterium nucleatum is a common resident of the human mouth and gut and varies in its pathogenic potential. In this study, we demonstrate that highly invasive F. nucleatum isolates derived from the inflamed guts of Crohn's disease patients evoked significantly greater MUC2 and tumor necrosis factor alpha (TNF-α) gene expression than minimally invasive strains isolated from the noninflamed gut in human colonic epithelial cells and in a rat ligated colonic loop model of infection. Only live F. nucleatum induced mucin secretion and TNF-α expression in direct contact with and/or during invasion of colonic cells. In rat colons, mucin secretion was augmented in response to a highly invasive F. nucleatum isolate but was unaffected by treatment with a minimally invasive strain. Taken together, these studies reveal that F. nucleatum may represent a challenging pathogen in the etiology of gut inflammatory diseases and highlight the importance of different pathotypes of candidate bacterial species in disease pathogenesis.
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18
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Blockade of complement activation product C5a activity using specific antibody attenuates intestinal damage in trinitrobenzene sulfonic acid induced model of colitis. J Transl Med 2011; 91:472-83. [PMID: 21102504 DOI: 10.1038/labinvest.2010.183] [Citation(s) in RCA: 33] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023] Open
Abstract
Complement represents a chief component of innate immunity in host defense. However, excessive complement activation has been involved in the pathogenesis of inflammatory diseases. In this study, we investigated the contribution of complement to intestinal pathology of patients and rodents with inflammatory bowel disease. The expression of complement effectors (C3a and C3) was increased remarkably in inflamed colons of IBD patients compared with those of normal counterparts. In accordance with this, the sustained activation of complement in serum and colon (including elevated C3a and C5a levels, enhanced hemolytic activity, downregulated expression of C5a receptors) was observed, following the establishment of 2,4,6-trinitrobenzene sulfonic acid (TNBS)-induced colitis, which peaked at 24 h. Mice pretreated with neutralizing anti-C5a antibodies (-2, 0, and 2 days after TNBS instillation) had significantly reduced weight loss and improved macroscopic/microscopic scores, comparable to the efficacy of prednisolone treatment. Strikingly, treatment with anti-C5a at 24 h after TNBS instillation showed remarkable therapeutic effects, whereas prednisolone did not. The efficacy of anti-C5a administration was associated with decreased release of proinflammatory chemokines and cytokines, inhibition of infiltration of neutrophils into colons, and enhanced Th2 response. These findings suggest a disease-promoting role of complement, particular C5a, in the pathology of TNBS-induced colitis in mice, indicating possible therapeutic potentials for C5a-specific antibody in IBD.
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19
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Allison CC, Kufer TA, Kremmer E, Kaparakis M, Ferrero RL. Helicobacter pylori induces MAPK phosphorylation and AP-1 activation via a NOD1-dependent mechanism. THE JOURNAL OF IMMUNOLOGY 2010; 183:8099-109. [PMID: 20007577 DOI: 10.4049/jimmunol.0900664] [Citation(s) in RCA: 147] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
Helicobacter pylori rapidly activates MAPKs and transcription factors, NF-kappaB and AP-1, in gastric epithelial cells following host attachment. Activation of these signal transducers is largely dependent on the cag pathogenicity island (cagPAI)-encoded Type IV Secretion System. H. pylori was shown to translocate peptidoglycan through the Type IV Secretion System, which is recognized by the pathogen recognition molecule, NOD1, thus resulting in NF-kappaB activation. The mechanisms of H. pylori-induced MAPK and AP-1 activation, however, are less well defined and therefore, we assessed the contribution of NOD1 to their activation. For this, we used gastric epithelial cell lines, stably expressing siRNA to either NOD1 or a control gene. In siNOD1-expressing cells stimulated with cagPAI(+) H. pylori, we observed significant reductions in p38 and ERK phosphorylation (p < 0.05), whereas the levels of Jnk phosphorylation remained unchanged. Consistent with a previous report, however, we were able to demonstrate NOD1-dependent Jnk phosphorylation by the invasive pathogen Shigella flexneri, highlighting pathogen-specific host responses to infection. We also show that NOD1 was essential for H. pylori induction of not only NF-kappaB, but also AP-1 activation, implying that NOD1 induces robust proinflammatory responses, in an attempt to rapidly control infection. Pharmacological inhibition of p38 and ERK activity significantly reduced IL-8 production in response to H. pylori, further emphasizing the importance of MAPKs in innate immune responses to the pathogen. Thus, for the first time we have shown the important role for NOD1 in MAPK and AP-1 activation in response to cagPAI(+) H. pylori.
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Affiliation(s)
- Cody C Allison
- Department of Microbiology, Monash University, Clayton, Australia
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20
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Peterson DE, Barker NP, Akhmadullina LI, Rodionova I, Sherman NZ, Davidenko IS, Rakovskaya GN, Gotovkin EA, Shinkarev SA, Kopp MV, Kulikov EP, Moiseyenko VM, Gertner JM, Firsov I, Tuleneva T, Yarosh A, Woon CW. Phase II, randomized, double-blind, placebo-controlled study of recombinant human intestinal trefoil factor oral spray for prevention of oral mucositis in patients with colorectal cancer who are receiving fluorouracil-based chemotherapy. J Clin Oncol 2009; 27:4333-8. [PMID: 19636011 DOI: 10.1200/jco.2008.21.2381] [Citation(s) in RCA: 47] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
PURPOSE This study evaluated the safety and efficacy of recombinant human intestinal trefoil factor (rhITF) administered as topical oral spray for prevention and treatment of chemotherapy-induced oral mucositis (OM). PATIENTS AND METHODS Ninety-nine patients with colorectal cancer who had moderate to severe OM (WHO grade >or= 2) in the first cycle of chemotherapy were randomly assigned to receive either placebo, rhITF 10 mg/mL (ie, low dose), or rhITF 80 mg/mL (ie, high dose) by oral spray (300 microL, eight times each day) for 14 consecutive days in the second chemotherapy cycle. Patients were assessed on days 1, 3, 5, 7, 10, 12, 14, and 21 (+/- 2 days for the last assessment) for safety and for OM incidence and severity. RESULTS Treatment of patients at high risk for developing OM with low- or high-dose rhITF significantly reduced the amount of incidence (75% to 81%; low-dose rhITF P < .001; high-dose rhITF P = .002). Frequencies of WHO grade >or= 2 OM in the placebo, low-dose rhITF, and high-dose rhITF groups were 48.5%, 9.1%, and 12.1%, respectively. Assessment of the area under the curve revealed statistically significant reductions in OM severity in the rhITF-treated groups versus placebo. Only a minority of patients (6.1%) reported treatment-emergent adverse events (TEAEs), all of which were mild to moderate in intensity and resolved without sequelae. The incidence of TEAEs was not significantly different among treatment groups. CONCLUSION rhITF oral spray formulation was safe and effective when used for the reduction of chemotherapy-associated OM in patients with colorectal cancer. Patients exhibited high compliance in dosing administration. Future clinical study is planned to develop this drug for use in OM management in patients with cancer.
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Affiliation(s)
- Douglas E Peterson
- Department of Oral Health and Diagnostic Sciences, School of Dental Medicine, Neag Comprehensive Cancer Center, University of Connecticut Health Center, 263 Farmington Ave, Farmington, CT 06030-1605, USA.
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21
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O'Brien DP, Romero-Gallo J, Schneider BG, Chaturvedi R, Delgado A, Harris EJ, Krishna U, Ogden SR, Israel DA, Wilson KT, Peek RM. Regulation of the Helicobacter pylori cellular receptor decay-accelerating factor. J Biol Chem 2008; 283:23922-30. [PMID: 18579524 PMCID: PMC2527108 DOI: 10.1074/jbc.m801144200] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2008] [Revised: 06/23/2008] [Indexed: 12/24/2022] Open
Abstract
Chronic gastritis induced by Helicobacter pylori is the strongest known risk factor for peptic ulceration and distal gastric cancer, and adherence of H. pylori to gastric epithelial cells is critical for induction of inflammation. One H. pylori constituent that increases disease risk is the cag pathogenicity island, which encodes a secretion system that translocates bacterial effector molecules into host cells. Decay-accelerating factor (DAF) is a cellular receptor for H. pylori and a mediator of the inflammatory response to this pathogen. H. pylori induces DAF expression in human gastric epithelial cells; therefore, we sought to define the mechanism by which H. pylori up-regulates DAF and to extend these findings into a murine model of H. pylori-induced injury. Co-culture of MKN28 gastric epithelial cells with the wild-type H. pylori cag(+) strain J166 induced transcriptional expression of DAF, which was attenuated by disruption of a structural component of the cag secretion system (cagE). H. pylori-induced expression of DAF was dependent upon activation of the p38 mitogen-activated protein kinase pathway but not NF-kappaB. Hypergastrinemic INS-GAS mice infected with wild-type H. pylori demonstrated significantly increased DAF expression in gastric epithelium versus uninfected controls or mice infected with an H. pylori cagE(-) isogenic mutant strain. These results indicate that H. pylori cag(+) strains induce up-regulation of a cognate cellular receptor in vitro and in vivo in a cag-dependent manner, representing the first evidence of regulation of an H. pylori host receptor by the cag pathogenicity island.
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Affiliation(s)
- Daniel P. O'Brien
- Division of Gastroenterology, Department
of Medicine, Department of Cancer Biology, and
Department of Pathology, Vanderbilt University
School of Medicine, Nashville, Tennessee 37232-2279 and
Department of Veterans Affairs Medical Center,
Nashville, Tennessee 37212
| | - Judith Romero-Gallo
- Division of Gastroenterology, Department
of Medicine, Department of Cancer Biology, and
Department of Pathology, Vanderbilt University
School of Medicine, Nashville, Tennessee 37232-2279 and
Department of Veterans Affairs Medical Center,
Nashville, Tennessee 37212
| | - Barbara G. Schneider
- Division of Gastroenterology, Department
of Medicine, Department of Cancer Biology, and
Department of Pathology, Vanderbilt University
School of Medicine, Nashville, Tennessee 37232-2279 and
Department of Veterans Affairs Medical Center,
Nashville, Tennessee 37212
| | - Rupesh Chaturvedi
- Division of Gastroenterology, Department
of Medicine, Department of Cancer Biology, and
Department of Pathology, Vanderbilt University
School of Medicine, Nashville, Tennessee 37232-2279 and
Department of Veterans Affairs Medical Center,
Nashville, Tennessee 37212
| | - Alberto Delgado
- Division of Gastroenterology, Department
of Medicine, Department of Cancer Biology, and
Department of Pathology, Vanderbilt University
School of Medicine, Nashville, Tennessee 37232-2279 and
Department of Veterans Affairs Medical Center,
Nashville, Tennessee 37212
| | - Elizabeth J. Harris
- Division of Gastroenterology, Department
of Medicine, Department of Cancer Biology, and
Department of Pathology, Vanderbilt University
School of Medicine, Nashville, Tennessee 37232-2279 and
Department of Veterans Affairs Medical Center,
Nashville, Tennessee 37212
| | - Uma Krishna
- Division of Gastroenterology, Department
of Medicine, Department of Cancer Biology, and
Department of Pathology, Vanderbilt University
School of Medicine, Nashville, Tennessee 37232-2279 and
Department of Veterans Affairs Medical Center,
Nashville, Tennessee 37212
| | - Seth R. Ogden
- Division of Gastroenterology, Department
of Medicine, Department of Cancer Biology, and
Department of Pathology, Vanderbilt University
School of Medicine, Nashville, Tennessee 37232-2279 and
Department of Veterans Affairs Medical Center,
Nashville, Tennessee 37212
| | - Dawn A. Israel
- Division of Gastroenterology, Department
of Medicine, Department of Cancer Biology, and
Department of Pathology, Vanderbilt University
School of Medicine, Nashville, Tennessee 37232-2279 and
Department of Veterans Affairs Medical Center,
Nashville, Tennessee 37212
| | - Keith T. Wilson
- Division of Gastroenterology, Department
of Medicine, Department of Cancer Biology, and
Department of Pathology, Vanderbilt University
School of Medicine, Nashville, Tennessee 37232-2279 and
Department of Veterans Affairs Medical Center,
Nashville, Tennessee 37212
| | - Richard M. Peek
- Division of Gastroenterology, Department
of Medicine, Department of Cancer Biology, and
Department of Pathology, Vanderbilt University
School of Medicine, Nashville, Tennessee 37232-2279 and
Department of Veterans Affairs Medical Center,
Nashville, Tennessee 37212
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22
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Shao J, Yang VW, Sheng H. Prostaglandin E2 and Krüppel-like transcription factors synergistically induce the expression of decay-accelerating factor in intestinal epithelial cells. Immunology 2008; 125:397-407. [PMID: 18435741 DOI: 10.1111/j.1365-2567.2008.02847.x] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
The decay-accelerating factor (DAF) prevents the intestinal mucosa from bystander killing by complement. Prostaglandin E(2) (PGE(2)) induces the expression of DAF that may protect the tumour environment from complement attack. In the present study, we demonstrate synergistic actions of PGE(2) and two Krüppel-like factors (KLFs), which are zinc finger-containing transcription factors, in DAF regulation. Overexpression of KLF4 and KLF5 robustly induced transcriptional activity of the DAF promoter. In combination, PGE(2) and either KLF4 or KLF5 increased the expression of DAF in a synergistic fashion. Moreover, cyclooxygenase (COX-1 and COX-2) enzymes, KLF4/5 and DAF protein were coordinately expressed in normal intestinal mucosa as well as in intestinal neoplasm. In radiation-injured mouse intestine, COX-1 was rapidly induced and remained at relatively high levels. While KLF5 was quickly elevated after irradiation, KLF4 exhibited a delayed increase. Interestingly, levels of DAF increased gradually following the induction of COX-1 and KLFs. Mimicking the circumstances in vivo, coexpression of both COX and KLFs resulted in a synergistic or additive induction of DAF transcription in intestinal epithelial cells. Our data suggest that COX-derived PGE(2) may collaborate with KLF4/5 to regulate the activation of the complement system and exert diverse effects on the intestinal epithelium.
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Affiliation(s)
- Jinyi Shao
- Department of Surgery, Indiana University School of Medicine, Indianapolis, IN, USA
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23
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Narkar Y, Burnette R, Bleher R, Albrecht R, Kandela A, Robinson JR. Evaluation of Mucosal Damage and Recovery in the Gastrointestinal Tract of Rats by a Penetration Enhancer. Pharm Res 2007; 25:25-38. [DOI: 10.1007/s11095-007-9509-8] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2007] [Accepted: 08/15/2007] [Indexed: 02/07/2023]
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24
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Bowen JM, Gibson RJ, Tsykin A, Stringer AM, Logan RM, Keefe DMK. Gene expression analysis of multiple gastrointestinal regions reveals activation of common cell regulatory pathways following cytotoxic chemotherapy. Int J Cancer 2007; 121:1847-56. [PMID: 17594691 DOI: 10.1002/ijc.22895] [Citation(s) in RCA: 37] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/21/2023]
Abstract
Gastrointestinal mucositis involves many changes at the gene level, affecting epithelial/subepithelial interactions and leading to overt damage. The regional specificity and time course of these changes, and how they relate to subsequent mucositis development however remain unknown. The aim of this study was to determine the early time course of gene expression changes along the gastrointestinal tract of the DA rat following chemotherapy. Female DA rats were treated with a single dose of 200 mg/kg irinotecan to induce mucositis, and were killed at short intervals following treatment. Small sections of stomach, jejunum and colon were harvested for analysis of genetic profiles. RNA was hybridised to high density Affymetrix oligonucleotide microarrays. Data analysis was carried out with software package, TimeCourse, freely available through Bioconductor. As early as 1 hr following chemotherapy, expression of hundreds of genes was altered, including those for transcription factors, stress response proteins and protein turnover. These genes are involved in cell proliferation, differentiation and apoptosis along with other cellular processes. At early time points, there was a significant response involving the mitogen-activated protein kinase pathway, cell cycle regulation and cytokine receptor signalling. At later time points, changes to the complement cascade became prominent. We have shown that changes in gene expression following chemotherapy occur by 1 hr, and persist for at least 72 hr after treatment. Many of these changes are highly likely to be specifically related to the subsequent development of gastrointestinal mucositis.
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Affiliation(s)
- Joanne M Bowen
- Department of Medical Oncology, Royal Adelaide Hospital, North Terrace, Adelaide, South Australia, Australia.
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25
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Loos M, De Creus A, Thim L, Remaut E, Rottiers P. Murine trefoil factor 3 does not directly modulate LPS-mediated dendritic cell function. Scand J Immunol 2007; 66:35-42. [PMID: 17587344 DOI: 10.1111/j.1365-3083.2007.01944.x] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/20/2023]
Abstract
Peptides of the trefoil factor family (TFF) are expressed along the gastro-intestinal tract. They protect mucous epithelia from damage and contribute to mucosal repair, which is essential for preventing inflammation. Moreover, it has been suggested that TFF2 and TFF3, in particular, play a role in regulating immune responses. Depending on their activation status, dendritic cells (DC) can initiate either tolerance or immunity. This study, by comparing LPS-induced maturation of mTFF3-treated DC and non-treated DC, investigated whether murine TFF3 directly regulated DC function. mTFF3-treated DC and non-treated DC did not differ phenotypically or functionally. Both populations expressed, both before and after LPS-stimulation, similar levels of co-stimulatory molecules and cytokines, and were both efficient stimulators of T-cells. Our results suggest that mTFF3 does not govern immune responses on the level of DC function.
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Affiliation(s)
- M Loos
- Department for Molecular Biomedical Research, VIB, Ghent, BelgiumDepartment of Molecular Biology, Ghent University, Ghent, BelgiumDepartment of Protein Chemistry, Novo Nordisk, Bagsvaerd, Denmark
| | - A De Creus
- Department for Molecular Biomedical Research, VIB, Ghent, BelgiumDepartment of Molecular Biology, Ghent University, Ghent, BelgiumDepartment of Protein Chemistry, Novo Nordisk, Bagsvaerd, Denmark
| | - L Thim
- Department for Molecular Biomedical Research, VIB, Ghent, BelgiumDepartment of Molecular Biology, Ghent University, Ghent, BelgiumDepartment of Protein Chemistry, Novo Nordisk, Bagsvaerd, Denmark
| | - E Remaut
- Department for Molecular Biomedical Research, VIB, Ghent, BelgiumDepartment of Molecular Biology, Ghent University, Ghent, BelgiumDepartment of Protein Chemistry, Novo Nordisk, Bagsvaerd, Denmark
| | - P Rottiers
- Department for Molecular Biomedical Research, VIB, Ghent, BelgiumDepartment of Molecular Biology, Ghent University, Ghent, BelgiumDepartment of Protein Chemistry, Novo Nordisk, Bagsvaerd, Denmark
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26
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Kjellev S, Thim L, Pyke C, Poulsen SS. Cellular localization, binding sites, and pharmacologic effects of TFF3 in experimental colitis in mice. Dig Dis Sci 2007; 52:1050-9. [PMID: 17342398 DOI: 10.1007/s10620-006-9256-4] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/31/2006] [Accepted: 02/08/2006] [Indexed: 12/15/2022]
Abstract
Trefoil factors (TFFs) are essential for protection and restitution of the gastrointestinal mucosa but many aspects of TFF biology are unclear. Our aim was to compare the localization of endogenous TFFs and binding sites for injected TFF3 in the colon of healthy and colitic mice and to study the effect of TFF3 on dextrane sulfate sodium (DSS)-induced colitis in mice. Expression of endogenous TFF1-3 was examined by in situ hybridization and immunohistochemistry, and the distribution of intravenously, intraperitoneally, and subcutaneously administered (125)I-TFF3 by autoradiography and gamma-counting. The effect of systemically administered TFF3 on DSS-induced colitis was assessed. We found increased expression of endogenous TFF3 and increased binding of injected (125)I-TFF3 in the colon of animals with DSS-induced colitis. The distribution of intraperitoneally and subcutaneously administered (125)I-TFF3 was comparable. Systemic administration of the peptides reduced the severity of colitis. Expression of endogenous TFF3 and binding of systemically administered TFF3 are increased in DSS-induced colitis. Systemic administration of TFF3 attenuates the disease. These findings suggest a role of TFF3 in mucosal protection.
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Affiliation(s)
- Stine Kjellev
- Pharmacology Research 4, Novo Nordisk A/S, Maaloev, Denmark
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27
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Cauvi DM, Cauvi G, Pollard KM. Constitutive expression of murine decay-accelerating factor 1 is controlled by the transcription factor Sp1. THE JOURNAL OF IMMUNOLOGY 2006; 177:3837-47. [PMID: 16951346 PMCID: PMC1766464 DOI: 10.4049/jimmunol.177.6.3837] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/19/2022]
Abstract
The complement regulatory protein decay-accelerating factor (DAF or CD55) protects host tissue from complement-mediated injury by inhibiting the classical and alternative complement pathways. Besides its role in complement regulation, DAF has also been shown to be a key player in T cell immunity. Modulation of DAF expression could therefore represent a critical regulatory mechanism in both innate and adaptive immune responses. To identify and characterize key transcriptional regulatory elements controlling mouse Daf1 expression, a 2.5-kb fragment corresponding to the 5' flanking region of the mouse Daf1 gene was cloned. Sequence analysis showed that the mouse Daf1 promoter lacks conventional TATA and CCAAT boxes and displays a high guanine and cytosine content. RACE was used to identify one major and two minor transcription start sites 47, 20, and 17 bp upstream of the translational codon. Positive and negative regulatory regions were identified by transiently transfecting sequential 5'deletion constructs of the 5'flanking region into NIH/3T3, M12.4, and RAW264.7 cells. Mutational analyses of the promoter region combined with Sp1-specific ELISA showed that the transcription factor Sp1 is required for basal transcription and LPS-induced expression of the Daf1 gene. These findings provide new information on the regulation of the mouse Daf1 promoter and will facilitate further studies on the expression of Daf1 during immune responses.
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Affiliation(s)
| | | | - K. Michael Pollard
- Address correspondence and reprint requests to Dr. K. Michael Pollard, Department of Molecular and Experimental Medicine, MEM131, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037. E-mail address:
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Comalada M, Bailón E, de Haro O, Lara-Villoslada F, Xaus J, Zarzuelo A, Gálvez J. The effects of short-chain fatty acids on colon epithelial proliferation and survival depend on the cellular phenotype. J Cancer Res Clin Oncol 2006; 132:487-97. [PMID: 16788843 DOI: 10.1007/s00432-006-0092-x] [Citation(s) in RCA: 153] [Impact Index Per Article: 8.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2005] [Accepted: 03/01/2006] [Indexed: 12/12/2022]
Abstract
PURPOSE The short-chain fatty acids (SCFA) are produced via anaerobic bacterial fermentation of dietary fiber within the colonic lumen. Among them, butyrate is thought to protect against colon carcinogenesis. However, few studies analyze the effects of butyrate, and other SCFA, on normal epithelial cells and on epithelial regeneration during disease recovery. Since there are controversial in vitro studies, we have explored the effects of SCFA on different biological processes. METHODS We used both tumoral (HT-29) and normal (FHC) epithelial cells at different phenotypic states. In addition, we analyzed the in vivo activity of soluble dietary fiber and SCFA production in the proliferation rate and regeneration of intestinal epithelial cells. RESULTS The effect of butyrate on epithelial cells depends on the phenotypic cellular state. Thus, in nondifferentiated, high proliferative adenocarcinoma cells, butyrate significantly inhibited proliferation while increased differentiation and apoptosis, whereas other SCFA studied did not. However, in normal cells or in differentiated cultures as well as in in vivo studies, the normal proliferation and regeneration of damaged epithelium is not affected by butyrate or SCFA exposure. CONCLUSION Although butyrate could exert antiproliferative effects in tumor progression, its production is safe and without consequences for the normal epithelium growth.
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Affiliation(s)
- Mònica Comalada
- Department of Pharmacology, School of Pharmacy, University of Granada, Campus Universitario "La Cartuja" s/n, 18071, Granada, Spain.
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Weinstock JV, Summers RW, Elliott DE. Role of helminths in regulating mucosal inflammation. ACTA ACUST UNITED AC 2005; 27:249-71. [PMID: 15959781 DOI: 10.1007/s00281-005-0209-3] [Citation(s) in RCA: 40] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2004] [Accepted: 04/28/2005] [Indexed: 12/26/2022]
Abstract
The rapid rise in prevalence of ulcerative colitis (UC) and Crohn's disease (CD) in highly developed countries suggests that environmental change engenders risk for inflammatory bowel disease (IBD). Eradication of parasitic worms (helminths) through increased hygiene may be one such change that has led to increased prevalence of these diseases. Helminths alter host mucosal and systemic immunity, inhibiting dysregulated inflammatory responses. Animals exposed to helminths are protected from experimental colitis, encephalitis, and diabetes. Patients with CD or UC improve when exposed to whipworm. Lamina propria (LP) mononuclear cells from helminth-colonized mice make less interleukin (IL)-12 p40 and IFN-gamma, but more IL-4, IL-13, IL-10, TGF-beta, and PGE(2) compared to LP mononuclear cells from naive mice. Systemic immune responses show similar skewing toward Th2 and regulatory cytokine production in worm-colonized animal models and humans. Recent reports suggest that helminths induce regulatory T cell activity. These effects by once ubiquitous organisms may have protected individuals from many of the emerging immune-mediated illnesses like IBD, multiple sclerosis, type I diabetes, and asthma.
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Affiliation(s)
- Joel V Weinstock
- Department of Internal Medicine, Division of Gastroenterology-Hepatology, University of Iowa, Iowa City, IA 52242-1009, USA.
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Xu LF, Li J, Sun M, Sun HW. Expression of intestinal trefoil factor, proliferating cell nuclear antigen and histological changes in intestine of rats after intrauterine asphyxia. World J Gastroenterol 2005; 11:2291-2295. [PMID: 15818741 PMCID: PMC4305814 DOI: 10.3748/wjg.v11.i15.2291] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/07/2004] [Revised: 05/08/2004] [Accepted: 08/05/2004] [Indexed: 02/06/2023] Open
Abstract
AIM To study the expressions of intestinal trefoil factor (ITF) and proliferating cell nuclear antigen (PCNA) and histologic changes in intestine, to investigate the relationship between ITF and intestinal damage and repair after intrauterine hypoxia so as to understand the mechanism of intestinal injury and to find a new way to prevent and treat gastrointestinal diseases. METHODS Wistar rats, pregnant for 21 d, were used to establish animal models of intrauterine asphyxia by clamping one side of vessels supplying blood to uterus for 20 min, another side was regarded as sham operation group. Intestinal tissues were taken away at 0, 24, 48 and 72 h after birth and stored in different styles. ITF mRNA was detected by RT-PCR. PCNA expression was measured by immunohistochemistry. Intestinal tissues were studied histologically by HE staining in order to observe the areas and degree of injury and to value the intestinal mucosa injury index (IMDI). RESULTS ITF mRNA appeared in full-term rats and increased with age. After ischemia, ITF mRNA was decreased to the minimum (0.59+/-0.032) 24 h after birth, then began to increase higher after 72 h than it was in the control group (P<0.01). PCNA positive staining located in goblet cell nuclei. The PCNA level had a remarkable decline (53.29+/-1.97) 48 h after ischemia. Structure changes were obvious in 48-h group, IMDI (3.40+/-0.16) was significantly increased. Correlation analyses showed that IMDI had a negative correlation with ITF mRNA and PCNA (r = -0.543, P<0.05; r = -0.794, P<0.01, respectively). CONCLUSION Intrauterine ischemia can result in an early decrease of ITF mRNA expression. ITF and PCNA may play an important role in the damage and repair of intestinal mucosa.
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Affiliation(s)
- Ling-Fen Xu
- Department of Pediatrics, Second Affiliated Hospital, China Medical University, Shenyang 110004, Liaoning Province, China.
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31
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Singh JCI, Cruickshank SM, Newton DJ, Wakenshaw L, Graham A, Lan J, Lodge JPA, Felsburg PJ, Carding SR. Toll-like receptor-mediated responses of primary intestinal epithelial cells during the development of colitis. Am J Physiol Gastrointest Liver Physiol 2005; 288:G514-24. [PMID: 15499080 DOI: 10.1152/ajpgi.00377.2004] [Citation(s) in RCA: 57] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
The interleukin-2-deficient (IL-2(-/-)) mouse model of ulcerative colitis was used to test the hypothesis that colonic epithelial cells (CEC) directly respond to bacterial antigens and that alterations in Toll-like receptor (TLR)-mediated signaling may occur during the development of colitis. TLR expression and activation of TLR-mediated signaling pathways in primary CEC of healthy animals was compared with CEC in IL-2(-/-) mice during the development of colitis. In healthy animals, CEC expressed functional TLR, and in response to the TLR4 ligand LPS, proliferated and secreted the cytokines IL-6 and monocyte chemoattractant protein-1 (MCP-1). However, the TLR-responsiveness of CEC in IL-2(-/-) mice was different with decreased TLR4 responsiveness and augmented TLR2 responses that result in IL-6 and MCP-1 secretion. TLR signaling in CEC did not involve NF-kappaB (p65) activation with the inhibitory p50 form of NF-kappaB predominating in CEC in both the healthy and inflamed colon. Development of colitis was, however, associated with the activation of MAPK family members and upregulation of MyD88-independent signaling pathways characterized by increased caspase-1 activity and IL-18 production. These findings identify changes in TLR expression and signaling during the development of colitis that may contribute to changes in the host response to bacterial antigens seen in colitis.
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MESH Headings
- Adaptor Proteins, Signal Transducing
- Animals
- Antigens, Differentiation/physiology
- Bacteria/metabolism
- Blotting, Western
- Caspase 1/metabolism
- Cell Separation
- Cells, Cultured
- Colitis/pathology
- DNA, Complementary/biosynthesis
- DNA, Complementary/genetics
- Electrophoretic Mobility Shift Assay
- Enzyme-Linked Immunosorbent Assay
- Epithelial Cells/pathology
- Flow Cytometry
- Interleukin-18/biosynthesis
- Intestines/pathology
- Membrane Glycoproteins/genetics
- Membrane Glycoproteins/physiology
- Mice
- Mice, Inbred C57BL
- Myeloid Differentiation Factor 88
- RNA, Messenger/biosynthesis
- RNA, Messenger/isolation & purification
- Receptors, Cell Surface/genetics
- Receptors, Cell Surface/physiology
- Receptors, Immunologic/physiology
- Reverse Transcriptase Polymerase Chain Reaction
- Signal Transduction/physiology
- Toll-Like Receptor 2
- Toll-Like Receptor 4
- Toll-Like Receptors
- Up-Regulation/physiology
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Holla VR, Wang D, Brown JR, Mann JR, Katkuri S, DuBois RN. Prostaglandin E2 Regulates the Complement Inhibitor CD55/Decay-accelerating Factor in Colorectal Cancer. J Biol Chem 2005; 280:476-83. [PMID: 15520008 DOI: 10.1074/jbc.m407403200] [Citation(s) in RCA: 45] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022] Open
Abstract
Cyclooxygenase-derived prostaglandin E(2) (PGE(2)) stimulates tumor progression by modulating several proneoplastic pathways. The mechanisms by which PGE(2) promotes tumor growth and metastasis through stimulation of cell migration, invasion, and angiogenesis have been fairly well characterized. Much less is known, however, about the molecular mechanisms responsible for the immunosuppressive effects of PGE(2). We identified PGE(2) target genes and subsequently studied their biologic role in colorectal cancer cells. The complement regulatory protein decay-accelerating factor (DAF or CD55) was induced following PGE(2) treatment of LS174T colon cancer cells. Analysis of PGE(2)-mediated activation of the DAF promoter employing 5'-deletion luciferase constructs suggests that regulation occurs at the transcriptional level via a cyclic AMP/protein kinase A-dependent pathway. Nonsteroidal anti-inflammatory drugs blocked DAF expression in HCA-7 colon cancer cells, which could be restored by the addition of exogenous PGE(2). Finally, we observed an increase in DAF expression in the intestinal mucosa of Apc(Min+/-) mice treated with PGE(2) in vivo. In summary, these results indicate a novel immunosuppressive role for PGE(2) in the development of colorectal carcinomas.
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Affiliation(s)
- Vijaykumar R Holla
- Department of Medicine, Vanderbilt University Medical Center, Nashville, TN 37232-2279, USA
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Zhang Z, Stanley SL. Stereotypic and specific elements of the human colonic response to Entamoeba histolytica and Shigella flexneri. Cell Microbiol 2004; 6:535-54. [PMID: 15104595 DOI: 10.1111/j.1462-5822.2004.00381.x] [Citation(s) in RCA: 17] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
Abstract
The clinical presentations of bacillary dysentery caused by shigella, and amoebic dysentery caused by the protozoan parasite Entamoeba histolytica, can be indistinguishable, with both organisms causing colonic mucosal damage and ulceration. However, the two organisms are quite distinct, and have very different pathogenic mechanisms. This raises the fundamental question of whether the similar clinical manifestations reflect a stereotypic response of the human gut to mucosal injury, or whether there are differences at the molecular level in the host response to individual gut pathogens. To characterize the human colonic response to each pathogen at the molecular level, we measured the differential transcription of nearly 40,000 human genes in sections of human colonic xenografts obtained 4 and 24 h following infection with Shigella flexneri or E. histolytica. Our results indicate that much of the human colonic response to these two pathogens is stereotypic, with increased expression of genes activated in cells undergoing stress and/or hypoxic responses, genes encoding cytokines, chemokines, and mediators that are involved in immune and inflammatory responses, and genes encoding proteins involved in responses to tissue injury and in tissue repair. The responses to amoeba and Shigella were not identical however, and we found unique elements in each response that may provide new insights into the distinct pathogenic mechanisms of E. histolytica and S. flexneri.
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MESH Headings
- Animals
- Colon/metabolism
- Colon/microbiology
- Colon/parasitology
- Colon/transplantation
- Dysentery, Amebic/genetics
- Dysentery, Amebic/immunology
- Dysentery, Amebic/parasitology
- Dysentery, Amebic/pathology
- Dysentery, Bacillary/genetics
- Dysentery, Bacillary/immunology
- Dysentery, Bacillary/microbiology
- Dysentery, Bacillary/pathology
- Entamoeba histolytica/growth & development
- Gene Expression Profiling
- Gene Expression Regulation
- Genes
- Humans
- Inflammation
- Mice
- Mice, SCID
- Oligonucleotide Array Sequence Analysis
- Shigella flexneri/growth & development
- Transplantation, Heterologous
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Affiliation(s)
- Zhi Zhang
- Department of Medicine, Washington University School of Medicine, USA
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Emami S, Rodrigues S, Rodrigue CM, Le Floch N, Rivat C, Attoub S, Bruyneel E, Gespach C. Trefoil factor family (TFF) peptides and cancer progression. Peptides 2004; 25:885-98. [PMID: 15177885 DOI: 10.1016/j.peptides.2003.10.019] [Citation(s) in RCA: 88] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/29/2003] [Accepted: 10/27/2003] [Indexed: 12/15/2022]
Abstract
TFF peptides are involved in mucosal maintenance and repair through motogenic and antiapoptotic activities. These peptides are overexpressed during inflammatory processes and cancer progression. They also function as scatter factors, proinvasive and angiogenic agents. Such a divergence is related to the pathophysiological state of tissues submitted to persistent aggressive situations during digestive processes in the normal gastrointestinal tract, inflammatory and neoplastic diseases. In agreement with this model, TFF peptides are connected with multiple oncogenic pathways. As a consequence, the TFF signaling pathways may serve as potential targets in the control of chronic inflammation and progression of human solid tumors.
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Affiliation(s)
- Shahin Emami
- INSERM U482, Signal Transduction and Cellular Functions in Diabetes and Digestive Cancers, Hôpital Saint-Antoine, 75571 Paris Cedex 12, France.
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Lin F, Spencer D, Hatala DA, Levine AD, Medof ME. Decay-Accelerating Factor Deficiency Increases Susceptibility to Dextran Sulfate Sodium-Induced Colitis: Role for Complement in Inflammatory Bowel Disease. THE JOURNAL OF IMMUNOLOGY 2004; 172:3836-41. [PMID: 15004190 DOI: 10.4049/jimmunol.172.6.3836] [Citation(s) in RCA: 48] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/19/2022]
Abstract
Decay-accelerating factor (DAF or CD55) is expressed on colonic epithelial cells but its function in the mucosa is unknown. In humans, a proportion of DAF-deficient (Cromer INAB) patients develop inflammatory bowel disease (IBD). To evaluate how DAF deficiency may contribute to gut inflammation and thus could play a role in IBD pathogenesis, we compared the severity of dextran sulfate sodium-induced colitis in Daf1 gene-targeted and control mice. Seven days after consuming 3% dextran sulfate sodium in their drinking water, Daf1(-/-) mice suffered markedly greater weight loss (-24.7 +/- 7.5% vs -14.2% +/- 4.9%), exhibited uniformly bloody diarrhea as compared with soft stool in control mice, developed shortened colons, and had larger spleens. Histological examination of distal colons showed massively increased neutrophilic and mononuclear cell infiltration, greater epithelial cell destruction, and increased ulcerations. Cytokine production in organ cultures of colonic explants showed increased levels of IL-12 and IL-6. Fourteen days after switching back to regular water, in contrast to the Daf1(+/+) controls which showed little stool abnormality, all Daf1(-/-) mice continued to have diarrhea. Organ culture cytokine measurements at this time point, i.e., the end of the recovery phase, showed markedly increased levels of IL-10 (6-fold), IL-12 (4-fold), and IL-6 (2-fold), as well as TNF-alpha (>10-fold) compared with the controls. Our findings argue that, as shown for IL-10 in IL-10(-/-) mice and IL-2 in IL-2(-/-) mice, DAF control of complement additionally is important in regulating gut homeostasis and consequently its activity may participate in protecting against IBD.
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Affiliation(s)
- Feng Lin
- Institute of Pathology, Division of Gastroenterology, Case Western Reserve University, Cleveland, OH 44106, USA
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Abstract
Maintaining the integrity of the gastrointestinal tract, despite the continual presence of microbial flora and injurious agents, is essential. Epithelial continuity depends on a family of small, yet abundant, secreted proteins--the trefoil factors (TFFs). TFFs protect mucous epithelia from a range of insults and contribute to mucosal repair, although the signalling events that mediate these responses are only partially understood.
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Affiliation(s)
- Douglas Taupin
- The Canberra Hospital, Canberra, Australian Capital Territory, Australia
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I, 4. Immunology of the gut. ACTA ACUST UNITED AC 2003. [DOI: 10.1016/s0168-7069(03)09005-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register]
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Affiliation(s)
- Tadao Bamba
- Shiga University of Medical Science, Seta-Tsukinowa, Otsu 520-2192, Japan
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Mason JC, Ahmed Z, Mankoff R, Lidington EA, Ahmad S, Bhatia V, Kinderlerer A, Randi AM, Haskard DO. Statin-induced expression of decay-accelerating factor protects vascular endothelium against complement-mediated injury. Circ Res 2002; 91:696-703. [PMID: 12386146 DOI: 10.1161/01.res.0000038151.57577.19] [Citation(s) in RCA: 65] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
Complement-mediated vascular injury is important in the pathophysiology of atherosclerosis and myocardial infarction. Because recent evidence shows that statins have beneficial effects on endothelial cell (EC) function independent of lipid lowering, we explored the hypothesis that statins modulate vascular EC resistance to complement through the upregulation of complement-inhibitory proteins. Human umbilical vein and aortic ECs were treated with atorvastatin or simvastatin, and decay-accelerating factor (DAF), membrane cofactor protein, and CD59 expression was measured by flow cytometry. A dose-dependent increase in DAF expression of up to 4-fold was seen 24 to 48 hours after treatment. Statin-induced upregulation of DAF required increased steady-state mRNA and de novo protein synthesis. L-Mevalonate and geranylgeranyl pyrophosphate reversed the effect, confirming the role of 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibition and suggesting that constitutive DAF expression is negatively regulated by geranylgeranylation. Neither farnesyl pyrophosphate nor squalene inhibited statin-induced DAF expression, suggesting that the effect is independent of cholesterol lowering. Statin-induced DAF upregulation was mediated by the activation of protein kinase Calpha and inhibition of RhoA and was independent of phosphatidylinositol-3 kinase and NO activity. The increased DAF expression was functionally effective, resulting in significant reduction of C3 deposition and complement-mediated lysis of antibody-coated ECs. These observations provide evidence for a novel cytoprotective action of statins on vascular endothelium that is independent of the effect on lipids and results in enhanced protection against complement-mediated injury. Modulation of complement regulatory protein expression may contribute to the early beneficial effects of statins in reducing the morbidity and mortality associated with atherosclerosis.
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Affiliation(s)
- Justin C Mason
- British Heart Foundation Cardiovascular Medicine Unit, National Heart and Lung Institute, Imperial College, Hammersmith Hospital, London, UK.
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