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Yang Y, Gong Z, Yang J, Cai Y, Hong S, Mao W, Guo Z, Qiu M, Fan Z, Cui B. Exploring shared mechanisms between ulcerative colitis and psoriasis and predicting therapeutic natural compounds through bioinformatics and molecular docking. Heliyon 2024; 10:e37624. [PMID: 39309918 PMCID: PMC11416260 DOI: 10.1016/j.heliyon.2024.e37624] [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: 05/27/2024] [Revised: 08/05/2024] [Accepted: 09/06/2024] [Indexed: 09/25/2024] Open
Abstract
Introduction Previous studies have suggested a potential correlation between psoriasis (PS) and ulcerative colitis (UC). However, studies exploring the shared mechanisms of both diseases remain limited. Current treatments primarily involve using immunosuppressive drugs, which can lead to potential side effects and drug resistance. Traditional Chinese medicine has demonstrated favorable efficacy in treating UC and PS with fewer side effects. This study aims to elucidate the shared biological mechanisms underlying UC and PS and to predict natural compounds effective for treating both disorders. Method We collected and validated differentially expressed genes associated with UC and PS from the Gene Expression Omnibus database. A protein-protein interaction network was constructed using the STRING database, aiding in identifying core targets. The Gene Ontology and Kyoto Encyclopedia of Genes and Genomes databases were utilized to analyze the functions and genomic enrichment of the identified core targets. The CIBERSORT method was employed to assess the correlation of core targets with immune cells. Compounds with potential therapeutic values were selected from the Coremine and TCMSP databases, and their therapeutic efficacy was predicted via molecular docking. Results In UC and PS, 20 common core targets were identified, with matrix metalloproteinase 9 (MMP9), matrix metalloproteinase 1 (MMP1), cluster of differentiation 274 (CD274), C-X-C motif chemokine ligand 10 (CXCL10), and topoisomerase II alpha (TOP2A) emerging as the most relevant targets shared between both conditions. Elevated levels of macrophages and dendritic cells were observed in UC and PS, with CXCL10 exhibiting the closest association with macrophages. UC and PS shared common signaling pathways, including IL-17, TNF, and chemokine signaling pathways, among others. Molecular docking revealed that quercetin, baicalen, irisolidone, rutaecarpine, epigallocatechin-3-gallate, and others held potential as natural compounds for treating both disorders. Conclusion MMP9, MMP1, and CXCL10, central mediators in the inflammatory pathways of UC and PS, establish a shared mechanism by triggering cytokine and chemokine activation, leading to tissue damage and positioning them as promising therapeutic targets for both conditions. Compounds such as quercetin, luteolin, irisolidone, rutaecarpine, and so on may be key drugs for treating both conditions. These findings suggest the potential advancement of therapeutic strategies and the enhancement of patient care by exploring shared mechanisms and predicting promising natural compounds for treating UC and PS.
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Affiliation(s)
- Yixuan Yang
- Department of Dermatology, Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, 100053, China
| | - Zhuozhi Gong
- Wangjing Hospital, China Academy of Chinese Medical Sciences, Beijing, 100102, China
| | - Jiao Yang
- Department of Dermatology, Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, 100053, China
| | - Ying Cai
- Jiangsu Province Hospital of Chinese Medicine, Nanjing University of Chinese Medicine, Nanjing, 210023, China
| | - Shengwei Hong
- Jiangsu Province Hospital of Chinese Medicine, Nanjing University of Chinese Medicine, Nanjing, 210023, China
| | - Wenjun Mao
- Jiangsu Province Hospital of Chinese Medicine, Nanjing University of Chinese Medicine, Nanjing, 210023, China
| | - Zijian Guo
- Department of Dermatology, Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, 100053, China
| | - Mengting Qiu
- Jiangsu Province Hospital of Chinese Medicine, Nanjing University of Chinese Medicine, Nanjing, 210023, China
| | - Zhu Fan
- Department of Dermatology, Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, 100053, China
| | - Bingnan Cui
- Department of Dermatology, Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, 100053, China
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Arosa L, Camba-Gómez M, Lorenzo-Martín LF, Clavaín L, López M, Conde-Aranda J. RNA Expression of MMP12 Is Strongly Associated with Inflammatory Bowel Disease and Is Regulated by Metabolic Pathways in RAW 264.7 Macrophages. Int J Mol Sci 2024; 25:3167. [PMID: 38542140 PMCID: PMC10970096 DOI: 10.3390/ijms25063167] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2024] [Revised: 03/06/2024] [Accepted: 03/07/2024] [Indexed: 04/04/2024] Open
Abstract
Macrophage metalloelastase or matrix metalloproteinase-12 (MMP12) is a macrophage-specific proteolytic enzyme involved in the physiopathology of many inflammatory diseases, including inflammatory bowel disease. Although previously published data suggested that the modulation of MMP12 in macrophages could be a determinant for the development of intestinal inflammation, scarce information is available on the mechanisms underlying the regulation of MMP12 expression in those phagocytes. Therefore, in this study, we aimed to delineate the association of MMP12 with inflammatory bowel disease and the molecular events leading to the transcriptional control of this metalloproteinase. For that, we used publicly available transcriptional data. Also, we worked with the RAW 264.7 macrophage cell line for functional experiments. Our results showed a strong association of MMP12 expression with the severity of inflammatory bowel disease and the response to relevant biological therapies. In vitro assays revealed that the inhibition of mechanistic target of rapamycin complex 1 (mTORC1) and the stimulation of the AMP-activated protein kinase (AMPK) signaling pathway potentiated the expression of Mmp12. Additionally, AMPK and mTOR required a functional downstream glycolytic pathway to fully engage with Mmp12 expression. Finally, the pharmacological inhibition of MMP12 abolished the expression of the proinflammatory cytokine Interleukin-6 (Il6) in macrophages. Overall, our findings provide a better understanding of the mechanistic regulation of MMP12 in macrophages and its relationship with inflammation.
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Affiliation(s)
- Laura Arosa
- Molecular and Cellular Gastroenterology Group, Health Research Institute of Santiago de Compostela (IDIS), 15706 Santiago de Compostela, Spain; (L.A.); (M.C.-G.)
| | - Miguel Camba-Gómez
- Molecular and Cellular Gastroenterology Group, Health Research Institute of Santiago de Compostela (IDIS), 15706 Santiago de Compostela, Spain; (L.A.); (M.C.-G.)
| | | | - Laura Clavaín
- EGO Genomics, Scientific Park of the University of Salamanca, Adaja Street 4, Building M2, 37185 Villamayor, Spain;
| | - Miguel López
- NeurObesity Group, Department of Physiology, Center for Research in Molecular Medicine and Chronic Diseases (CIMUS), University of Santiago de Compostela, 15782 Santiago de Compostela, Spain;
- CIBER Fisiopatologia de la Obesidad y Nutrición (CIBERobn), 15706 Santiago de Compostela, Spain
| | - Javier Conde-Aranda
- Molecular and Cellular Gastroenterology Group, Health Research Institute of Santiago de Compostela (IDIS), 15706 Santiago de Compostela, Spain; (L.A.); (M.C.-G.)
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Biel C, Faber KN, Bank RA, Olinga P. Matrix metalloproteinases in intestinal fibrosis. J Crohns Colitis 2024; 18:462-478. [PMID: 37878770 PMCID: PMC10906956 DOI: 10.1093/ecco-jcc/jjad178] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/20/2023] [Revised: 10/03/2023] [Accepted: 10/24/2023] [Indexed: 10/27/2023]
Abstract
Intestinal fibrosis is a common complication in patients with inflammatory bowel disease [IBD], in particular Crohn's disease [CD]. Unfortunately, at present intestinal fibrosis is not yet preventable, and cannot be treated by interventions other than surgical removal. Intestinal fibrosis is characterized by excessive accumulation of extracellular matrix [ECM], which is caused by activated fibroblasts and smooth muscle cells. Accumulation of ECM results from an imbalanced production and degradation of ECM. ECM degradation is mainly performed by matrix metalloproteinases [MMPs], enzymes that are counteracted by tissue inhibitors of MMPs [TIMPs]. In IBD patients, MMP activity [together with other protease activities] is increased. At the same time, CD patients have a generally lower MMP activity compared to ulcerative colitis patients, who usually do not develop intestinal strictures or fibrosis. The exact regulation and role[s] of these MMPs in fibrosis are far from understood. Here, we review the current literature about ECM remodelling by MMPs in intestinal fibrosis and their potential role as biomarkers for disease progression or druggable targets.
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Affiliation(s)
- Carin Biel
- Department of Pharmaceutical Technology and Biopharmacy, University of Groningen, the Netherlands
| | - Klaas Nico Faber
- Department of Gastroenterology and Hepatology, University Medical Center Groningen, Groningen, The Netherlands
| | - Ruud A Bank
- Department of Pathology and Medical Biology, University of Groningen, University Medical Center Groningen, 9713 GZ Groningen, The Netherlands
| | - Peter Olinga
- Department of Pharmaceutical Technology and Biopharmacy, University of Groningen, the Netherlands
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Identification of Novel Core Genes Involved in Malignant Transformation of Inflamed Colon Tissue Using a Computational Biology Approach and Verification in Murine Models. Int J Mol Sci 2023; 24:ijms24054311. [PMID: 36901742 PMCID: PMC10001800 DOI: 10.3390/ijms24054311] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2023] [Revised: 02/18/2023] [Accepted: 02/20/2023] [Indexed: 02/24/2023] Open
Abstract
Inflammatory bowel disease (IBD) is a complex and multifactorial systemic disorder of the gastrointestinal tract and is strongly associated with the development of colorectal cancer. Despite extensive studies of IBD pathogenesis, the molecular mechanism of colitis-driven tumorigenesis is not yet fully understood. In the current animal-based study, we report a comprehensive bioinformatics analysis of multiple transcriptomics datasets from the colon tissue of mice with acute colitis and colitis-associated cancer (CAC). We performed intersection of differentially expressed genes (DEGs), their functional annotation, reconstruction, and topology analysis of gene association networks, which, when combined with the text mining approach, revealed that a set of key overexpressed genes involved in the regulation of colitis (C3, Tyrobp, Mmp3, Mmp9, Timp1) and CAC (Timp1, Adam8, Mmp7, Mmp13) occupied hub positions within explored colitis- and CAC-related regulomes. Further validation of obtained data in murine models of dextran sulfate sodium (DSS)-induced colitis and azoxymethane/DSS-stimulated CAC fully confirmed the association of revealed hub genes with inflammatory and malignant lesions of colon tissue and demonstrated that genes encoding matrix metalloproteinases (acute colitis: Mmp3, Mmp9; CAC: Mmp7, Mmp13) can be used as a novel prognostic signature for colorectal neoplasia in IBD. Finally, using publicly available transcriptomics data, translational bridge interconnecting of listed colitis/CAC-associated core genes with the pathogenesis of ulcerative colitis, Crohn's disease, and colorectal cancer in humans was identified. Taken together, a set of key genes playing a core function in colon inflammation and CAC was revealed, which can serve both as promising molecular markers and therapeutic targets to control IBD and IBD-associated colorectal neoplasia.
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Lebish EJ, Morgan NJ, Valentine JF, Beswick EJ. MK2 Inhibitors as a Potential Crohn's Disease Treatment Approach for Regulating MMP Expression, Cleavage of Checkpoint Molecules and T Cell Activity. Pharmaceuticals (Basel) 2022; 15:ph15121508. [PMID: 36558958 PMCID: PMC9784662 DOI: 10.3390/ph15121508] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2022] [Revised: 11/28/2022] [Accepted: 12/01/2022] [Indexed: 12/11/2022] Open
Abstract
Crohn's Disease (CD) and Ulcerative Colitis (UC) are the two major forms of inflammatory bowel disease (IBD), which are incurable chronic immune-mediated diseases of the gastrointestinal tract. Both diseases present with chronic inflammation that leads to epithelial barrier dysfunction accompanied by loss of immune tolerance and inflammatory damage to the mucosa of the GI tract. Despite extensive research in the field, some of the mechanisms associated with the pathology in IBD remain elusive. Here, we identified a mechanism by which the MAPK-activated protein kinase 2 (MK2) pathway contributes to disease pathology in CD by regulating the expression of matrix metalloproteinases (MMPs), which cleave checkpoint molecules on immune cells and enhance T cell activity. By utilizing pharmaceuticals targeting MMPs and MK2, we show that the cleavage of checkpoint molecules and enhanced T cell responses may be reduced. The data presented here suggest the potential for MK2 inhibitors as a therapeutic approach for the treatment of CD.
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Jacenik D, Fichna J, Małecka-Wojciesko E, Mokrowiecka A. Protease-Activated Receptors - Key Regulators of Inflammatory Bowel Diseases Progression. J Inflamm Res 2022; 14:7487-7497. [PMID: 35002281 PMCID: PMC8721023 DOI: 10.2147/jir.s335502] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2021] [Accepted: 12/03/2021] [Indexed: 12/12/2022] Open
Abstract
The pathogenesis and course of inflammatory bowel diseases are related to both immune system disorders and dysfunction of colon permeability. Moreover, co-existing diseases in patients with Crohn's disease and ulcerative colitis are identified. Currently, there are some therapeutic strategies that affect the function of cytokine/s causing inflammation in the intestinal wall. However, additional approaches which target other components of inflammatory bowel diseases pathogenesis are still needed. Accumulating evidence suggests that proteases and protease-activated receptors seem to be responsible for colitis progression. Experimental and observational studies showed alteration of protease-activated receptors expression in the colon of patients with Crohn's disease and ulcerative colitis. Furthermore, it was suggested that the expression of protease-activated receptors correlated with inflammatory bowel diseases activity. Moreover, regulation of protease-activated receptors seems to be responsible for the modulation of colitis and clinical manifestation of inflammatory bowel diseases. In this review, we present the current state of knowledge about the contribution of protease-activated receptors to Crohn's disease and ulcerative colitis and its implications for diagnosis and treatment.
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Affiliation(s)
- Damian Jacenik
- Department of Cytobiochemistry, Faculty of Biology and Environmental Protection, University of Lodz, Lodz, Poland
| | - Jakub Fichna
- Department of Biochemistry, Faculty of Medicine, Medical University of Lodz, Lodz, Poland
| | - Ewa Małecka-Wojciesko
- Department of Digestive Tract Diseases, Faculty of Medicine, Medical University of Lodz, Lodz, Poland
| | - Anna Mokrowiecka
- Department of Digestive Tract Diseases, Faculty of Medicine, Medical University of Lodz, Lodz, Poland
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Fat of the Gut: Epithelial Phospholipids in Inflammatory Bowel Diseases. Int J Mol Sci 2021; 22:ijms222111682. [PMID: 34769112 PMCID: PMC8584226 DOI: 10.3390/ijms222111682] [Citation(s) in RCA: 40] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2021] [Revised: 10/20/2021] [Accepted: 10/27/2021] [Indexed: 12/15/2022] Open
Abstract
Inflammatory bowel diseases (IBD) comprise a distinct set of clinical symptoms resulting from chronic inflammation within the gastrointestinal (GI) tract. Despite the significant progress in understanding the etiology and development of treatment strategies, IBD remain incurable for thousands of patients. Metabolic deregulation is indicative of IBD, including substantial shifts in lipid metabolism. Recent data showed that changes in some phospholipids are very common in IBD patients. For instance, phosphatidylcholine (PC)/phosphatidylethanolamine (PE) and lysophosphatidylcholine (LPC)/PC ratios are associated with the severity of the inflammatory process. Composition of phospholipids also changes upon IBD towards an increase in arachidonic acid and a decrease in linoleic and a-linolenic acid levels. Moreover, an increase in certain phospholipid metabolites, such as lysophosphatidylcholine, sphingosine-1-phosphate and ceramide, can result in enhanced intestinal inflammation, malignancy, apoptosis or necroptosis. Because some phospholipids are associated with pathogenesis of IBD, they may provide a basis for new strategies to treat IBD. Current attempts are aimed at controlling phospholipid and fatty acid levels through the diet or via pharmacological manipulation of lipid metabolism.
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Walshe M, Nayeri S, Ji J, Hernandez-Rocha C, Sabic K, Hu L, Giri M, Nayar S, Brant S, McGovern DPB, Rioux JD, Duerr RH, Cho JH, Schumm PL, Lazarev M, Silverberg MS. A Role for CXCR3 Ligands as Biomarkers of Post-Operative Crohn's Disease Recurrence. J Crohns Colitis 2021; 16:900-910. [PMID: 34698823 PMCID: PMC9282882 DOI: 10.1093/ecco-jcc/jjab186] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
BACKGROUND AND AIMS Crohn's disease [CD] recurrence following ileocolic resection [ICR] is common. We sought to identify blood-based biomarkers associated with CD recurrence. METHODS CD patients undergoing ICR were recruited across six centres. Serum samples were obtained at post-operative colonoscopy. A multiplex immunoassay was used to analyse 92 inflammation-related proteins [Olink Proteomics]. Bayesian analysis was used to identify proteins associated with increasing Rutgeerts score. Identified proteins were used in receiver operating characteristic [ROC] analysis to examine the ability to identify CD recurrence [Rutgeerts score ≥i2]. Existing single cell data were interrogated to further elucidate the role of the identified proteins. RESULTS Data from 276 colonoscopies in 213 patients were available. Median time from surgery to first and second colonoscopy was 7 (interquartile range [IQR] 6-9) and 19 [IQR 16-23] months, respectively. Disease recurrence was evident at 60 [30%] first and 36 [49%] second colonoscopies. Of 14 proteins significantly associated with Rutgeerts score, the strongest signal was seen for CXCL9 and MMP1. Among patients on anti-tumour necrosis factor drugs, CXCL9 and CXCL11 were most strongly associated with Rutgeerts score. Both are CXCR3 ligands. Incorporation of identified proteins into ROC analysis improved the ability to identify disease recurrence as compared to C-reactive protein alone: area under the curve [AUC] 0.75 (95% confidence interval [CI]: 0.66-0.82] vs 0.64 [95% CI 0.56-0.72], p = 0.012. Single cell transcriptomic data provide evidence that innate immune cells are the primary source of the identified proteins. CONCLUSIONS CXCR3 ligands are associated with CD recurrence following ICR. Incorporation of novel blood-based candidate biomarkers may aid in identification of CD recurrence.
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Affiliation(s)
- Margaret Walshe
- Zane Cohen Centre for Digestive Diseases, Lunenfeld-Tanenbaum Research Institute, Sinai Health System, Toronto, Ontario, Canada,Division of Gastroenterology, Mount Sinai Hospital, Sinai Health System, University of Toronto, Toronto, Ontario, Canada
| | - Shadi Nayeri
- Zane Cohen Centre for Digestive Diseases, Lunenfeld-Tanenbaum Research Institute, Sinai Health System, Toronto, Ontario, Canada
| | - Jiayi Ji
- Department of Population Health Science and Policy, Icahn School of Medicine at Mount Sinai, New York, NY, USA,The Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Cristian Hernandez-Rocha
- Zane Cohen Centre for Digestive Diseases, Lunenfeld-Tanenbaum Research Institute, Sinai Health System, Toronto, Ontario, Canada,Division of Gastroenterology, Mount Sinai Hospital, Sinai Health System, University of Toronto, Toronto, Ontario, Canada
| | - Ksenija Sabic
- The Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA,Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Liangyuan Hu
- Department of Population Health Science and Policy, Icahn School of Medicine at Mount Sinai, New York, NY, USA,The Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Mamta Giri
- The Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA,Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Shikha Nayar
- The Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA,Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Steven Brant
- Crohn’s and Colitis Center of New Jersey, Division of Gastroenterology and Hepatology, Department of Medicine, Rutgers Robert Wood Johnson Medical School, New Brunswick, NJ, USA
| | - Dermot P B McGovern
- F. Widjaja Foundation Inflammatory Bowel and Immunobiology Research Institute, Cedars Sinai Medical Center, Los Angeles, CA, USA
| | - John D Rioux
- Research Centre, Montreal Heart Institute, Montréal, QC, Canada,Faculty of Medicine, Université de Montréal, Montréal, QC, Canada
| | - Richard H Duerr
- Division of Gastroenterology, Hepatology and Nutrition, University of Pittsburgh, Pittsburgh, PA,USA
| | - Judy H Cho
- The Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA,Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Phil L Schumm
- Department of Health Sciences, University of Chicago, Chicago, IL, USA
| | | | - Mark S Silverberg
- Corresponding author: Dr Mark Silverberg, MD, PhD, FRCPC, University of Toronto, Division of Gastroenterology, Mount Sinai Hospital Inflammatory Bowel Disease Centre, 441–600 University Avenue, Toronto, Ontario, M5G1X5, Canada. Tel: +1-416-586-4800 ext 8236; Fax: +1-416-619-5524;
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Mariaule V, Kriaa A, Soussou S, Rhimi S, Boudaya H, Hernandez J, Maguin E, Lesner A, Rhimi M. Digestive Inflammation: Role of Proteolytic Dysregulation. Int J Mol Sci 2021; 22:ijms22062817. [PMID: 33802197 PMCID: PMC7999743 DOI: 10.3390/ijms22062817] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2021] [Revised: 03/04/2021] [Accepted: 03/05/2021] [Indexed: 12/11/2022] Open
Abstract
Dysregulation of the proteolytic balance is often associated with diseases. Serine proteases and matrix metalloproteases are involved in a multitude of biological processes and notably in the inflammatory response. Within the framework of digestive inflammation, several studies have stressed the role of serine proteases and matrix metalloproteases (MMPs) as key actors in its pathogenesis and pointed to the unbalance between these proteases and their respective inhibitors. Substantial efforts have been made in developing new inhibitors, some of which have reached clinical trial phases, notwithstanding that unwanted side effects remain a major issue. However, studies on the proteolytic imbalance and inhibitors conception are directed toward host serine/MMPs proteases revealing a hitherto overlooked factor, the potential contribution of their bacterial counterpart. In this review, we highlight the role of proteolytic imbalance in human digestive inflammation focusing on serine proteases and MMPs and their respective inhibitors considering both host and bacterial origin.
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Affiliation(s)
- Vincent Mariaule
- Microbiota Interaction with Human and Animal Team (MIHA), Micalis Institute, AgroParisTech, Université Paris-Saclay, INRAE, F-78350 Jouy-en-Josas, France; (V.M.); (A.K.); (S.S.); (S.R.); (H.B.); (E.M.)
| | - Aicha Kriaa
- Microbiota Interaction with Human and Animal Team (MIHA), Micalis Institute, AgroParisTech, Université Paris-Saclay, INRAE, F-78350 Jouy-en-Josas, France; (V.M.); (A.K.); (S.S.); (S.R.); (H.B.); (E.M.)
| | - Souha Soussou
- Microbiota Interaction with Human and Animal Team (MIHA), Micalis Institute, AgroParisTech, Université Paris-Saclay, INRAE, F-78350 Jouy-en-Josas, France; (V.M.); (A.K.); (S.S.); (S.R.); (H.B.); (E.M.)
| | - Soufien Rhimi
- Microbiota Interaction with Human and Animal Team (MIHA), Micalis Institute, AgroParisTech, Université Paris-Saclay, INRAE, F-78350 Jouy-en-Josas, France; (V.M.); (A.K.); (S.S.); (S.R.); (H.B.); (E.M.)
| | - Houda Boudaya
- Microbiota Interaction with Human and Animal Team (MIHA), Micalis Institute, AgroParisTech, Université Paris-Saclay, INRAE, F-78350 Jouy-en-Josas, France; (V.M.); (A.K.); (S.S.); (S.R.); (H.B.); (E.M.)
| | - Juan Hernandez
- Department of Clinical Sciences, Nantes-Atlantic College of Veterinary Medicine and Food Sciences (Oniris), University of Nantes, 101 Route de Gachet, 44300 Nantes, France;
| | - Emmanuelle Maguin
- Microbiota Interaction with Human and Animal Team (MIHA), Micalis Institute, AgroParisTech, Université Paris-Saclay, INRAE, F-78350 Jouy-en-Josas, France; (V.M.); (A.K.); (S.S.); (S.R.); (H.B.); (E.M.)
| | - Adam Lesner
- Faculty of Chemistry, University of Gdansk, Wita Stwosza 63, PL80-308 Gdansk, Poland;
| | - Moez Rhimi
- Microbiota Interaction with Human and Animal Team (MIHA), Micalis Institute, AgroParisTech, Université Paris-Saclay, INRAE, F-78350 Jouy-en-Josas, France; (V.M.); (A.K.); (S.S.); (S.R.); (H.B.); (E.M.)
- Correspondence:
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Derkacz A, Olczyk P, Olczyk K, Komosinska-Vassev K. The Role of Extracellular Matrix Components in Inflammatory Bowel Diseases. J Clin Med 2021; 10:jcm10051122. [PMID: 33800267 PMCID: PMC7962650 DOI: 10.3390/jcm10051122] [Citation(s) in RCA: 51] [Impact Index Per Article: 12.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2021] [Revised: 03/01/2021] [Accepted: 03/02/2021] [Indexed: 02/07/2023] Open
Abstract
The remodeling of extracellular matrix (ECM) within the intestine tissues, which simultaneously involves an increased degradation of ECM components and excessive intestinal fibrosis, is a defining trait of the progression of inflammatory bowel diseases (IBDs), which include ulcerative colitis (UC) and Crohn's disease (CD). The increased activity of proteases, especially matrix metalloproteinases (MMPs), leads to excessive degradation of the extracellular matrix and the release of protein and glycoprotein fragments, previously joined with the extracellular matrix, into the circulation. MMPs participate in regulating the functions of the epithelial barrier, the immunological response, and the process of wound healing or intestinal fibrosis. At a later stage of fibrosis during IBD, excessive formation and deposition of the matrix is observed. To assess changes in the extracellular matrix, quantitative measurement of the concentration in the blood of markers dependent on the activity of proteases, involved in the breakdown of extracellular matrix proteins as well as markers indicating the formation of a new ECM, has recently been proposed. This paper describes attempts to use the quantification of ECM components as markers to predict intestinal fibrosis and evaluate the healing process of the gut. The markers which reflect increased ECM degradation, together with the ones which show the process of creating a new matrix during IBD, allow the attainment of important information regarding the changes in the intestinal tissue, epithelial integrity and extracellular matrix remodeling. This paper contains evidence confirming that ECM remodeling is an integral part of directional cell signaling in the progression of IBD, and not only a basis for the ongoing processes.
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Affiliation(s)
- Alicja Derkacz
- Department of Clinical Chemistry and Laboratory Diagnostics, Faculty of Pharmaceutical Sciences in Sosnowiec, Medical University of Silesia in Katowice, 41-200 Sosnowiec, Poland; (A.D.); (K.O.)
| | - Paweł Olczyk
- Department of Community Pharmacy, Faculty of Pharmaceutical Sciences in Sosnowiec, Medical University of Silesia in Katowice, 41-200 Sosnowiec, Poland;
| | - Krystyna Olczyk
- Department of Clinical Chemistry and Laboratory Diagnostics, Faculty of Pharmaceutical Sciences in Sosnowiec, Medical University of Silesia in Katowice, 41-200 Sosnowiec, Poland; (A.D.); (K.O.)
| | - Katarzyna Komosinska-Vassev
- Department of Clinical Chemistry and Laboratory Diagnostics, Faculty of Pharmaceutical Sciences in Sosnowiec, Medical University of Silesia in Katowice, 41-200 Sosnowiec, Poland; (A.D.); (K.O.)
- Correspondence: ; Tel.: +48-32364-1150
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Camba-Gómez M, Gualillo O, Conde-Aranda J. New Perspectives in the Study of Intestinal Inflammation: Focus on the Resolution of Inflammation. Int J Mol Sci 2021; 22:ijms22052605. [PMID: 33807591 PMCID: PMC7962019 DOI: 10.3390/ijms22052605] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2021] [Revised: 02/25/2021] [Accepted: 03/02/2021] [Indexed: 12/14/2022] Open
Abstract
Inflammation is an essential physiological process that is directed to the protection of the organism against invading pathogens or tissue trauma. Most of the existing knowledge related to inflammation is focused on the factors and mechanisms that drive the induction phase of this process. However, since the recognition that the resolution of the inflammation is an active and tightly regulated process, increasing evidence has shown the relevance of this process for the development of chronic inflammatory diseases, such as inflammatory bowel disease. For that reason, with this review, we aimed to summarize the most recent and interesting information related to the resolution process in the context of intestinal inflammation. We discussed the advances in the understanding of the pro-resolution at intestine level, as well as the new mediators with pro-resolutive actions that could be interesting from a therapeutic point of view.
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Affiliation(s)
- Miguel Camba-Gómez
- Molecular and Cellular Gastroenterology, Health Research Institute of Santiago de Compostela (IDIS), 15706 Santiago de Compostela, Spain;
| | - Oreste Gualillo
- SERGAS (Servizo Galego de Saúde) and IDIS (Instituto de Investigación Sanitaria de Santiago), The NEIRID Lab (Neuroendocrine Interactions in Rheumatology and Inflammatory Diseases), Research Laboratory 9, Santiago University Clinical Hospital, 15706 Santiago de Compostela, Spain;
| | - Javier Conde-Aranda
- Molecular and Cellular Gastroenterology, Health Research Institute of Santiago de Compostela (IDIS), 15706 Santiago de Compostela, Spain;
- Correspondence: ; Tel.: +34-981-955-091
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12
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Shimshoni E, Adir I, Afik R, Solomonov I, Shenoy A, Adler M, Puricelli L, Sabino F, Savickas S, Mouhadeb O, Gluck N, Fishman S, Werner L, Salame TM, Shouval DS, Varol C, Auf dem Keller U, Podestà A, Geiger T, Milani P, Alon U, Sagi I. Distinct extracellular-matrix remodeling events precede symptoms of inflammation. Matrix Biol 2021; 96:47-68. [PMID: 33246101 DOI: 10.1016/j.matbio.2020.11.001] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2020] [Revised: 11/15/2020] [Accepted: 11/17/2020] [Indexed: 02/04/2023]
Abstract
Identification of early processes leading to complex tissue pathologies, such as inflammatory bowel diseases, poses a major scientific and clinical challenge that is imperative for improved diagnosis and treatment. Most studies of inflammation onset focus on cellular processes and signaling molecules, while overlooking the environment in which they take place, the continuously remodeled extracellular matrix. In this study, we used colitis models for investigating extracellular-matrix dynamics during disease onset, while treating the matrix as a complete and defined entity. Through the analysis of matrix structure, stiffness and composition, we unexpectedly revealed that even prior to the first clinical symptoms, the colon displays its own unique extracellular-matrix signature and found specific markers of clinical potential, which were also validated in human subjects. We also show that the emergence of this pre-symptomatic matrix is mediated by subclinical infiltration of immune cells bearing remodeling enzymes. Remarkably, whether the inflammation is chronic or acute, its matrix signature converges at pre-symptomatic states. We suggest that the existence of a pre-symptomatic extracellular-matrix is general and relevant to a wide range of diseases.
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Affiliation(s)
- Elee Shimshoni
- Department of Biological Regulation, Weizmann Institute of Science, Rehovot, IL 76100, Israel
| | - Idan Adir
- Department of Biological Regulation, Weizmann Institute of Science, Rehovot, IL 76100, Israel
| | - Ran Afik
- Department of Biological Regulation, Weizmann Institute of Science, Rehovot, IL 76100, Israel
| | - Inna Solomonov
- Department of Biological Regulation, Weizmann Institute of Science, Rehovot, IL 76100, Israel
| | - Anjana Shenoy
- Department of Human Molecular Genetics and Biochemistry, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv-Yafo, Israel
| | - Miri Adler
- Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot, Israel
| | - Luca Puricelli
- CIMAINA and Department of Physics, Università degli Studi di Milano, Milano, Italy
| | - Fabio Sabino
- Department of Biotechnology and Biomedicine, Technical University of Denmark, Kgs. Lyngby, Denmark
| | - Simonas Savickas
- Department of Biotechnology and Biomedicine, Technical University of Denmark, Kgs. Lyngby, Denmark
| | - Odelia Mouhadeb
- Research Center for Digestive Tract and Liver Diseases, Tel Aviv Sourasky Medical Center, Tel Aviv-Yafo, Israel; Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv-Yafo, Israel
| | - Nathan Gluck
- Research Center for Digestive Tract and Liver Diseases, Tel Aviv Sourasky Medical Center, Tel Aviv-Yafo, Israel; Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv-Yafo, Israel
| | - Sigal Fishman
- Research Center for Digestive Tract and Liver Diseases, Tel Aviv Sourasky Medical Center, Tel Aviv-Yafo, Israel; Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv-Yafo, Israel
| | - Lael Werner
- Pediatric Gastroenterology Unit, Edmond and Lily Safra Children's Hospital, Sheba Medical Center, Tel Hashomer, Israel; Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv-Yafo, Israel
| | - Tomer-Meir Salame
- Flow Cytometry Unit, Life Sciences Core Facilities, Weizmann Institute of Science, Rehovot, Israel
| | - Dror S Shouval
- Pediatric Gastroenterology Unit, Edmond and Lily Safra Children's Hospital, Sheba Medical Center, Tel Hashomer, Israel; Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv-Yafo, Israel
| | - Chen Varol
- Research Center for Digestive Tract and Liver Diseases, Tel Aviv Sourasky Medical Center, Tel Aviv-Yafo, Israel; Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv-Yafo, Israel
| | - Ulrich Auf dem Keller
- Department of Biotechnology and Biomedicine, Technical University of Denmark, Kgs. Lyngby, Denmark
| | - Alessandro Podestà
- CIMAINA and Department of Physics, Università degli Studi di Milano, Milano, Italy
| | - Tamar Geiger
- Department of Human Molecular Genetics and Biochemistry, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv-Yafo, Israel
| | - Paolo Milani
- CIMAINA and Department of Physics, Università degli Studi di Milano, Milano, Italy
| | - Uri Alon
- Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot, Israel
| | - Irit Sagi
- Department of Biological Regulation, Weizmann Institute of Science, Rehovot, IL 76100, Israel.
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13
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Lam S, Singh R, Dillman JR, Trout AT, Serai SD, Sharma D, Sheridan R, Su W, Fei L, Karns R, Haramija MM, Ridgway G, Goldfinger M, Squires JE, Denson LA, Hyams JS, Miethke AG. Serum Matrix Metalloproteinase 7 Is a Diagnostic Biomarker of Biliary Injury and Fibrosis in Pediatric Autoimmune Liver Disease. Hepatol Commun 2020; 4:1680-1693. [PMID: 33163837 PMCID: PMC7603534 DOI: 10.1002/hep4.1589] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/21/2020] [Revised: 07/08/2020] [Accepted: 07/11/2020] [Indexed: 12/17/2022] Open
Abstract
In autoimmune liver disease (AILD), including autoimmune hepatitis (AIH), primary sclerosing cholangitis (PSC), and overlap syndrome of AIH and PSC (ASC), the presence of biliary injury portends a worse prognosis. We studied serum matrix metalloproteinase 7 (sMMP7) as a biomarker for pediatric sclerosing cholangitis (SC). We prospectively enrolled 54 children (median age, 16 years) with AILD (AIH, n = 26; ASC, n = 16; and PSC, n = 12) at our center. The sMMP7 concentrations were higher in patients with SC compared to those without cholangiopathy (P < 0.001). An sMMP7 concentration >23.7 ng/mL had a sensitivity and specificity of 79% and 96%, respectively, and outperformed alkaline phosphatase (ALP) and gamma-glutamyltransferase (GGT) in segregating patients with SC. Serum concentrations correlated with liver gene expression levels for MMP7 (r = 0.70; P < 0.001). Using immunofluorescence, MMP7 was localized primarily to the cholangiocytes of patients with SC. In 46 subjects with liver biopsy available for blinded review, elevation in sMMP7 concentrations segregated with the presence of lymphocytic and neutrophilic cholangitis and periductal fibrosis and correlated with Ishak, Ludwig, and Nakanuma scoring systems. Liver stiffness measured by magnetic resonance elastography also correlated with sMMP7 concentrations (r = 0.56; P < 0.01). Using magnetic resonance cholangiopancreatography plus (MRCP+), sMMP7 in 34 patients correlated with the number of biliary dilatations (r = 0.54; P < 0.01) and strictures (r = 0.56; P < 0.01). MMP7 as a marker of biliary injury was validated in an independent cohort of children with ulcerative colitis. Higher sMMP7 concentrations also correlated with a history of SC-related complication. Conclusion: MMP7 is a promising biomarker for pediatric SC that diagnostically outperforms ALP and GGT. sMMP7 may directly reflect biliary injury and fibrosis, the main drivers of disease progression in SC.
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Affiliation(s)
- Simon Lam
- Division of Gastroenterology, Hepatology and NutritionCincinnati Children's Hospital Medical CenterCincinnatiOHUSA
- Department of PediatricsUniversity of Cincinnati College of MedicineCincinnatiOHUSA
- Section of Pediatric GastroenterologyDepartment of PediatricsAlberta Children’s HospitalUniversity of CalgaryCalgaryCanada
| | - Ruchi Singh
- Division of Gastroenterology, Hepatology and NutritionCincinnati Children's Hospital Medical CenterCincinnatiOHUSA
| | - Jonathan R. Dillman
- Department of PediatricsUniversity of Cincinnati College of MedicineCincinnatiOHUSA
- Department of RadiologyCincinnati Children's Hospital Medical CenterUniversity of Cincinnati College of MedicineCincinnatiOHUSA
| | - Andrew T. Trout
- Department of PediatricsUniversity of Cincinnati College of MedicineCincinnatiOHUSA
- Department of RadiologyCincinnati Children's Hospital Medical CenterUniversity of Cincinnati College of MedicineCincinnatiOHUSA
| | - Suraj D. Serai
- Department of RadiologyChildren’s Hospital of PhiladelphiaPhiladelphiaPAUSA
| | - Divya Sharma
- Division of PathologyUniversity of CincinnatiCincinnatiOHUSA
| | - Rachel Sheridan
- Department of PathologyDayton Children’s HospitalDaytonOHUSA
| | - Weizhe Su
- Division of Biostatistics and EpidemiologyCincinnati Children's Hospital Medical CenterCincinnatiOHUSA
| | - Lin Fei
- Division of Biostatistics and EpidemiologyCincinnati Children's Hospital Medical CenterCincinnatiOHUSA
| | - Rebekah Karns
- Division of Gastroenterology, Hepatology and NutritionCincinnati Children's Hospital Medical CenterCincinnatiOHUSA
| | | | - Ged Ridgway
- Perspectum Diagnostics Ltd.South San FranciscoCAUSA
| | | | | | - Lee A. Denson
- Division of Gastroenterology, Hepatology and NutritionCincinnati Children's Hospital Medical CenterCincinnatiOHUSA
- Department of PediatricsUniversity of Cincinnati College of MedicineCincinnatiOHUSA
| | - Jeffery S. Hyams
- Division of Digestive DiseasesHepatology, and NutritionConnecticut Children’s Hospital Medical CenterHartfordCTUSA
| | - Alexander G. Miethke
- Division of Gastroenterology, Hepatology and NutritionCincinnati Children's Hospital Medical CenterCincinnatiOHUSA
- Department of PediatricsUniversity of Cincinnati College of MedicineCincinnatiOHUSA
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14
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Omori W, Hattori K, Kajitani N, Okada-Tsuchioka M, Boku S, Kunugi H, Okamoto Y, Takebayashi M. Increased matrix metalloproteinases in cerebrospinal fluids of patients with major depressive disorder and schizophrenia. Int J Neuropsychopharmacol 2020; 23:pyaa049. [PMID: 32671384 PMCID: PMC7745248 DOI: 10.1093/ijnp/pyaa049] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/20/2020] [Revised: 06/20/2020] [Accepted: 07/10/2020] [Indexed: 12/26/2022] Open
Abstract
BACKGROUND Chronic inflammation of the brain has a pivotal role in the pathophysiology of major depressive disorder (MDD) and schizophrenia (SCZ). Matrix metalloproteinases (MMPs) are extracellular proteases involved in pro-inflammatory processes and interact with IL-6, which is increased in the cerebrospinal fluid (CSF) of patients with MDD and SCZ. However, MMPs in the CSF in patients with MDD and SCZ remains unclear. Therefore, we compared MMPs in the CSF of patients with MDD and SCZ to those of healthy controls (HC). METHODS Japanese patients were diagnosed with DSM-IV-TR and clinical symptoms were assessed with the Hamilton Rating Scale for Depression for MDD and the Positive and Negative Syndrome Scale for SCZ. CSF was obtained from MDD (n=90), SCZ (n=86) and from age- and sex-matched HC (n=106). The levels of MMPs in CSF were measured with multiplex bead-based immunoassay. RESULTS The levels of MMP-2 in CSF were higher in both MDD and SCZ than HC and were positively correlated with clinical symptomatic scores in MDD, but not in SCZ. Regardless of diagnosis, the levels of MMP-2, -7 and -10 were positively correlated with each other, and the levels of MMP-7 and -10 were higher in MDD, but not in SCZ, compared to HC. CONCLUSION Increased CSF levels of MMP-2 in MDD and SCZ may be associated with brain inflammation. State-dependent alteration of MMP-2 and activation of cascades involving MMP-2, -7, and -10 appeared to have a role in the pathophysiology of MDD.
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Affiliation(s)
- Wataru Omori
- Division of Psychiatry and Neuroscience, Institute for Clinical Research, National Hospital Organization (NHO) Kure Medical Center and Chugoku Cancer Center, Kure, Hiroshima, Japan
- Department of Psychiatry, NHO Kure Medical Center and Chugoku Cancer Center, Kure, Hiroshima, Japan
- Department of Psychiatry and Neurosciences, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Kotaro Hattori
- Department of Mental Disorder Research, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Tokyo, Japan
- Medical Genome Center, National Center of Neurology and Psychiatry, Tokyo, Japan
| | - Naoto Kajitani
- Division of Psychiatry and Neuroscience, Institute for Clinical Research, National Hospital Organization (NHO) Kure Medical Center and Chugoku Cancer Center, Kure, Hiroshima, Japan
- Department of Neuropsychiatry, Faculty of Life Science, Kumamoto University, Kumamoto, Japan
| | - Mami Okada-Tsuchioka
- Division of Psychiatry and Neuroscience, Institute for Clinical Research, National Hospital Organization (NHO) Kure Medical Center and Chugoku Cancer Center, Kure, Hiroshima, Japan
| | - Shuken Boku
- Department of Neuropsychiatry, Faculty of Life Science, Kumamoto University, Kumamoto, Japan
| | - Hiroshi Kunugi
- Department of Mental Disorder Research, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Tokyo, Japan
- Department of Psychiatry, Teikyo University School of Medicine, Tokyo, Japan
| | - Yasumasa Okamoto
- Department of Psychiatry and Neurosciences, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Minoru Takebayashi
- Division of Psychiatry and Neuroscience, Institute for Clinical Research, National Hospital Organization (NHO) Kure Medical Center and Chugoku Cancer Center, Kure, Hiroshima, Japan
- Department of Neuropsychiatry, Faculty of Life Science, Kumamoto University, Kumamoto, Japan
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15
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Lin WW, Lu YC, Chuang CH, Cheng TL. Ab locks for improving the selectivity and safety of antibody drugs. J Biomed Sci 2020; 27:76. [PMID: 32586313 PMCID: PMC7318374 DOI: 10.1186/s12929-020-00652-z] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2020] [Accepted: 04/22/2020] [Indexed: 02/06/2023] Open
Abstract
Monoclonal antibodies (mAbs) are a major targeted therapy for malignancies, infectious diseases, autoimmune diseases, transplant rejection and chronic inflammatory diseases due to their antigen specificity and longer half-life than conventional drugs. However, long-term systemic antigen neutralization by mAbs may cause severe adverse events. Improving the selectivity of mAbs to distinguish target antigens at the disease site from normal healthy tissue and reducing severe adverse events caused by the mechanisms-of-action of mAbs is still a pressing need. Development of pro-antibodies (pro-Abs) by installing a protease-cleavable Ab lock is a novel and advanced recombinant Ab-based strategy that efficiently masks the antigen binding ability of mAbs in the normal state and selectively "turns on" the mAb activity when the pro-Ab reaches the proteolytic protease-overexpressed diseased tissue. In this review, we discuss the design and advantages/disadvantages of different Ab lock strategies, focusing particularly on spatial-hindrance-based and affinity peptide-based approaches. We expect that the development of different masking strategies for mAbs will benefit the local reactivity of mAbs at the disease site, increase the therapeutic efficacy and safety of long-term treatment with mAbs in chronic diseases and even permit scientists to develop Ab drugs for formerly undruggable targets and satisfy the unmet medical needs of mAb therapy.
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Affiliation(s)
- Wen-Wei Lin
- Department of Laboratory Medicine, School of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
- Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
- Drug Development and Value Creation Research Center, Kaohsiung Medical University, Kaohsiung, Taiwan
- Department of Medical Research, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan
| | - Yun-Chi Lu
- Drug Development and Value Creation Research Center, Kaohsiung Medical University, Kaohsiung, Taiwan
- Department of Biomedical and Environmental Biology, Kaohsiung Medical University, 100 Shih-Chuan 1st Road, Kaohsiung, 80708, Taiwan
| | - Chih-Hung Chuang
- Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
- Drug Development and Value Creation Research Center, Kaohsiung Medical University, Kaohsiung, Taiwan
- Department of Medical Laboratory Science and Biotechnology, College of Health Sciences, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Tian-Lu Cheng
- Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.
- Drug Development and Value Creation Research Center, Kaohsiung Medical University, Kaohsiung, Taiwan.
- Department of Medical Research, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan.
- Department of Biomedical and Environmental Biology, Kaohsiung Medical University, 100 Shih-Chuan 1st Road, Kaohsiung, 80708, Taiwan.
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16
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Krämer M, Plum PS, Velazquez Camacho O, Folz-Donahue K, Thelen M, Garcia-Marquez I, Wölwer C, Büsker S, Wittig J, Franitza M, Altmüller J, Löser H, Schlößer H, Büttner R, Schröder W, Bruns CJ, Alakus H, Quaas A, Chon SH, Hillmer AM. Cell type-specific transcriptomics of esophageal adenocarcinoma as a scalable alternative for single cell transcriptomics. Mol Oncol 2020; 14:1170-1184. [PMID: 32255255 PMCID: PMC7266280 DOI: 10.1002/1878-0261.12680] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2019] [Revised: 02/17/2020] [Accepted: 03/27/2020] [Indexed: 12/26/2022] Open
Abstract
Single‐cell transcriptomics have revolutionized our understanding of the cell composition of tumors and allowed us to identify new subtypes of cells. Despite rapid technological advancements, single‐cell analysis remains resource‐intense hampering the scalability that is required to profile a sufficient number of samples for clinical associations. Therefore, more scalable approaches are needed to understand the contribution of individual cell types to the development and treatment response of solid tumors such as esophageal adenocarcinoma where comprehensive genomic studies have only led to a small number of targeted therapies. Due to the limited treatment options and late diagnosis, esophageal adenocarcinoma has a poor prognosis. Understanding the interaction between and dysfunction of individual cell populations provides an opportunity for the development of new interventions. In an attempt to address the technological and clinical needs, we developed a protocol for the separation of esophageal carcinoma tissue into leukocytes (CD45+), epithelial cells (EpCAM+), and fibroblasts (two out of PDGFRα, CD90, anti‐fibroblast) by fluorescence‐activated cell sorting and subsequent RNA sequencing. We confirm successful separation of the three cell populations by mapping their transcriptomic profiles to reference cell lineage expression data. Gene‐level analysis further supports the isolation of individual cell populations with high expression of CD3, CD4, CD8, CD19, and CD20 for leukocytes, CDH1 and MUC1 for epithelial cells, and FAP, SMA, COL1A1, and COL3A1 for fibroblasts. As a proof of concept, we profiled tumor samples of nine patients and explored expression differences in the three cell populations between tumor and normal tissue. Interestingly, we found that angiogenesis‐related genes were upregulated in fibroblasts isolated from tumors compared with normal tissue. Overall, we suggest our protocol as a complementary and more scalable approach compared with single‐cell RNA sequencing to investigate associations between clinical parameters and transcriptomic alterations of specific cell populations in esophageal adenocarcinoma.
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Affiliation(s)
- Max Krämer
- Institute of Pathology, Faculty of Medicine and University Hospital Cologne, University of Cologne, Germany
| | - Patrick S Plum
- Institute of Pathology, Faculty of Medicine and University Hospital Cologne, University of Cologne, Germany.,Department of General, Visceral and Cancer Surgery, Faculty of Medicine and University Hospital Cologne, University of Cologne, Germany
| | - Oscar Velazquez Camacho
- Institute of Pathology, Faculty of Medicine and University Hospital Cologne, University of Cologne, Germany
| | - Kat Folz-Donahue
- FACS & Imaging Core Facility, Max Planck Institute for Biology of Ageing, Cologne, Germany
| | - Martin Thelen
- Department of General, Visceral and Cancer Surgery, Faculty of Medicine and University Hospital Cologne, University of Cologne, Germany.,Center for Molecular Medicine Cologne, University of Cologne, Germany
| | | | - Christina Wölwer
- Institute of Pathology, Faculty of Medicine and University Hospital Cologne, University of Cologne, Germany
| | - Sören Büsker
- Institute of Pathology, Faculty of Medicine and University Hospital Cologne, University of Cologne, Germany
| | - Jana Wittig
- Institute of Pathology, Faculty of Medicine and University Hospital Cologne, University of Cologne, Germany
| | - Marek Franitza
- Cologne Center for Genomics, University of Cologne, Germany
| | | | - Heike Löser
- Institute of Pathology, Faculty of Medicine and University Hospital Cologne, University of Cologne, Germany
| | - Hans Schlößer
- Department of General, Visceral and Cancer Surgery, Faculty of Medicine and University Hospital Cologne, University of Cologne, Germany.,Center for Molecular Medicine Cologne, University of Cologne, Germany
| | - Reinhard Büttner
- Institute of Pathology, Faculty of Medicine and University Hospital Cologne, University of Cologne, Germany
| | - Wolfgang Schröder
- Department of General, Visceral and Cancer Surgery, Faculty of Medicine and University Hospital Cologne, University of Cologne, Germany
| | - Christiane J Bruns
- Department of General, Visceral and Cancer Surgery, Faculty of Medicine and University Hospital Cologne, University of Cologne, Germany
| | - Hakan Alakus
- Department of General, Visceral and Cancer Surgery, Faculty of Medicine and University Hospital Cologne, University of Cologne, Germany
| | - Alexander Quaas
- Institute of Pathology, Faculty of Medicine and University Hospital Cologne, University of Cologne, Germany
| | - Seung-Hun Chon
- Department of General, Visceral and Cancer Surgery, Faculty of Medicine and University Hospital Cologne, University of Cologne, Germany
| | - Axel M Hillmer
- Institute of Pathology, Faculty of Medicine and University Hospital Cologne, University of Cologne, Germany.,Center for Molecular Medicine Cologne, University of Cologne, Germany.,Cancer Therapeutics and Stratified Oncology, Genome Institute of Singapore, Agency for Science, Technology and Research (A*STAR), Singapore City, Singapore
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17
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Dosh RH, Jordan-Mahy N, Sammon C, Le Maitre C. Interleukin 1 is a key driver of inflammatory bowel disease-demonstration in a murine IL-1Ra knockout model. Oncotarget 2019; 10:3559-3575. [PMID: 31191826 PMCID: PMC6544399 DOI: 10.18632/oncotarget.26894] [Citation(s) in RCA: 39] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2018] [Accepted: 04/03/2019] [Indexed: 02/07/2023] Open
Abstract
Interleukin 1 (IL-1) is an important mediator of inflammation and tissue damage in inflammatory bowel disease (IBD). The balance between IL-1 and IL-1Ra as a natural inhibitor plays a vital role in a variety of diseases. Here, we investigated whether changes seen during IBD are induced spontaneously in mice lacking a functional IL-1rn gene. Histological staining was performed on the jejunum and ileum of BALB/c IL-1rn+/+ and IL-1rn-/- mice to characterize crypt-villus height, villus width, and number of goblet cells per villus. Pro-inflammatory cytokines, immune cell infiltration and matrix-degrading enzymes, together with the production of intestinal enzymes and the integrity of tight and adherent junction proteins were determined using immunohistochemistry. In the small intestine of BALB/c IL-1rn-/- mice the villus heights were significantly reduced; and in the ileum this was accompanied by a decrease in villi width. There was also an increase in goblet cell number and mucin production compared to wild-type mice. IL-1α and IL-1β immunopositivity were increased, whilst IL-1R1 expression was decreased in IL-1rn-/- mice. IL-15 and TNFα were also increased in older IL-1rn-/- mice. Increased polymorphonuclear and macrophage infiltration were seen in IL-1rn-/- mice, whilst expression of matrix-degrading enzymes and digestive enzymes were unchanged, except for dipeptidyl peptidase IV which was increased in younger IL-1rn-/- mice compared to wild type mice. The expression of tight and adhesion junctions were also dramatically decreased in IL-1rn-/- mice. In conclusion, IL-1rn-/- mice developed spontaneous abnormalities which displayed features associated with IBD, demonstrating a clear role for IL-1 in IBD.
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Affiliation(s)
- Rasha H. Dosh
- Biomolecular Sciences Research Centre, Sheffield Hallam University, Sheffield, UK
- Department of Anatomy and Histology, Faculty of Medicine, University of Kufa, Kufa, Iraq
| | - Nicola Jordan-Mahy
- Biomolecular Sciences Research Centre, Sheffield Hallam University, Sheffield, UK
| | - Christopher Sammon
- Materials and Engineering Research Institute, Sheffield Hallam University, Sheffield, UK
| | - Christine Le Maitre
- Biomolecular Sciences Research Centre, Sheffield Hallam University, Sheffield, UK
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18
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Burge K, Gunasekaran A, Eckert J, Chaaban H. Curcumin and Intestinal Inflammatory Diseases: Molecular Mechanisms of Protection. Int J Mol Sci 2019; 20:ijms20081912. [PMID: 31003422 PMCID: PMC6514688 DOI: 10.3390/ijms20081912] [Citation(s) in RCA: 109] [Impact Index Per Article: 18.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2019] [Revised: 04/15/2019] [Accepted: 04/17/2019] [Indexed: 02/07/2023] Open
Abstract
Intestinal inflammatory diseases, such as Crohn’s disease, ulcerative colitis, and necrotizing enterocolitis, are becoming increasingly prevalent. While knowledge of the pathogenesis of these related diseases is currently incomplete, each of these conditions is thought to involve a dysfunctional, or overstated, host immunological response to both bacteria and dietary antigens, resulting in unchecked intestinal inflammation and, often, alterations in the intestinal microbiome. This inflammation can result in an impaired intestinal barrier allowing for bacterial translocation, potentially resulting in systemic inflammation and, in severe cases, sepsis. Chronic inflammation of this nature, in the case of inflammatory bowel disease, can even spur cancer growth in the longer-term. Recent research has indicated certain natural products with anti-inflammatory properties, such as curcumin, can help tame the inflammation involved in intestinal inflammatory diseases, thus improving intestinal barrier function, and potentially, clinical outcomes. In this review, we explore the potential therapeutic properties of curcumin on intestinal inflammatory diseases, including its antimicrobial and immunomodulatory properties, as well as its potential to alter the intestinal microbiome. Curcumin may play a significant role in intestinal inflammatory disease treatment in the future, particularly as an adjuvant therapy.
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Affiliation(s)
- Kathryn Burge
- Department of Pediatrics, Division of Neonatology, University of Oklahoma Health Sciences Center, 1200 North Everett Drive, ETNP7504, Oklahoma City, OK 73104, USA.
| | - Aarthi Gunasekaran
- Department of Pediatrics, Division of Neonatology, University of Oklahoma Health Sciences Center, 1200 North Everett Drive, ETNP7504, Oklahoma City, OK 73104, USA.
| | - Jeffrey Eckert
- Department of Pediatrics, Division of Neonatology, University of Oklahoma Health Sciences Center, 1200 North Everett Drive, ETNP7504, Oklahoma City, OK 73104, USA.
| | - Hala Chaaban
- Department of Pediatrics, Division of Neonatology, University of Oklahoma Health Sciences Center, 1200 North Everett Drive, ETNP7504, Oklahoma City, OK 73104, USA.
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SMAD4 Protein Expression Is Downregulated in Ileal Epithelial Cells from Patients with Crohn's Disease with Significant Inverse Correlation to Disease Activity. Gastroenterol Res Pract 2018; 2018:9307848. [PMID: 29977289 PMCID: PMC5994270 DOI: 10.1155/2018/9307848] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/02/2018] [Revised: 04/04/2018] [Accepted: 05/08/2018] [Indexed: 12/22/2022] Open
Abstract
Background Small mothers against decapentaplegic (SMAD)4 and SMAD7 are key regulatory components in the immunosuppressive transforming growth factor- (TGF-) β signaling pathway, which is defective in inflammatory bowel disease (IBD). SMAD4 may play an important role in the pathogenesis of IBD as indicated in experimental models of colitis. Aims To examine the ileal expression levels of SMAD4 and to correlate these with CD disease activity. Methods The material comprised 29 CD patients (13 with active disease, 16 in remission) and 9 asymptomatic patients referred for ileocolonoscopy as part of an adenoma surveillance program serving as controls. Patients were examined with ileocolonoscopy. Corresponding ileal biopsies were obtained for histological analysis and assessment of SMAD4 and SMAD7 protein expression by immunohistochemistry (IHC). Results The protein expression of SMAD4 was significantly downregulated in ileal tissue sections from CD patients as compared to healthy controls (p < 0.001). Further, luminal SMAD4 expression was inversely correlated with endoscopic (rs = -0.315; p = 0.05) and histopathological activity (rs = -0.40; p = 0.013). Conclusions The SMAD4 epithelial protein level was markedly downregulated in CD patients and inversely correlated with disease activity. This may contribute to defective mucosal TGF-β signaling in active IBD.
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Chami B, Martin NJJ, Dennis JM, Witting PK. Myeloperoxidase in the inflamed colon: A novel target for treating inflammatory bowel disease. Arch Biochem Biophys 2018; 645:61-71. [PMID: 29548776 DOI: 10.1016/j.abb.2018.03.012] [Citation(s) in RCA: 180] [Impact Index Per Article: 25.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2018] [Revised: 03/08/2018] [Accepted: 03/12/2018] [Indexed: 12/17/2022]
Abstract
Inflammatory bowel disease (IBD) is a debilitating disorder involving inflammation of the gastrointestinal tract. The incidence of IBD is increasing worldwide. Immunological responses in the gastrointestinal (GI) tract to altered gut microbiota, mucosal injury and loss of intestinal epithelial cell function all contribute to a complex mechanism underlying IBD pathogenesis. Immune cell infiltration, particularly neutrophils, is a histological feature of IBD. This innate immune response is aimed at resolving intestinal damage however, neutrophils and monocytes that are recruited and accumulate in the GI wall, participate in IBD pathogenesis by producing inflammatory cytokines and soluble mediators such as reactive oxygen species (ROS; one- and two-electron oxidants). Unregulated ROS production in host tissue is linked to oxidative damage and inflammation and may potentiate mucosal injury. Neutrophil-myeloperoxidase (MPO) is an abundant granule enzyme that catalyses production of potent ROS; biomarkers of oxidative damage (and MPO protein) are increased in the mucosa of patients with IBD. Targeting MPO may mitigate oxidative damage to host tissue and ensuing inflammation. Here we identify mechanisms by which MPO activity perpetuates inflammation and contributes to host-tissue injury in patients with IBD and discuss MPO as a potential therapeutic target to protect the colon from inflammatory injury.
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Affiliation(s)
- Belal Chami
- Redox Biology Group, Discipline of Pathology, Sydney Medical School, Charles Perkins Centre, The University of Sydney NSW 2006 Australia
| | - Nathan J J Martin
- Redox Biology Group, Discipline of Pathology, Sydney Medical School, Charles Perkins Centre, The University of Sydney NSW 2006 Australia
| | - Joanne M Dennis
- Redox Biology Group, Discipline of Pathology, Sydney Medical School, Charles Perkins Centre, The University of Sydney NSW 2006 Australia
| | - Paul K Witting
- Redox Biology Group, Discipline of Pathology, Sydney Medical School, Charles Perkins Centre, The University of Sydney NSW 2006 Australia.
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Tantravedi S, Vesuna F, Winnard PT, Van Voss MRH, Van Diest PJ, Raman V. Role of DDX3 in the pathogenesis of inflammatory bowel disease. Oncotarget 2017; 8:115280-115289. [PMID: 29383159 PMCID: PMC5777771 DOI: 10.18632/oncotarget.23323] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2017] [Accepted: 11/26/2017] [Indexed: 12/14/2022] Open
Abstract
When crypt stem cells of the gastrointestinal tract become injured, the result is increased synthesis of pro-inflammatory cytokines and matrix metalloproteinases by their progeny – the colonic epithelium. Chronic inflammation of the gastrointestinal tract is a characteristic of inflammatory bowel disease, which includes Crohn’s Disease and Ulcerative Colitis. In our ongoing investigation to decipher the characteristic functions of a RNA helicase gene, DDX3, we identified high DDX3 expression by immunohistochemistry of colon biopsy samples, which included chronic/mild Morbus Crohn, active Morbus Crohn, Chronic/mild Colitis Ulcerosa and active Colitis Ulcerosa in epithelium and stromal compartments. We used a small molecule inhibitor of DDX3, RK-33, on two human colonic epithelial cell lines, HCEC1CT and HCEC2CT and found that RK-33 was able to decrease expression of MMP-1, MMP-2, MMP-3, and MMP-10. Moreover, forced differentiation of a human colonic cancer cell line, HT29, resulted in decreased DDX3 levels, indicating that DDX3 contributes to the modulation of colonic epithelium differentiation. In conclusion, our results revealed novel functions of DDX3 in inflammatory bowel disease and indicate a potential for using RK-33 as a systemic therapy to promote not only differentiation of transformed colonic epithelium but also to reduce MMP expression and thus elicit a decreased inflammatory response.
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Affiliation(s)
- Saritha Tantravedi
- Department of Radiology and Radiological Science, Johns Hopkins University, School of Medicine, Baltimore, MD, USA
| | - Farhad Vesuna
- Department of Radiology and Radiological Science, Johns Hopkins University, School of Medicine, Baltimore, MD, USA
| | - Paul T Winnard
- Department of Radiology and Radiological Science, Johns Hopkins University, School of Medicine, Baltimore, MD, USA
| | - Marise R Heerma Van Voss
- Department of Radiology and Radiological Science, Johns Hopkins University, School of Medicine, Baltimore, MD, USA.,Department of Pathology, University Medical Center Utrecht, Utrecht, The Netherlands
| | - Paul J Van Diest
- Department of Pathology, University Medical Center Utrecht, Utrecht, The Netherlands
| | - Venu Raman
- Department of Radiology and Radiological Science, Johns Hopkins University, School of Medicine, Baltimore, MD, USA.,Department of Pathology, University Medical Center Utrecht, Utrecht, The Netherlands.,Department of Oncology, Johns Hopkins University, School of Medicine, Baltimore, MD, USA
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Metformin transiently inhibits colorectal cancer cell proliferation as a result of either AMPK activation or increased ROS production. Sci Rep 2017; 7:15992. [PMID: 29167573 PMCID: PMC5700100 DOI: 10.1038/s41598-017-16149-z] [Citation(s) in RCA: 102] [Impact Index Per Article: 12.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2016] [Accepted: 11/08/2017] [Indexed: 12/15/2022] Open
Abstract
Metformin is a widely used and well-tolerated anti-diabetic drug that can reduce cancer risk and improve the prognosis of certain malignancies. However, the mechanism underlying its anti-cancer effect is still unclear. We studied the anti-cancer activity of metformin on colorectal cancer (CRC) by using the drug to treat HT29, HCT116 and HCT116 p53−/− CRC cells. Metformin reduced cell proliferation and migration by inducing cell cycle arrest in the G0/G1 phase. This was accompanied by a sharp decrease in the expression of c-Myc and down-regulation of IGF1R. The anti-proliferative action of metformin was mediated by two different mechanisms: AMPK activation and increase in the production of reactive oxygen species, which suppressed the mTOR pathway and its downstream targets S6 and 4EBP1. A reduction in CD44 and LGR5 expression suggested that the drug had an effect on tumour cells with stem characteristics. However, a colony formation assay showed that metformin slowed the cells’ ability to form colonies without arresting cell growth, as confirmed by absence of apoptosis, autophagy or senescence. Our finding that metformin only transiently arrests CRC cell growth suggests that efforts should be made to identify compounds that combined with the biguanide can act synergistically to induce cell death.
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Saeed MA, Ng GZ, Däbritz J, Wagner J, Judd L, Han JX, Dhar P, Kirkwood CD, Sutton P. Protease-activated Receptor 1 Plays a Proinflammatory Role in Colitis by Promoting Th17-related Immunity. Inflamm Bowel Dis 2017; 23:593-602. [PMID: 28296821 DOI: 10.1097/mib.0000000000001045] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
BACKGROUND Proteolytic cleavage of protease-activated receptor 1 (PAR1) can result in potent downstream regulatory effects on inflammation. Although PAR1 is expressed throughout the gastrointestinal tract and activating proteases are increased in inflammatory bowel disease, the effect of PAR1 activation on colitis remains poorly understood, and has not previously been studied in pediatric disease. METHODS Expression of PAR1 and inflammatory cytokines in colonic biopsies from pediatric patients with Crohn's disease exhibiting active moderate to severe colitis was measured by quantitative PCR. The functional relevance of these clinical data was further studied in a mouse model of Citrobacter rodentium-induced colitis. RESULTS PAR1 expression was significantly upregulated in the inflamed colons of pediatric patients with Crohn's disease, with expression levels directly correlating to disease severity. In patients with severe colitis, PAR1 expression uniquely correlated with Th17-related (IL17A, IL22, and IL23A) cytokines. Infection of PAR1-deficient (PAR1) and wildtype mice with colitogenic C. rodentium revealed that disease severity and colonic pathology were strongly attenuated in mice lacking PAR1. Furthermore, Th17-type immune response was completely abolished in the colons of infected PAR1 but not wildtype mice. Finally, PAR1 was shown to be essential for secretion of the Th17-driving cytokine IL-23 by C. rodentium-stimulated macrophages. CONCLUSIONS This study demonstrates a strong link between PAR1 expression, Th17-type immunity, and disease severity in both pediatric patients with Crohn's disease and C. rodentium-induced colitis in mice. The data presented suggest PAR1 exerts a proinflammatory role in colitis in both humans and mice by promoting a Th17-type immune response, potentially by supporting the production of IL-23.
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Affiliation(s)
- Muhammad A Saeed
- *Murdoch Childrens Research Institute, Royal Children's Hospital, Parkville, Melbourne, Victoria, Australia; †Centre for Animal Biotechnology, Faculty of Veterinary and Agricultural Science, University of Melbourne, Melbourne, Victoria, Australia; ‡Department of Paediatrics, University Medicine Rostock, Rostock, Mecklenburg-Vorpommern, Germany; and §Department of Paediatrics, University of Melbourne, Melbourne, Victoria, Australia
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Van Spaendonk H, Ceuleers H, Witters L, Patteet E, Joossens J, Augustyns K, Lambeir AM, De Meester I, De Man JG, De Winter BY. Regulation of intestinal permeability: The role of proteases. World J Gastroenterol 2017; 23:2106-2123. [PMID: 28405139 PMCID: PMC5374123 DOI: 10.3748/wjg.v23.i12.2106] [Citation(s) in RCA: 130] [Impact Index Per Article: 16.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/26/2016] [Revised: 01/20/2017] [Accepted: 03/02/2017] [Indexed: 02/06/2023] Open
Abstract
The gastrointestinal barrier is - with approximately 400 m2 - the human body's largest surface separating the external environment from the internal milieu. This barrier serves a dual function: permitting the absorption of nutrients, water and electrolytes on the one hand, while limiting host contact with noxious luminal antigens on the other hand. To maintain this selective barrier, junction protein complexes seal the intercellular space between adjacent epithelial cells and regulate the paracellular transport. Increased intestinal permeability is associated with and suggested as a player in the pathophysiology of various gastrointestinal and extra-intestinal diseases such as inflammatory bowel disease, celiac disease and type 1 diabetes. The gastrointestinal tract is exposed to high levels of endogenous and exogenous proteases, both in the lumen and in the mucosa. There is increasing evidence to suggest that a dysregulation of the protease/antiprotease balance in the gut contributes to epithelial damage and increased permeability. Excessive proteolysis leads to direct cleavage of intercellular junction proteins, or to opening of the junction proteins via activation of protease activated receptors. In addition, proteases regulate the activity and availability of cytokines and growth factors, which are also known modulators of intestinal permeability. This review aims at outlining the mechanisms by which proteases alter the intestinal permeability. More knowledge on the role of proteases in mucosal homeostasis and gastrointestinal barrier function will definitely contribute to the identification of new therapeutic targets for permeability-related diseases.
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Swarnakar S, Roy A, Ghosh S, Majumder R, Paul S. Gastric Pathology and Metalloproteinases. PATHOPHYSIOLOGICAL ASPECTS OF PROTEASES 2017:489-513. [DOI: 10.1007/978-981-10-6141-7_19] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/06/2025]
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Fonseca FLA, da Costa Aguiar Alves B, Azzalis LA, Belardo TMG. Matrix Metalloproteases as Biomarkers of Disease. Methods Mol Biol 2017; 1579:299-311. [PMID: 28299745 DOI: 10.1007/978-1-4939-6863-3_17] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Matrix metalloprotease play a vital role in many cellular processes. Dysfunction in activity of these enzymes has been implicated in the pathogenesis of a number of diseases. Factors that affect the balanced interaction between MMPs and their inhibitors, such as genetic mutations of extracellular matrix components or dysregulation of MMP expression, can lead to various diseases. Due to their essential role in ECM remodeling, MMPs have become targets of interest as biomarkers for the diagnosis and prognosis of diseases associated with alterations of the ECM.
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Affiliation(s)
- Fernando Luiz Affonso Fonseca
- Departamento de Ciências Biológicas, Instituto de Ciências Químicas, Ambientais e Farmacêuticas, Universidade Federal de São Paulo, Diadema, SP, Brazil. .,Laboratório de Análises Clínicas-Anexo 3, Faculdade de Medicina do ABC, Vila Principe de Gales, n.821, Santo André, SP, 09060-650, Brazil.
| | - Beatriz da Costa Aguiar Alves
- Laboratório de Análises Clínicas-Anexo 3, Faculdade de Medicina do ABC, Vila Principe de Gales, n.821, Santo André, SP, 09060-650, Brazil
| | - Ligia Ajaime Azzalis
- Departamento de Ciências Biológicas, Instituto de Ciências Químicas, Ambientais e Farmacêuticas, Universidade Federal de São Paulo, Diadema, SP, Brazil
| | - Thaís Moura Gáscon Belardo
- Laboratório de Análises Clínicas-Anexo 3, Faculdade de Medicina do ABC, Vila Principe de Gales, n.821, Santo André, SP, 09060-650, Brazil
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Anti-MMP-9 Antibody: A Promising Therapeutic Strategy for Treatment of Inflammatory Bowel Disease Complications with Fibrosis. Inflamm Bowel Dis 2016; 22:2041-57. [PMID: 27542125 DOI: 10.1097/mib.0000000000000863] [Citation(s) in RCA: 58] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/30/2023]
Abstract
BACKGROUND Despite medical treatments or surgical options, more than one-third of patients with Crohn's disease suffer from recurring fistulae. Matrix metalloprotease 9 (MMP-9), a type IV collagenase that cleaves components of the extracellular matrix leading to tissue remodeling, is upregulated in crypt abscesses and around fistulae suggesting an important role for this enzyme in fistula formation. Our aims were (1) to correlate serum levels of MMP-9 degradation products in patients with CD with the presence of fistulae and (2) to investigate the impact of selective MMP-9 inhibition in a mouse model of intestinal fibrosis. METHODS Serum MMP-9 degradation products were quantified in subjects affected with nonstricturing and nonpenetrating CD (n = 50), stricturing CD (n = 41), penetrating CD (n = 22), CD with perianal fistula (n = 29), and healthy controls (n = 10). Therapeutic efficacy of anti-MMP-9 monoclonal antibodies was assessed in a heterotopic xenograft model of intestinal fibrosis. RESULTS C3M, an MMP-9 degradation product of collagen III, demonstrated the highest serum levels in patients with penetrating CD and differentiated penetrating CD from other CD subgroups and healthy controls, P = 0.0005. Anti-MMP-9 treatments reduced collagen deposition and hydroxyproline content in day-14 intestinal grafts indicating reduced fibrosis. CONCLUSIONS The serologic biomarker C3M can discriminate penetrating CD from other CD subgroups and could serve as marker for the development of penetrating CD. Anti-MMP-9 antibody has therapeutic potential to prevent intestinal fibrosis in CD complications.
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Matrix Metalloproteinases in Non-Neoplastic Disorders. Int J Mol Sci 2016; 17:ijms17071178. [PMID: 27455234 PMCID: PMC4964549 DOI: 10.3390/ijms17071178] [Citation(s) in RCA: 67] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2016] [Revised: 06/16/2016] [Accepted: 07/04/2016] [Indexed: 12/23/2022] Open
Abstract
The matrix metalloproteinases (MMPs) are zinc-dependent endopeptidases belonging to the metzincin superfamily. There are at least 23 members of MMPs ever reported in human, and they and their substrates are widely expressed in many tissues. Recent growing evidence has established that MMP not only can degrade a variety of components of extracellular matrix, but also can cleave and activate various non-matrix proteins, including cytokines, chemokines and growth factors, contributing to both physiological and pathological processes. In normal conditions, MMP expression and activity are tightly regulated via interactions between their activators and inhibitors. Imbalance among these factors, however, results in dysregulated MMP activity, which causes tissue destruction and functional alteration or local inflammation, leading to the development of diverse diseases, such as cardiovascular disease, arthritis, neurodegenerative disease, as well as cancer. This article focuses on the accumulated evidence supporting a wide range of roles of MMPs in various non-neoplastic diseases and provides an outlook on the therapeutic potential of inhibiting MMP action.
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Al-Ghadban S, Kaissi S, Homaidan FR, Naim HY, El-Sabban ME. Cross-talk between intestinal epithelial cells and immune cells in inflammatory bowel disease. Sci Rep 2016; 6:29783. [PMID: 27417573 PMCID: PMC4945922 DOI: 10.1038/srep29783] [Citation(s) in RCA: 74] [Impact Index Per Article: 8.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2015] [Accepted: 06/20/2016] [Indexed: 12/13/2022] Open
Abstract
Inflammatory bowel disease (IBD) involves functional impairment of intestinal epithelial cells (IECs), concomitant with the infiltration of the lamina propria by inflammatory cells. We explored the reciprocal paracrine and direct interaction between human IECs and macrophages (MΦ) in a co-culture system that mimics some aspects of IBD. We investigated the expression of intercellular junctional proteins in cultured IECs under inflammatory conditions and in tissues from IBD patients. IECs establish functional gap junctions with IECs and MΦ, respectively. Connexin (Cx26) and Cx43 expression in cultured IECs is augmented under inflammatory conditions; while, Cx43-associated junctional complexes partners, E-cadherin, ZO-1, and β-catenin expression is decreased. The expression of Cx26 and Cx43 in IBD tissues is redistributed to the basal membrane of IEC, which is associated with decrease in junctional complex proteins' expression, collagen type IV expression and infiltration of MΦ. These data support the notion that the combination of paracrine and hetero-cellular communication between IECs and MΦs may regulate epithelial cell function through the establishment of junctional complexes between inflammatory cells and IECs, which ultimately contribute to the dys-regulation of intestinal epithelial barrier.
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Affiliation(s)
- Sara Al-Ghadban
- Department of Anatomy, Cell Biology, and Physiological Sciences, Faculty of Medicine, American university of Beirut, Beirut, Lebanon
| | - Samira Kaissi
- Department of Anatomy, Cell Biology, and Physiological Sciences, Faculty of Medicine, American university of Beirut, Beirut, Lebanon
| | - Fadia R Homaidan
- Inflammation group-Nature Conservation Center (NCC) for Sustainable Futures, American University of Beirut, Lebanon
| | - Hassan Y Naim
- Department of Physiological Chemistry, University of Veterinary Medicine Hannover, Hannover, Germany
| | - Marwan E El-Sabban
- Department of Anatomy, Cell Biology, and Physiological Sciences, Faculty of Medicine, American university of Beirut, Beirut, Lebanon
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de Bruyn M, Vandooren J, Ugarte-Berzal E, Arijs I, Vermeire S, Opdenakker G. The molecular biology of matrix metalloproteinases and tissue inhibitors of metalloproteinases in inflammatory bowel diseases. Crit Rev Biochem Mol Biol 2016; 51:295-358. [PMID: 27362691 DOI: 10.1080/10409238.2016.1199535] [Citation(s) in RCA: 61] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
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Argyropoulos AJ, Robichaud P, Balimunkwe RM, Fisher GJ, Hammerberg C, Yan Y, Quan T. Alterations of Dermal Connective Tissue Collagen in Diabetes: Molecular Basis of Aged-Appearing Skin. PLoS One 2016; 11:e0153806. [PMID: 27104752 PMCID: PMC4841569 DOI: 10.1371/journal.pone.0153806] [Citation(s) in RCA: 69] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2016] [Accepted: 04/04/2016] [Indexed: 12/15/2022] Open
Abstract
Alterations of the collagen, the major structural protein in skin, contribute significantly to human skin connective tissue aging. As aged-appearing skin is more common in diabetes, here we investigated the molecular basis of aged-appearing skin in diabetes. Among all known human matrix metalloproteinases (MMPs), diabetic skin shows elevated levels of MMP-1 and MMP-2. Laser capture microdissection (LCM) coupled real-time PCR indicated that elevated MMPs in diabetic skin were primarily expressed in the dermis. Furthermore, diabetic skin shows increased lysyl oxidase (LOX) expression and higher cross-linked collagens. Atomic force microscopy (AFM) further indicated that collagen fibrils were fragmented/disorganized, and key mechanical properties of traction force and tensile strength were increased in diabetic skin, compared to intact/well-organized collagen fibrils in non-diabetic skin. In in vitro tissue culture system, multiple MMPs including MMP-1 and MM-2 were induced by high glucose (25 mM) exposure to isolated primary human skin dermal fibroblasts, the major cells responsible for collagen homeostasis in skin. The elevation of MMPs and LOX over the years is thought to result in the accumulation of fragmented and cross-linked collagen, and thus impairs dermal collagen structural integrity and mechanical properties in diabetes. Our data partially explain why old-looking skin is more common in diabetic patients.
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Affiliation(s)
- Angela J. Argyropoulos
- Department of Psychiatry, University of Washington, Seattle, Washington, United States of America
| | - Patrick Robichaud
- Department of Dermatology, University of Michigan Medical School, Ann Arbor, Michigan, United States of America
| | - Rebecca Mutesi Balimunkwe
- Department of Dermatology, University of Michigan Medical School, Ann Arbor, Michigan, United States of America
| | - Gary J. Fisher
- Department of Dermatology, University of Michigan Medical School, Ann Arbor, Michigan, United States of America
| | - Craig Hammerberg
- Department of Dermatology, University of Michigan Medical School, Ann Arbor, Michigan, United States of America
| | - Yan Yan
- Department of Dermatology, Plastic Surgery Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China
| | - Taihao Quan
- Department of Dermatology, University of Michigan Medical School, Ann Arbor, Michigan, United States of America
- * E-mail:
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Pang L, Wang DW, Zhang N, Xu DH, Meng XW. Elevated serum levels of MMP-11 correlate with poor prognosis in colon cancer patients. Cancer Biomark 2016; 16:599-607. [PMID: 27002762 DOI: 10.3233/cbm-160601] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022]
Abstract
BACKGROUND Matrix metalloproteinase 11 (MMP11) has been shown to play a key role in human tumor progression and indicates poor clinical outcome in cancer patients. OBJECTIVE The current study aimed to evaluate the relationship between serum levels of MMP-11 and prognosis in colon cancer patients. METHODS Serum levels of MMP-11 were determined in 92 colon cancer patients and 92 healthy individuals using an enzyme-linked immunosorbent assay (ELISA). Associations between serum MMP-11 levels and clinicopathological characteristics of the patients and their outcomes were investigated. Survival analyses were performed to measure the 5-year overall survival (OS) and disease-free survival (DFS). RESULTS Serum MMP-11 levels were substantially higher in colon cancer patients than in healthy controls. Moreover, serum MMP-11 levels were significantly higher in patients with advanced T status, lymph node metastasis, distant metastasis, and a higher TNM stage. Elevated serum levels of MMP-11 were identified as an independent prognostic factor for 5-year mortality and adverse events associated with colon cancer. Multivariate Cox regression analysis identified the serum MMP-11 level as an independent predictor of OS and DFS. CONCLUSION Our study established that high serum levels of MMP-11 are associated with poor clinical outcome and may serve as a prognostic biomarker in colon cancer patients.
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Affiliation(s)
- Li Pang
- Department of Emergency, The First Hospital of Jilin University, Changchun, Jilin, China
| | - Da-Wei Wang
- Department of Emergency, The First Hospital of Jilin University, Changchun, Jilin, China
| | - Nan Zhang
- Department of Emergency, The First Hospital of Jilin University, Changchun, Jilin, China
| | - Da-Hai Xu
- Department of Emergency, The First Hospital of Jilin University, Changchun, Jilin, China
| | - Xiang-Wei Meng
- Department of Gastrointestinal Medicine, The First Hospital of Jilin University, Changchun, Jilin, China
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Zhang X, Huang S, Guo J, Zhou L, You L, Zhang T, Zhao Y. Insights into the distinct roles of MMP-11 in tumor biology and future therapeutics (Review). Int J Oncol 2016; 48:1783-93. [PMID: 26892540 DOI: 10.3892/ijo.2016.3400] [Citation(s) in RCA: 84] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2015] [Accepted: 01/21/2016] [Indexed: 11/06/2022] Open
Abstract
The biological processes of cancer cells such as tumorigenesis, proliferation, angiogenesis, apoptosis and invasion are greatly influenced by the surrounding microenvironment. The ability of solid malignant tumors to alter the microenvironment represents an important characteristic through which tumor cells are able to acquire specific functions necessary for their malignant biological behaviors. Matrix metalloproteinases (MMPs) are a family of zinc-dependent endopeptidases with the capacity of remodeling extracellular matrix (ECM) by degrading almost all ECM proteins, which plays essential roles during the invasion and metastasis process of solid malignant tumors, including allowing tumor cells to modify the ECM components and release cytokines, ultimately facilitating protease-dependent tumor progression. MMP-11, also named stromelysin-3, is a member of the stromelysin subgroup belonging to MMPs superfamily, which has been detected in cancer cells, stromal cells and adjacent microenvironment. Differently, MMP-11 exerts a dual effect on tumors. On the one hand MMP-11 promotes cancer development by inhibiting apoptosis as well as enhancing migration and invasion of cancer cells, on the other hand MMP-11 plays a negative role against cancer development via suppressing metastasis in animal models. Overexpression of MMP-11 was discovered in sera of cancer patients compared with normal control group as well as in multiple tumor tissue specimens, such as gastric cancer, breast cancer, and pancreatic cancer. At present, some evidence supports that MMP-11 may work as a significant tumor biomarker for early detection of cancer, tumor staging, prognostic analysis, monitoring recurrence during follow-up and also a potential target for immunotherapy against cancer. In view of the importance of MMP-11 in modifying tumor microenvironment and potent antitumoral effects on solid tumors, there is an urgent need for a deeper understanding of how MMP-11 modulates tumor progression, and exploring its potential clinical application.
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Affiliation(s)
- Xu Zhang
- Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences/Peking Union Medical College, Beijing 100730, P.R. China
| | - Shuai Huang
- Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences/Peking Union Medical College, Beijing 100730, P.R. China
| | - Junchao Guo
- Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences/Peking Union Medical College, Beijing 100730, P.R. China
| | - Li Zhou
- Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences/Peking Union Medical College, Beijing 100730, P.R. China
| | - Lei You
- Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences/Peking Union Medical College, Beijing 100730, P.R. China
| | - Taiping Zhang
- Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences/Peking Union Medical College, Beijing 100730, P.R. China
| | - Yupei Zhao
- Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences/Peking Union Medical College, Beijing 100730, P.R. China
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Marshall DC, Lyman SK, McCauley S, Kovalenko M, Spangler R, Liu C, Lee M, O’Sullivan C, Barry-Hamilton V, Ghermazien H, Mikels-Vigdal A, Garcia CA, Jorgensen B, Velayo AC, Wang R, Adamkewicz JI, Smith V. Selective Allosteric Inhibition of MMP9 Is Efficacious in Preclinical Models of Ulcerative Colitis and Colorectal Cancer. PLoS One 2015; 10:e0127063. [PMID: 25961845 PMCID: PMC4427291 DOI: 10.1371/journal.pone.0127063] [Citation(s) in RCA: 156] [Impact Index Per Article: 15.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2014] [Accepted: 04/11/2015] [Indexed: 12/20/2022] Open
Abstract
Expression of matrix metalloproteinase 9 (MMP9) is elevated in a variety of inflammatory and oncology indications, including ulcerative colitis and colorectal cancer. MMP9 is a downstream effector and an upstream mediator of pathways involved in growth and inflammation, and has long been viewed as a promising therapeutic target. However, previous efforts to target matrix metalloproteinases (MMPs), including MMP9, have utilized broad-spectrum or semi-selective inhibitors. While some of these drugs showed signs of efficacy in patients, all MMP-targeted inhibitors have been hampered by dose-limiting toxicity or insufficient clinical benefit, likely due to their lack of specificity. Here, we show that selective inhibition of MMP9 did not induce musculoskeletal syndrome (a characteristic toxicity of pan-MMP inhibitors) in a rat model, but did reduce disease severity in a dextran sodium sulfate-induced mouse model of ulcerative colitis. We also found that MMP9 inhibition decreased tumor growth and metastases incidence in a surgical orthotopic xenograft model of colorectal carcinoma, and that inhibition of either tumor- or stroma-derived MMP9 was sufficient to reduce primary tumor growth. Collectively, these data suggest that selective MMP9 inhibition is a promising therapeutic strategy for treatment of inflammatory and oncology indications in which MMP9 is upregulated and is associated with disease pathology, such as ulcerative colitis and colorectal cancer. In addition, we report the development of a potent and highly selective allosteric MMP9 inhibitor, the humanized monoclonal antibody GS-5745, which can be used to evaluate the therapeutic potential of MMP9 inhibition in patients.
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MESH Headings
- Allosteric Regulation
- Animals
- Antibodies, Monoclonal, Humanized/biosynthesis
- Antibodies, Monoclonal, Humanized/isolation & purification
- Antibodies, Monoclonal, Humanized/pharmacology
- Antineoplastic Agents/isolation & purification
- Antineoplastic Agents/metabolism
- Antineoplastic Agents/pharmacology
- Colitis, Ulcerative/chemically induced
- Colitis, Ulcerative/drug therapy
- Colitis, Ulcerative/enzymology
- Colitis, Ulcerative/genetics
- Colorectal Neoplasms/drug therapy
- Colorectal Neoplasms/enzymology
- Colorectal Neoplasms/genetics
- Colorectal Neoplasms/pathology
- Dextran Sulfate
- Disease Models, Animal
- Drug Evaluation, Preclinical
- Epitope Mapping
- Female
- Gene Expression Regulation, Neoplastic
- Humans
- Hybridomas/immunology
- Male
- Matrix Metalloproteinase 9/administration & dosage
- Matrix Metalloproteinase 9/genetics
- Matrix Metalloproteinase 9/metabolism
- Matrix Metalloproteinase Inhibitors/isolation & purification
- Matrix Metalloproteinase Inhibitors/metabolism
- Matrix Metalloproteinase Inhibitors/pharmacology
- Mice
- Mice, Nude
- Rats
- Rats, Inbred Lew
- Recombinant Proteins/administration & dosage
- Recombinant Proteins/genetics
- Recombinant Proteins/metabolism
- Signal Transduction
- Xenograft Model Antitumor Assays
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Affiliation(s)
- Derek C. Marshall
- Department of Biology, Gilead Sciences, Inc., Foster City, California, United States of America
| | - Susan K. Lyman
- Department of Biology, Gilead Sciences, Inc., Foster City, California, United States of America
| | - Scott McCauley
- Department of Biology, Gilead Sciences, Inc., Foster City, California, United States of America
| | - Maria Kovalenko
- Department of Biology, Gilead Sciences, Inc., Foster City, California, United States of America
| | - Rhyannon Spangler
- Department of Biology, Gilead Sciences, Inc., Foster City, California, United States of America
| | - Chian Liu
- Department of Biology, Gilead Sciences, Inc., Foster City, California, United States of America
| | - Michael Lee
- Department of Biology, Gilead Sciences, Inc., Foster City, California, United States of America
| | - Christopher O’Sullivan
- Department of Biology, Gilead Sciences, Inc., Foster City, California, United States of America
| | - Vivian Barry-Hamilton
- Department of Biology, Gilead Sciences, Inc., Foster City, California, United States of America
| | - Haben Ghermazien
- Department of Biology, Gilead Sciences, Inc., Foster City, California, United States of America
| | - Amanda Mikels-Vigdal
- Department of Biology, Gilead Sciences, Inc., Foster City, California, United States of America
| | - Carlos A. Garcia
- Department of Process Development, Gilead Sciences, Inc., Oceanside, California, United States of America
| | - Brett Jorgensen
- Department of Biology, Gilead Sciences, Inc., Foster City, California, United States of America
| | - Arleene C. Velayo
- Department of Process Development, Gilead Sciences, Inc., Oceanside, California, United States of America
| | - Ruth Wang
- Department of Biology, Gilead Sciences, Inc., Foster City, California, United States of America
| | - Joanne I. Adamkewicz
- Department of Biology, Gilead Sciences, Inc., Foster City, California, United States of America
| | - Victoria Smith
- Department of Biology, Gilead Sciences, Inc., Foster City, California, United States of America
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Matrix metalloproteinases in inflammatory bowel disease: an update. Mediators Inflamm 2015; 2015:964131. [PMID: 25948887 PMCID: PMC4408746 DOI: 10.1155/2015/964131] [Citation(s) in RCA: 98] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/04/2014] [Accepted: 09/07/2014] [Indexed: 02/07/2023] Open
Abstract
Matrix metalloproteinases (MMPs) are known to be upregulated in inflammatory bowel disease (IBD) and other inflammatory conditions, but while their involvement is clear, their role in many settings has yet to be determined. Studies of the involvement of MMPs in IBD since 2006 have revealed an array of immune and stromal cells which release the proteases in response to inflammatory cytokines and growth factors. Through digestion of the extracellular matrix and cleavage of bioactive proteins, a huge diversity of roles have been revealed for the MMPs in IBD, where they have been shown to regulate epithelial barrier function, immune response, angiogenesis, fibrosis, and wound healing. For this reason, MMPs have been recognised as potential biomarkers for disease activity in IBD and inhibition remains a huge area of interest. This review describes new roles of MMPs in the pathophysiology of IBD and suggests future directions for the development of treatment strategies in this condition.
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Shimshoni E, Yablecovitch D, Baram L, Dotan I, Sagi I. ECM remodelling in IBD: innocent bystander or partner in crime? The emerging role of extracellular molecular events in sustaining intestinal inflammation. Gut 2015; 64:367-72. [PMID: 25416065 PMCID: PMC4345769 DOI: 10.1136/gutjnl-2014-308048] [Citation(s) in RCA: 88] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Affiliation(s)
- Elee Shimshoni
- Department of Biological Regulation, Weizmann Institute of Science, Rehovot, Israel
| | - Doron Yablecovitch
- Department of Biological Regulation, Weizmann Institute of Science, Rehovot, Israel,Department of Gastroenterology, Chaim Sheba Medical Center, Tel HaShomer, Israel
| | - Liran Baram
- IBD Center, Department of Gastroenterology and Liver Diseases, Tel Aviv Sourasky Medical Center and the Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Iris Dotan
- IBD Center, Department of Gastroenterology and Liver Diseases, Tel Aviv Sourasky Medical Center and the Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Irit Sagi
- Department of Biological Regulation, Weizmann Institute of Science, Rehovot, Israel
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Martinesi M, Ambrosini S, Treves C, Zuegel U, Steinmeyer A, Vito A, Milla M, Bonanomi AG, Stio M. Role of vitamin D derivatives in intestinal tissue of patients with inflammatory bowel diseases. J Crohns Colitis 2014; 8:1062-1071. [PMID: 24630484 DOI: 10.1016/j.crohns.2014.02.005] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/14/2013] [Revised: 02/07/2014] [Accepted: 02/07/2014] [Indexed: 02/08/2023]
Abstract
BACKGROUND AND AIM The adhesion molecule expression and matrix metalloproteinases (MMPs) are proposed to be major factors for intestinal injury mediated by T cells in (IBD) and are up-regulated in intestinal mucosa of IBD patients. To investigate the effect of vitamin D derivatives on adhesion molecules and MMPs in colonic biopsies of IBD patients. METHODS Biopsies from inflamed and non-inflamed tract of terminal ileum and colon and PBMC from the same IBD patients were cultured with or without vitamin D derivatives. MMP activity and adhesion molecule levels were determined. RESULTS 1,25(OH)2D3 and ZK 191784 significantly decrease ICAM-1 protein levels in the biopsies obtained only from the inflamed region of intestine of UC patients, while MAdCAM-1 levels decrease in the presence of 1,25(OH)2D3 in the non-inflamed region, and, in the presence of ZK, in the inflamed one. In CD patients 1,25(OH)2D3 and ZK decrease ICAM-1 and MAdCAM-1 in the biopsies obtained from the non-inflamed and inflamed regions, with the exception of ICAM-1 in the inflamed region in the presence of 1,25(OH)2D3. The expression of MMP-9, MMP-2, and MMP-3 decreases in the presence of vitamin D derivatives in UC and CD with the exception of 1,25(OH)2D3 that does not affect the levels of MMP-9 and MMP-2 in CD. Vitamin D derivatives always affect MMP-9, MMP-2 and ICAM-1 in PBMC of UC and CD patients. CONCLUSIONS Based on the increased expression of ICAM-1, MAdCAM-1 and MMP-2,-9,-3 in IBD, our study suggests that vitamin D derivatives may be effective in the management of these diseases.
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Affiliation(s)
- Maria Martinesi
- Department of Biomedical, Experimental and Clinical Sciences, University of Florence, Viale Morgagni 50, 50134 Florence, Italy
| | - Stefano Ambrosini
- Department of Biomedical, Experimental and Clinical Sciences, University of Florence, Viale Morgagni 50, 50134 Florence, Italy
| | - Cristina Treves
- Department of Biomedical, Experimental and Clinical Sciences, University of Florence, Viale Morgagni 50, 50134 Florence, Italy
| | - Ulrich Zuegel
- Clinical Sciences, Global Biomarker, Global Discovery, Bayer Healthcare, Bayer, 10178 Berlin, Germany
| | - Andreas Steinmeyer
- Medicinal Chemistry, Global Drug Discovery, Bayer Healthcare, Bayer, 10178 Berlin, Germany
| | - Annese Vito
- Division of Gastroenterology 2, Careggi Hospital, 50134 Florence, Italy
| | - Monica Milla
- Regional Referral Center for IBD, Careggi Hospital, 50134 Florence, Italy
| | - Andrea G Bonanomi
- Division of Gastroenterology 2, Careggi Hospital, 50134 Florence, Italy
| | - Maria Stio
- Department of Biomedical, Experimental and Clinical Sciences, University of Florence, Viale Morgagni 50, 50134 Florence, Italy.
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Eum SY, Jaraki D, Bertrand L, András IE, Toborek M. Disruption of epithelial barrier by quorum-sensing N-3-(oxododecanoyl)-homoserine lactone is mediated by matrix metalloproteinases. Am J Physiol Gastrointest Liver Physiol 2014; 306:G992-G1001. [PMID: 24742991 PMCID: PMC4042118 DOI: 10.1152/ajpgi.00016.2014] [Citation(s) in RCA: 45] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
The intestinal epithelium forms a selective barrier maintained by tight junctions (TJs) and separating the luminal environment from the submucosal tissues. N-acylhomoserine lactone (AHL) quorum-sensing molecules produced by gram-negative bacteria in the gut can influence homeostasis of the host intestinal epithelium. In the present study, we evaluated the regulatory mechanisms affecting the impact of two representative long- and short-chain AHLs, N-3-(oxododecanoyl)-homoserine lactone (C12-HSL) and N-butyryl homoserine lactone (C4-HSL), on barrier function of human intestinal epithelial Caco-2 cells. Treatment with C12-HSL, but not with C4-HSL, perturbed Caco-2 barrier function; the effect was associated with decreased levels of the TJ proteins occludin and tricellulin and their delocalization from the TJs. C12-HSL also induced matrix metalloprotease (MMP)-2 and MMP-3 activation via lipid raft- and protease-activated receptor (PAR)-dependent signaling. Pretreatment with lipid raft disruptors, PAR antagonists, or MMP inhibitors restored the C12-HSL-induced loss of the TJ proteins and increased permeability of Caco-2 cell monolayers. These results indicate that PAR/lipid raft-dependent MMP-2 and -3 activation followed by degradation of occludin and tricellulin are involved in C12-HSL-induced alterations of epithelial paracellular barrier functions.
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Affiliation(s)
- Sung Yong Eum
- 1Department of Biochemistry and Molecular Biology, University of Miami Miller School of Medicine, Miami, Florida; and
| | - Dima Jaraki
- 1Department of Biochemistry and Molecular Biology, University of Miami Miller School of Medicine, Miami, Florida; and
| | - Luc Bertrand
- 1Department of Biochemistry and Molecular Biology, University of Miami Miller School of Medicine, Miami, Florida; and
| | - Ibolya E. András
- 1Department of Biochemistry and Molecular Biology, University of Miami Miller School of Medicine, Miami, Florida; and
| | - Michal Toborek
- Department of Biochemistry and Molecular Biology, University of Miami Miller School of Medicine, Miami, Florida; and Jerzy Kukuczka Academy of Physical Education, Katowice, Poland
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Cervinková M, Horák P, Kanchev I, Matěj R, Fanta J, Sequens R, Kašpárek P, Sarnová L, Turečková J, Sedláček R. Differential expression and processing of matrix metalloproteinase 19 marks progression of gastrointestinal diseases. Folia Biol (Praha) 2014; 60:113-22. [PMID: 25056434 DOI: 10.14712/fb2014060030113] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2024]
Abstract
Matrix metalloproteinases (MMPs), responsible for extracellular matrix remodelling and processing of numerous soluble and cell-surface proteins, appear to play important roles in pathogenesis of gastrointestinal diseases. MMPs influence migration of inflammatory cells, mucosal destruction, matrix deposition and degradation. In this study, we analysed the expression of MMP-19 in the main forms of gastrointestinal diseases including inflammatory bowel diseases (IBD) such as ulcerative colitis and Crohn's disease, and colorectal carcinoma. We identified prominent MMP-19 expression in unaffected areas of intestinal epithelia and macrophages but not in other cells or tissues. Abundant expression of MMP-19 was also found in the endothelium of blood and lymphatic vessels of inflamed intestinal tissue. High MMP-19 immunoreactivity was also associated with macrophages in inflamed areas and myenteric plexuses. In comparison to the intestinal epithelium, all these cell types and compartments appeared to express MMP-19 irrespective of the disease pathogenesis and progression. Intestinal epithelia exhibited striking differential immunoreactivity for MMP-19. While immunoreactivity of monoclonal antibody recognizing the propeptide domain declined in virtually all IBD and colorectal carcinoma samples, other polyclonal antibodies against the hinge region and propetide domain did not show such an obvious decrease. Additional Western blotting analysis revealed that the antibodies against MMP-19 recognize differently processed forms of this MMP. The disappearance of immunoreactivity of the monoclonal anti-propeptide domain antibody does not mean down-regulation of MMP-19, but processing of the immature form. As this processing likely leads to the activation of this MMP, the differential staining pattern may be an important sign of disease progression.
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Affiliation(s)
- M Cervinková
- Laboratory of Transgenic Models of Diseases, Institute of Molecular Genetics of the ASCR, v. v. i., Prague, Czech Republic
| | - P Horák
- Department of Surgery, First Faculty of Medicine, Charles University in Prague and Na Bulovce Hospital, Prague, Czech Republic
| | - I Kanchev
- Laboratory of Transgenic Models of Diseases, Institute of Molecular Genetics of the ASCR, v. v. i., Prague, Czech Republic
| | - R Matěj
- Department of Pathology and Molecular Medicine, Thomayer Hospital, Prague, Czech Republic
| | - J Fanta
- Department of Surgery, First Faculty of Medicine, Charles University in Prague and Na Bulovce Hospital, Prague, Czech Republic
| | - R Sequens
- Gastroenterology Surgical Centre, Hospital of Merciful Sisters of St. Borromeo, Prague, Czech Republic
| | - P Kašpárek
- Laboratory of Transgenic Models of Diseases, Institute of Molecular Genetics of the ASCR, v. v. i., Prague, Czech Republic
| | - L Sarnová
- Laboratory of Transgenic Models of Diseases, Institute of Molecular Genetics of the ASCR, v. v. i., Prague, Czech Republic
| | - J Turečková
- Laboratory of Transgenic Models of Diseases, Institute of Molecular Genetics of the ASCR, v. v. i., Prague, Czech Republic
| | - R Sedláček
- Laboratory of Transgenic Models of Diseases, Institute of Molecular Genetics of the ASCR, v. v. i., Prague, Czech Republic
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Tan J, Buache E, Alpy F, Daguenet E, Tomasetto CL, Ren GS, Rio MC. Stromal matrix metalloproteinase-11 is involved in the mammary gland postnatal development. Oncogene 2013; 33:4050-9. [PMID: 24141782 DOI: 10.1038/onc.2013.434] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2012] [Revised: 08/01/2013] [Accepted: 08/02/2013] [Indexed: 01/29/2023]
Abstract
MMP-11 is a bad prognosis paracrine factor in invasive breast cancers. However, its mammary physiological function remains largely unknown. In the present study we have investigated MMP-11 function during postnatal mammary gland development and function using MMP-11-deficient (MMP-11-/-) mice. Histological and immunohistochemical analyses as well as whole-mount mammary gland staining show alteration of the mammary gland in the absence of MMP-11, where ductal tree, alveolar structures and milk production are reduced. Moreover, a series of transplantation experiments allowed us to demonstrate that MMP-11 exerts an essential local paracrine function that favors mammary gland branching and epithelial cell outgrowth and invasion through adjacent connective tissues. Indeed, MMP-11-/- cleared fat pads are not permissive for wild-type epithelium development, whereas MMP-11-/- epithelium transplants grow normally when implanted in wild-type cleared fat pads. In addition, using primary mammary epithelial organoids, we show in vitro that this MMP-11 pro-branching effect is not direct, suggesting that MMP-11 acts via production/release of stroma-associated soluble factor(s). Finally, the lack of MMP-11 leads to decreased periductal collagen content, suggesting that MMP-11 has a role in collagen homeostasis. Thus, local stromal MMP-11 might also regulate mammary epithelial cell behavior mechanically by promoting extracellular matrix stiffness. Collectively, the present data indicate that MMP-11 is a paracrine factor involved during postnatal mammary gland morphogenesis, and support the concept that the stroma strongly impact epithelial cell behavior. Interestingly, stromal MMP-11 has previously been reported to favor malignant epithelial cell survival and promote cancer aggressiveness. Thus, MMP-11 has a paracrine function during mammary gland development that might be harnessed to promote tumor progression, exposing a new link between development and malignancy.
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Affiliation(s)
- J Tan
- 1] Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Department of Functional Genomics and Cancer, Centre National de la Recherche Scientifique UMR 7104, Institut National de la Santé et de la Recherche Médicale U964, Université de Strasbourg, Strasbourg, France [2] Department of Endocrine and Breast Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - E Buache
- Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Department of Functional Genomics and Cancer, Centre National de la Recherche Scientifique UMR 7104, Institut National de la Santé et de la Recherche Médicale U964, Université de Strasbourg, Strasbourg, France
| | - F Alpy
- Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Department of Functional Genomics and Cancer, Centre National de la Recherche Scientifique UMR 7104, Institut National de la Santé et de la Recherche Médicale U964, Université de Strasbourg, Strasbourg, France
| | - E Daguenet
- Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Department of Functional Genomics and Cancer, Centre National de la Recherche Scientifique UMR 7104, Institut National de la Santé et de la Recherche Médicale U964, Université de Strasbourg, Strasbourg, France
| | - C-L Tomasetto
- Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Department of Functional Genomics and Cancer, Centre National de la Recherche Scientifique UMR 7104, Institut National de la Santé et de la Recherche Médicale U964, Université de Strasbourg, Strasbourg, France
| | - G-S Ren
- Department of Endocrine and Breast Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - M-C Rio
- 1] Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Department of Functional Genomics and Cancer, Centre National de la Recherche Scientifique UMR 7104, Institut National de la Santé et de la Recherche Médicale U964, Université de Strasbourg, Strasbourg, France [2] Equipe Labellisée Ligue National Contre le Cancer, Illkirch, France
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Groschwitz KR, Wu D, Osterfeld H, Ahrens R, Hogan SP. Chymase-mediated intestinal epithelial permeability is regulated by a protease-activating receptor/matrix metalloproteinase-2-dependent mechanism. Am J Physiol Gastrointest Liver Physiol 2013; 304:G479-89. [PMID: 23306080 PMCID: PMC3602679 DOI: 10.1152/ajpgi.00186.2012] [Citation(s) in RCA: 67] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
Mast cells regulate intestinal barrier function during disease and homeostasis. Secretion of the mast cell-specific serine protease chymase regulates homeostasis. In the present study, we employ in vitro model systems to delineate the molecular pathways involved in chymase-mediated intestinal epithelial barrier dysfunction. Chymase stimulation of intestinal epithelial (Caco-2 BBe) cell monolayers induced a significant reduction in transepithelial resistance, indicating decreased intestinal epithelial barrier function. The chymase-induced intestinal epithelial barrier dysfunction was characterized by chymase-induced protease-activated receptor (PAR)-2 activation and matrix metalloproteinase (MMP)-2 expression and activation. Consistent with this observation, in vitro analysis revealed chymase-induced PAR-2 activation and increased MAPK activity and MMP-2 expression. Pharmacological and small interfering RNA-mediated antagonism of PAR-2 and MMP-2 significantly attenuated chymase-stimulated barrier dysfunction. Additionally, the chymase/MMP-2-mediated intestinal epithelial dysfunction was associated with a significant reduction in the tight junction protein claudin-5, which was partially restored by MMP-2 inhibition. Finally, incubation of Caco-2 BBe cells with chymase-sufficient, but not chymase-deficient, bone marrow-derived mast cells decreased barrier function, which was attenuated by the chymase inhibitor chymostatin. Collectively, these results suggest that mast cell/chymase-mediated intestinal epithelial barrier function is mediated by PAR-2/MMP-2-dependent pathways.
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Affiliation(s)
- Katherine R. Groschwitz
- 1Division of Allergy and Immunology, Department of Pediatrics, Cincinnati Children's Hospital Medical Center, University of Cincinnati College of Medicine, Cincinnati, Ohio; and ,2Division of Immunobiology, Department of Pediatrics, Cincinnati Children's Hospital Medical Center, University of Cincinnati College of Medicine, Cincinnati, Ohio
| | - David Wu
- 1Division of Allergy and Immunology, Department of Pediatrics, Cincinnati Children's Hospital Medical Center, University of Cincinnati College of Medicine, Cincinnati, Ohio; and
| | - Heather Osterfeld
- 1Division of Allergy and Immunology, Department of Pediatrics, Cincinnati Children's Hospital Medical Center, University of Cincinnati College of Medicine, Cincinnati, Ohio; and
| | - Richard Ahrens
- 1Division of Allergy and Immunology, Department of Pediatrics, Cincinnati Children's Hospital Medical Center, University of Cincinnati College of Medicine, Cincinnati, Ohio; and
| | - Simon P. Hogan
- 1Division of Allergy and Immunology, Department of Pediatrics, Cincinnati Children's Hospital Medical Center, University of Cincinnati College of Medicine, Cincinnati, Ohio; and
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Kawamura Y, Sugata K, Nakai H, Asano Y, Ohashi M, Kato T, Nishimura N, Ozaki T, Yui A, Taniguchi K, Yoshikawa T. Correlation between serum matrix metalloproteinase and antigenemia levels in patients infected with rotavirus. J Med Virol 2012; 84:986-91. [DOI: 10.1002/jmv.23296] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/17/2023]
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Kofla-Dlubacz A, Matusiewicz M, Krzystek-Korpacka M, Iwanczak B. Correlation of MMP-3 and MMP-9 with Crohn's disease activity in children. Dig Dis Sci 2012; 57:706-12. [PMID: 21997756 PMCID: PMC3282895 DOI: 10.1007/s10620-011-1936-z] [Citation(s) in RCA: 37] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/15/2011] [Accepted: 09/28/2011] [Indexed: 12/18/2022]
Abstract
BACKGROUND Recently published data indicate that the inflammation in Crohn's disease (CD) may be accompanied by elevated levels of matrix metalloproteinases. AIMS The goals of the present study were the estimation of MMP-3 and -9 concentrations in sera of children with Crohn's disease, the examination of correlation between the concentrations of MMP-3 and -9 and clinical activity of the disease in the relation to the control group and the evaluation of the utility of MMP-3 and -9 concentration measurements as markers of disease activity. METHODS Serum concentrations of MMP-3 and -9 were estimated in 82 children (45 CD patients divided into severe, moderate and mild subgroups; 37 controls) and correlated with disease activity estimated by the Pediatric Crohn's Disease Activity Index (PCDAI), CRP, seromucoid and ESR. RESULTS Mean MMP-3 concentrations were: 2.49 ng/ml (95% CI: 1.76-3.52) for mild, 16.44 ng/ml (95% CI: 10.34-26.15) for moderate, 5.25 ng/ml (95% CI: 2.73-10.11) for severe CD and 1.95 ng/ml (95% CI: 1.53-2.48) for the control group (differences between all three groups were statistically significant; P < 0.001). Median MMP-9 concentrations were: 2.14 ng/ml (95% CI: 0-8.9) for mild, 14.21 ng/ml (95% CI: 4.53-21.48) for moderate, 42.2 ng/ml (95% CI: 5.74-61.27) for severe CD and 1.3 ng/ml (95% CI: 0.7-2.18) for the control group. MMP-9 concentrations in moderate and severe CD differed from the concentrations in mild CD (P = 0.002) and control group (P = 0.0001). MMP-3 concentration significantly correlated with MMP-9, PCDAI and ESR, while MMP-9 concentration significantly positively correlated with MMP-3, PCDAI, and CRP. Diagnostic utilities of the tests were: MMP-3 accuracy 75%, positive likelihood ratio (LR+) = 4.11 and negative likelihood ratio (LR-) = 0.51, sensitivity 56%, specificity 87%, Youden index 0.43; for MMP-9, accuracy 73%, LR+ = 5.14 and LR- = 0.50, sensitivity 56%, specificity 89%, Youden index 0.45; and for CRP, accuracy 74%, LR+ = 8.56 and LR- = 0.54, sensitivity 49%, specificity 94%, Youden index 0.43. CONCLUSIONS MMP-9 serum concentration increasing along with the activity of the disease, exhibiting high specificity and correlating well with the indices of inflammation might be of better usefulness in the prediction of CD activity status in children than MMP-3.
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Affiliation(s)
- Anna Kofla-Dlubacz
- 2nd Department and Clinic of Paediatrics, Gastroenterology and Nutrition, Wroclaw Medical University, Wroclaw, Poland
| | - Malgorzata Matusiewicz
- Department of Medical Biochemistry, Wroclaw Medical University, Chalubinskiego 10, 50-358 Wroclaw, Poland
| | | | - Barbara Iwanczak
- 2nd Department and Clinic of Paediatrics, Gastroenterology and Nutrition, Wroclaw Medical University, Wroclaw, Poland
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Shores DR, Binion DG, Freeman BA, Baker PR. New insights into the role of fatty acids in the pathogenesis and resolution of inflammatory bowel disease. Inflamm Bowel Dis 2011; 17:2192-204. [PMID: 21910181 PMCID: PMC4100336 DOI: 10.1002/ibd.21560] [Citation(s) in RCA: 69] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/23/2010] [Accepted: 10/05/2010] [Indexed: 12/12/2022]
Abstract
Dietary and endogenously modified lipids modulate inflammation by functioning as intra- and intercellular signaling molecules. Proinflammatory lipid mediators such as the eicosanoids compete against the signaling actions of newly discovered modified fatty acids that act to resolve inflammation. In inflammatory bowel disease, multiple aberrancies in lipid metabolism have been discovered, which shed further light on the pathogenesis of intestinal inflammation. Mechanisms by which lipids modulate inflammation, abnormalities of lipid metabolism in the setting of inflammatory bowel disease, and potential therapeutic application of lipid derivatives in this setting are discussed.
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Affiliation(s)
- Darla R. Shores
- Division of Pediatric Gastroenterology, Children’s Hospital of Pittsburgh, Pittsburgh, Pennsylvania
| | - David G. Binion
- Division of Gastroenterology, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania
| | - Bruce A. Freeman
- Department of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania
| | - Paul R.S. Baker
- Department of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania
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Efsen E, Saermark T, Hansen A, Bruun E, Brynskov J. Ramiprilate inhibits functional matrix metalloproteinase activity in Crohn's disease fistulas. Basic Clin Pharmacol Toxicol 2011; 109:208-16. [PMID: 21535409 DOI: 10.1111/j.1742-7843.2011.00713.x] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
Increased expression of matrix metalloproteinase (MMP)-2, -3 and -9 has been demonstrated in Crohn's disease fistulas, but it is unknown whether these enzymes are biologically active and represent a therapeutic target. Therefore, we investigated the proteolytic activity of MMPs in fistula tissue and examined the effect of inhibitors, including clinically available drugs that beside their main action also suppress MMPs. Fistula specimens were obtained by surgical excision from 22 patients with Crohn's disease and from 10 patients with fistulas resulting from other causes. Colonic endoscopic biopsies from six controls were also included. Total functional MMP activity was measured by a high-pressure liquid chromatography (HPLC)-based, fluorogenic MMP-substrate cleavage assay, and the specific activity of MMP-2, -3 and -9 by the MMP Biotrak Activity Assay. The MMP inhibitors comprised ethylene-diamine-tetraacetic acid (EDTA), the synthetic broad-spectrum inhibitor, GM6001, the angiotensin-converting enzyme (ACE) inhibitor, ramiprilate, and the tetracycline, doxycycline. In Crohn's disease fistulas, about 50% of the total protease activity was attributable to MMP activity. The average total MMP activity was significantly higher (about 3.5-times) in Crohn's fistulas (471 FU/μg protein, range 49-2661) compared with non-Crohn's fistulas [134 FU/μg protein, range 0-495, (p < 0.05)] and normal colon [153 FU/μg protein, range 77-243, (p < 0.01)]. MMP-3 activity was increased in Crohn's fistulas (1.4 ng/ml, range 0-9.83) compared with non-Crohn's fistulas, [0.32 ng/ml, range 0-2.66, (p < 0.02)]. The same applied to MMP-9 activity [0.64 ng/ml, range 0-5.66 and 0.17 ng/ml, range 0-1.1, respectively (p < 0.04)]. Ramiprilate significantly decreased the average total MMP activity level by 42% and suppressed the specific MMP-3 activity by 72%, which is comparable to the effect of GM6001 (87%). Moreover, MMP-9 activity was completely blunted by ramiprilate. Doxycycline had no effect on MMP activity. Increased functional MMP activity, notably MMP-3 and -9, is present in Crohn's fistulas and may be inhibited by ramiprilate, a widely available ACE inhibitor.
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Affiliation(s)
- Eva Efsen
- Department of Gastroenterology, Herlev Hospital, University of Copenhagen, Denmark.
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Couillard J, Estève PO, Pradhan S, St-Pierre Y. 5-Aza-2′-deoxycytidine and interleukin-1 cooperate to regulate matrix metalloproteinase-3 gene expression. Int J Cancer 2011; 129:2083-92. [DOI: 10.1002/ijc.25865] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2010] [Accepted: 11/30/2010] [Indexed: 12/31/2022]
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Peterson KM, Shu J, Duggal P, Haque R, Mondal D, Petri WA. Association between TNF-alpha and Entamoeba histolytica diarrhea. Am J Trop Med Hyg 2010; 82:620-5. [PMID: 20348510 DOI: 10.4269/ajtmh.2010.09-0493] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/07/2022] Open
Abstract
An association between tumor necrosis factor alpha (TNF-alpha) and Entamoeba histolytica diarrhea was assessed in a cohort of 138 non-related Bangladeshi children who have been prospectively followed since 2001. Peripheral blood mononuclear cells (PBMCs) obtained at study entry were purified, cultured, and stimulated with soluble amebic antigen before cytokine measurement from supernatant. Higher levels of TNF-alpha were associated with increased risk of first (P = 0.01) and recurrent E. histolytica-related diarrheal episodes (P = 0.005). Children who developed E. histolytica diarrhea had significantly higher TNF-alpha protein levels than those who experienced asymptomatic E. histolytica infection (P value = 0.027) or no infection (P value = 0.017). Microarray studies performed using RNA isolated from acute and convalescent whole blood and colon biopsy samples revealed higher but non-significant TNF-alpha messenger RNA (mRNA) levels in subjects with acute E. histolytica diarrhea compared with convalescence. We conclude that there is an association between higher TNF-alpha production and E. histolytica diarrhea.
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Affiliation(s)
- Kristine M Peterson
- Division of Infectious Diseases, University of Virginia Health Systems, PO BOX 801337, Building MR4, Room 2115, 409 Lane Road, Charlottesville, VA, USA.
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Martinesi M, Treves C, Bonanomi AG, Milla M, Bagnoli S, Zuegel U, Steinmeyer A, Stio M. Down-regulation of adhesion molecules and matrix metalloproteinases by ZK 156979 in inflammatory bowel diseases. Clin Immunol 2010; 136:51-60. [PMID: 20399147 DOI: 10.1016/j.clim.2010.03.004] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2009] [Revised: 03/08/2010] [Accepted: 03/08/2010] [Indexed: 10/19/2022]
Abstract
Intracellular adhesion molecules and matrix metalloproteinases (MMPs) are up-regulated in intestinal mucosa of patients with inflammatory bowel diseases (IBD), i.e. ulcerative colitis (UC) or Crohn's disease (CD). Our aim was to verify whether the vitamin D analogue ZK 156979 (ZK) down-regulates adhesion molecules, and decreases MMPs production by PBMC of IBD patients. ICAM-1 and LFA-1 levels increase, when PBMC were incubated with PHA or LPS or TNF-alpha, and decrease when these substances were used in combination with ZK. MMPs activity increases incubating the cells with PHA or LPS or TNF-alpha. MMP-9 decreases when ZK was used in association, while MMP-2 decreases only when ZK was used in combination with anti-TNF-alpha. Our results suggest that the down-regulation of ICAM-1 and LFA-1 on PBMC and the inhibition of MMP-9 activity by ZK could provide a potential role of this low calcemic vitamin D derivative in future strategies in IBD therapy.
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Affiliation(s)
- Maria Martinesi
- Department of Biochemical Sciences, University of Florence, Viale Morgagni 50, 50134 Florence, Italy
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Zhao ZS, Chu YQ, Ye ZY, Wang YY, Tao HQ. Overexpression of matrix metalloproteinase 11 in human gastric carcinoma and its clinicopathologic significance. Hum Pathol 2010; 41:686-96. [PMID: 20060156 DOI: 10.1016/j.humpath.2009.10.010] [Citation(s) in RCA: 33] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/09/2009] [Revised: 10/09/2009] [Accepted: 10/15/2009] [Indexed: 01/26/2023]
Abstract
Matrix metalloproteinase 11 (stromelysin-3) has recently been reported to play a key role in human tumor progression and poor clinical outcome. The aim of this study was to investigate the significance of matrix metalloproteinase 11 expression in gastric cancer. Using real-time quantitative reverse-transcription polymerase chain reaction analysis and immunohistochemistry, we studied matrix metalloproteinase 11 expression levels in non-malignant gastric tissues and in gastric cancer tissues. The association between matrix metalloproteinase 11 expression levels and tumor stage and grade, as well as metastatic potential, was analyzed. Our results show that matrix metalloproteinase 11 expression was significantly higher in gastric cancer specimens compared with nonmalignant tissues at both transcriptional and protein levels, indicating its positive role in the development of gastric cancer. In addition, increased matrix metalloproteinase 11 expression levels were associated with advanced-stage and high-grade tumors, suggesting its involvement in the progression of gastric cancer. More importantly, increased matrix metalloproteinase 11 expression in gastric cancer specimens was correlated with increased expression of IGF-1, a molecule known to stimulate the proliferation, enhanced survival, and migration of cancer cells. Our results demonstrate that matrix metalloproteinase 11 is a novel factor in the development and progression of gastric cancer and suggest that matrix metalloproteinase 11 is a marker for advanced gastric cancer.
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Affiliation(s)
- Zhong-Sheng Zhao
- Department of Pathology, Zhejiang Provincial People's Hospital, Hangzhou 310014, China.
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