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1
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Wei Y, Xu Z, Hu M, Wu Z, Liu A, Czajkowsky DM, Guo Y, Shao Z. Time-resolved transcriptomics of mouse gastric pit cells during postnatal development reveals features distinct from whole stomach development. FEBS Lett 2023; 597:418-426. [PMID: 36285639 DOI: 10.1002/1873-3468.14525] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2022] [Revised: 09/27/2022] [Accepted: 10/10/2022] [Indexed: 11/05/2022]
Abstract
Whole-organ transcriptomic analyses have emerged as a common method for characterizing developmental transitions in mammalian organs. However, it is unclear if all cell types in an organ follow the whole-organ defined developmental trajectory. Recently, a postnatal two-stage developmental process was described for the mouse stomach. Here, using laser capture microdissection to obtain in situ transcriptomic data, we show that mouse gastric pit cells exhibit four postnatal developmental stages. Interestingly, early stages are characterized by the up-regulation of genes associated with metabolism, a functionality not typically associated with pit cells. Hence, beyond revealing that not all constituent cells develop according to the whole-organ determined pathway, these results broaden our understanding of the pit cell phenotypic landscape during stomach development.
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Affiliation(s)
- Ying Wei
- School of Biomedical Engineering, State Key Laboratory for Oncogenes and Bio-ID Center, Shanghai Jiao Tong University, China
| | - Zeqian Xu
- School of Biomedical Engineering, State Key Laboratory for Oncogenes and Bio-ID Center, Shanghai Jiao Tong University, China
| | - Miaomiao Hu
- School of Biomedical Engineering, State Key Laboratory for Oncogenes and Bio-ID Center, Shanghai Jiao Tong University, China
| | - Zhongqin Wu
- School of Biomedical Engineering, State Key Laboratory for Oncogenes and Bio-ID Center, Shanghai Jiao Tong University, China
| | - Axian Liu
- School of Biomedical Engineering, State Key Laboratory for Oncogenes and Bio-ID Center, Shanghai Jiao Tong University, China
| | - Daniel M Czajkowsky
- School of Biomedical Engineering, State Key Laboratory for Oncogenes and Bio-ID Center, Shanghai Jiao Tong University, China
| | - Yan Guo
- School of Biomedical Engineering, State Key Laboratory for Oncogenes and Bio-ID Center, Shanghai Jiao Tong University, China
| | - Zhifeng Shao
- School of Biomedical Engineering, State Key Laboratory for Oncogenes and Bio-ID Center, Shanghai Jiao Tong University, China
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2
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Sharafutdinov I, Ekici A, Vieth M, Backert S, Linz B. Early and late genome-wide gastric epithelial transcriptome response during infection with the human carcinogen Helicobacterpylori. CELL INSIGHT 2022; 1:100032. [PMID: 37193047 PMCID: PMC10120309 DOI: 10.1016/j.cellin.2022.100032] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 12/20/2021] [Revised: 05/20/2022] [Accepted: 05/21/2022] [Indexed: 05/18/2023]
Abstract
Infection of the stomach by Helicobacter pylori is a major risk factor for the development of gastric cancer. Colonization of the gastric epithelium leads to the activation of multiple disease-related signaling pathways. Serine protease HtrA represents an important secreted virulence factor that mediates cleavage of cellular junctions. However, its potential role in nuclear responses is unknown. Here, we performed a genome-wide RNA-seq analysis of polarized gastric epithelial cells infected by wild-type (wt) and ΔhtrA mutant bacteria. Fluorescence microscopy showed that H. pylori wt, but not ΔhtrA bacteria, preferably localized at cellular junctions. Our results pinpointed early (2 h) and late (6 h) transcriptional responses, with most differentially expressed genes at 6 h post infection. The transcriptomes revealed HtrA-dependent targeting of genes associated with inflammation and apoptosis (e.g. IL8, ZFP36, TNF). Accordingly, infection with the ΔhtrA mutant induced increased apoptosis rates in host cells, which was associated with reduced H. pylori CagA expression. In contrast, transcription of various carcinogenesis-associated genes (e.g. DKK1, DOCK8) was affected by H. pylori independent of HtrA. These findings suggest that H. pylori disturbs previously unknown molecular pathways in an HtrA-dependent and HtrA-independent manner, and provide valuable new insights of this significant pathogen in humans and thus potential targets for better controlling the risk of malignant transformation.
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Affiliation(s)
- Irshad Sharafutdinov
- Department of Biology, Division of Microbiology, Friedrich Alexander Universität Erlangen-Nürnberg, Staudtstr. 5, D-91058, Erlangen, Germany
| | - Arif Ekici
- Institute of Human Genetics, University Hospital, Friedrich Alexander Universität Erlangen-Nürnberg, Schwabachanlage 10, D-91054, Erlangen, Germany
| | - Michael Vieth
- Institute of Pathology, Friedrich-Alexander-Universität Erlangen-Nürnberg, Klinikum Bayreuth, Preuschwitzer Str 101, D-95445, Bayreuth, Germany
| | - Steffen Backert
- Department of Biology, Division of Microbiology, Friedrich Alexander Universität Erlangen-Nürnberg, Staudtstr. 5, D-91058, Erlangen, Germany
| | - Bodo Linz
- Department of Biology, Division of Microbiology, Friedrich Alexander Universität Erlangen-Nürnberg, Staudtstr. 5, D-91058, Erlangen, Germany
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3
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Hu Z, Zhang C, Sifuentes-Dominguez L, Zarek CM, Propheter DC, Kuang Z, Wang Y, Pendse M, Ruhn KA, Hassell B, Behrendt CL, Zhang B, Raj P, Harris-Tryon TA, Reese TA, Hooper LV. Small proline-rich protein 2A is a gut bactericidal protein deployed during helminth infection. Science 2021; 374:eabe6723. [PMID: 34735226 DOI: 10.1126/science.abe6723] [Citation(s) in RCA: 53] [Impact Index Per Article: 13.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
A diverse group of antimicrobial proteins (AMPs) helps protect the mammalian intestine from varied microbial challenges. We show that small proline-rich protein 2A (SPRR2A) is an intestinal antibacterial protein that is phylogenetically unrelated to previously discovered mammalian AMPs. In this study, SPRR2A was expressed in Paneth cells and goblet cells and selectively killed Gram-positive bacteria by disrupting their membranes. SPRR2A shaped intestinal microbiota composition, restricted bacterial association with the intestinal surface, and protected against Listeria monocytogenes infection. SPRR2A differed from other intestinal AMPs in that it was induced by type 2 cytokines produced during helminth infection. Moreover, SPRR2A protected against helminth-induced bacterial invasion of intestinal tissue. Thus, SPRR2A is a distinctive AMP triggered by type 2 immunity that protects the intestinal barrier during helminth infection.
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Affiliation(s)
- Zehan Hu
- Department of Immunology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.,Howard Hughes Medical Institute, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
| | - Chenlu Zhang
- Department of Dermatology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
| | - Luis Sifuentes-Dominguez
- Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
| | - Christina M Zarek
- Department of Immunology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
| | - Daniel C Propheter
- Department of Immunology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
| | - Zheng Kuang
- Department of Immunology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
| | - Yuhao Wang
- Department of Immunology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
| | - Mihir Pendse
- Department of Immunology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
| | - Kelly A Ruhn
- Department of Immunology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
| | - Brian Hassell
- Department of Immunology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
| | - Cassie L Behrendt
- Department of Immunology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
| | - Bo Zhang
- Department of Immunology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
| | - Prithvi Raj
- Department of Immunology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
| | - Tamia A Harris-Tryon
- Department of Dermatology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
| | - Tiffany A Reese
- Department of Immunology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
| | - Lora V Hooper
- Department of Immunology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.,Howard Hughes Medical Institute, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
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4
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Mamgain G, Patra P, Naithani M, Nath UK. The Role of Microbiota in the Development of Cancer Tumour Cells and Lymphoma of B and T Cells. Cureus 2021; 13:e19047. [PMID: 34853760 PMCID: PMC8608681 DOI: 10.7759/cureus.19047] [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] [Accepted: 10/25/2021] [Indexed: 11/26/2022] Open
Abstract
Human body harbours enormous numbers of microbial organisms, including bacteria, viruses, and fungi which have a momentous role in well-being and illness in humans. Immune system shelters us from pathogenic bacteria, microorganisms found in human tissues have many benefits related to the functional movement of the host by regulating important procedures such as immunity, signalling, and breakdown. Lymphocytes assume a significant part in the reaction to bacterial colonization, primarily by prompting a safe reaction to obstruction or initiation. Most immunologically occupant cells have a place with the mucosal invulnerable framework and are continually motioned by dendritic cells or other Antigen introducing cells that gather intestinal samples. Thus, Microbiome is a key contributor to developing lymphoma and specific alterations to microbiome composition could attenuate the risk. There is an indication that microbial morphology can affect and control humanoids. The difference in the composition of these microorganisms is associated with tumour development. With the increased knowledge of the connection among the human microbiome and carcinogenesis, the use of these findings to prevent, predict or diagnose of lymphomas has attracted a great attention. In this article, we explored current knowledge of various microbial ecosystems, their connection with carcinogens and the potential for useful microorganisms to control and prevent B and T cell lymphoma.
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Affiliation(s)
- Garima Mamgain
- Medical Oncology and Haematology, All India Institute of Medical Sciences, Rishikesh, IND
| | - Priyanka Patra
- Biochemistry, All India Institute of Medical Sciences, Rishikesh, IND
| | - Manisha Naithani
- Biochemistry & Advanced Center of Continuous Professional Development, All India Institute of Medical Sciences, Rishikesh, IND
| | - Uttam Kumar Nath
- Medical Oncology and Haematology, All India Institute of Medical Sciences, Rishikesh, IND
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5
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Huynh KM, Wong ACY, Wu B, Horschman M, Zhao H, Brooks JD. Sprr2f protects against renal injury by decreasing the level of reactive oxygen species in female mice. Am J Physiol Renal Physiol 2020; 319:F876-F884. [PMID: 33017192 DOI: 10.1152/ajprenal.00318.2020] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/28/2022] Open
Abstract
Renal injury leads to chronic kidney disease, with which women are not only more likely to be diagnosed than men but have poorer outcomes as well. We have previously shown that expression of small proline-rich region 2f (Sprr2f), a member of the small proline-rich region (Sprr) gene family, is increased several hundredfold after renal injury using a unilateral ureteral obstruction (UUO) mouse model. To better understand the role of Sprr2f in renal injury, we generated a Sprr2f knockout (Sprr2f-KO) mouse model using CRISPR-Cas9 technology. Sprr2f-KO female mice showed greater renal damage after UUO compared with wild-type (Sprr2f-WT) animals, as evidenced by higher hydroxyproline levels and denser collagen staining, indicating a protective role of Sprr2f during renal injury. Gene expression profiling by RNA sequencing identified 162 genes whose expression levels were significantly different between day 0 and day 5 after UUO in Sprr2f-KO mice. Of the 162 genes, 121 genes were upregulated after UUO and enriched with those involved in oxidation-reduction, a phenomenon not observed in Sprr2f-WT animals, suggesting a protective role of Sprr2f in UUO through defense against oxidative damage. Consistently, bilateral ischemia-reperfusion injury resulted in higher serum blood urea nitrogen levels and higher tissue reactive oxygen species in Sprr2f-KO compared with Sprr2f-WT female mice. Moreover, cultured renal epithelial cells from Sprr2f-KO female mice showed lower viability after oxidative damage induced by menadione compared with Sprr2f-WT cells that could be rescued by supplementation with reduced glutathione, suggesting that Sprr2f induction after renal damage acts as a defense against reactive oxygen species.
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Affiliation(s)
- Kieu My Huynh
- Department of Urology, School of Medicine, Stanford University, Stanford, California
| | - Anny Chuu-Yun Wong
- Department of Urology, School of Medicine, Stanford University, Stanford, California
| | - Bo Wu
- Department of Urology, School of Medicine, Stanford University, Stanford, California
| | - Marc Horschman
- Department of Urology, School of Medicine, Stanford University, Stanford, California
| | - Hongjuan Zhao
- Department of Urology, School of Medicine, Stanford University, Stanford, California
| | - James D Brooks
- Department of Urology, School of Medicine, Stanford University, Stanford, California
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Podgorny OV, Lazarev VN. Laser microdissection: A promising tool for exploring microorganisms and their interactions with hosts. J Microbiol Methods 2017; 138:82-92. [PMID: 26775287 DOI: 10.1016/j.mimet.2016.01.001] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2015] [Revised: 11/11/2015] [Accepted: 01/01/2016] [Indexed: 12/14/2022]
Abstract
Laser microdissection is a method that allows for the isolation of homogenous cell populations from their native niches in tissues for downstream molecular assays. This method is widely used for genomic analysis, gene expression profiling and proteomic and metabolite assays in various fields of biology, but it remains an uncommon approach in microbiological research. In spite of the limited number of publications, laser microdissection was shown to be an extremely useful method for studying host-microorganism interactions in animals and plants, investigating bacteria within biofilms, identifying uncultivated bacteria and performing single prokaryotic cell analysis. The current paper describes the methodological aspects of commercially available laser microdissection instruments and representative examples that demonstrate the advantages of this method for resolving a variety of issues in microbiology.
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Affiliation(s)
- Oleg V Podgorny
- Federal Research and Clinical Center of Physical-Chemical Medicine of Federal Medical Biological Agency, 1a Malaya Pirogovskaya Str., Moscow 119435, Russia; Koltzov Institute of Developmental Biology of the Russian Academy of Sciences, 26 Vavilov Str., Moscow 119334, Russia.
| | - Vassili N Lazarev
- Federal Research and Clinical Center of Physical-Chemical Medicine of Federal Medical Biological Agency, 1a Malaya Pirogovskaya Str., Moscow 119435, Russia
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Floch P, Izotte J, Guillemaud J, Sifré E, Costet P, Rousseau B, Laur AM, Giese A, Korolik V, Mégraud F, Dubus P, Hahne M, Lehours P. A New Animal Model of Gastric Lymphomagenesis. THE AMERICAN JOURNAL OF PATHOLOGY 2017; 187:1473-1484. [DOI: 10.1016/j.ajpath.2017.03.004] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/06/2017] [Revised: 02/27/2017] [Accepted: 03/09/2017] [Indexed: 12/29/2022]
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8
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Zhang Y, Wei Z, Li J, Liu P. Molecular pathogenesis of lymphomas of mucosa-associated lymphoid tissue--from (auto)antigen driven selection to the activation of NF-κB signaling. SCIENCE CHINA-LIFE SCIENCES 2015; 58:1246-55. [PMID: 26612043 DOI: 10.1007/s11427-015-4977-2] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/16/2015] [Accepted: 10/16/2015] [Indexed: 12/14/2022]
Abstract
Lymphomas of mucosa-associated lymphoid tissue (MALT) are typically present at sites such as the stomach, lung or urinary tract, where lymphoid tissues scatter in mucosa lamina propria, intra- or sub-epithelial cells. The infection of certain pathogens, such as Helicobacter pylori, Chlamydophila psittaci, Borrelia burgdorferi, hepatitis C virus, or certain autoantigens cause these sites to generate a germinal center called the "acquired lymphoid tissue". The molecular pathogenesis of MALT lymphoma is a multi-step process. Receptor signaling, such as the contact stimulation of B cell receptors and CD4 positive T cells mediated by CD40/CD40-ligand and T helper cell type 2 cytokines like interleukin-4, contributes to tumor cell proliferation. A number of genetic alterations have been identified in MALT lymphoma, and among them are important translocations, such as t(11;18)(q21;q21), t(1;14)(p22;q32), t(14;18)(q32;q21) and t(3;14)(p13;q32). Fusion proteins generated by these translocations share the same NF-κB signaling pathway, which is activated by the caspase activation and recruitment domain containing molecules of the membrane associated guanylate kinase family, B cell lymphoma-10 and MALT1 (CBM) protein complex. They act downstream of cell surface receptors, such as B cell receptors, T cell receptors, B cell activating factors and Toll-like receptors, and participate in the biological process of MALT lymphoma. The discovery of therapeutic drugs that exclusively inhibit the antigen receptor signaling pathway will be beneficial for the treatment of B cell lymphomas in the future.
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Affiliation(s)
- YiAn Zhang
- Department of Hematology, Zhongshan Hospital, Fudan University, Shanghai, 200032, China
| | - Zheng Wei
- Department of Hematology, Zhongshan Hospital, Fudan University, Shanghai, 200032, China
| | - Jing Li
- Department of Hematology, Zhongshan Hospital, Fudan University, Shanghai, 200032, China
| | - Peng Liu
- Department of Hematology, Zhongshan Hospital, Fudan University, Shanghai, 200032, China.
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9
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Abstract
The intestinal microbiota and gut immune system must communicate to maintain a balance between tolerance and activation. Our immune system protects us from pathogenic microbes at the same time that our bodies are host to trillions of microbes, symbionts, mutualists, and some that are essential to human health. Since there is such a close interaction between the immune system and the intestinal microbiota, it is not surprising that some lymphomas such as mucosal-associated lymphoid tissue lymphoma have been shown to be caused by the presence of certain bacteria. Animal models have played an important role in elucidating the causation and establishing the mechanism of bacteria-induced mucosal-associated lymphoid tissue lymphoma. In this review, we discuss different ways that animal models have been applied to investigate links between the gut microbiota and lymphoma and have helped to reveal the mechanisms of microbiota-induced lymphoma. Although there is a paucity of published studies demonstrating the interplay between the microbiota and lymphoma development, we believe that the connection is real and that it can be exploited in the future to enhance our understanding of causation and to improve the prognosis and treatment of lymphoma.
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10
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Gaddy JA, Radin JN, Loh JT, Piazuelo MB, Kehl-Fie TE, Delgado AG, Ilca FT, Peek RM, Cover TL, Chazin WJ, Skaar EP, Scott Algood HM. The host protein calprotectin modulates the Helicobacter pylori cag type IV secretion system via zinc sequestration. PLoS Pathog 2014; 10:e1004450. [PMID: 25330071 PMCID: PMC4199781 DOI: 10.1371/journal.ppat.1004450] [Citation(s) in RCA: 70] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2014] [Accepted: 09/04/2014] [Indexed: 12/11/2022] Open
Abstract
Transition metals are necessary for all forms of life including microorganisms, evidenced by the fact that 30% of all proteins are predicted to interact with a metal cofactor. Through a process termed nutritional immunity, the host actively sequesters essential nutrient metals away from invading pathogenic bacteria. Neutrophils participate in this process by producing several metal chelating proteins, including lactoferrin and calprotectin (CP). As neutrophils are an important component of the inflammatory response directed against the bacterium Helicobacter pylori, a major risk factor for gastric cancer, it was hypothesized that CP plays a role in the host response to H. pylori. Utilizing a murine model of H. pylori infection and gastric epithelial cell co-cultures, the role CP plays in modifying H. pylori -host interactions and the function of the cag Type IV Secretion System (cag T4SS) was investigated. This study indicates elevated gastric levels of CP are associated with the infiltration of neutrophils to the H. pylori-infected tissue. When infected with an H. pylori strain harboring a functional cag T4SS, calprotectin-deficient mice exhibited decreased bacterial burdens and a trend toward increased cag T4SS -dependent inflammation compared to wild-type mice. In vitro data demonstrate that culturing H. pylori with sub-inhibitory doses of CP reduces the activity of the cag T4SS and the biogenesis of cag T4SS-associated pili in a zinc-dependent fashion. Taken together, these data indicate that zinc homeostasis plays a role in regulating the proinflammatory activity of the cag T4SS.
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Affiliation(s)
- Jennifer A. Gaddy
- Veterans Affairs Tennessee Valley Healthcare Services, Nashville, Tennessee, United States of America
- Department of Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee, United States of America
| | - Jana N. Radin
- Department of Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee, United States of America
| | - John T. Loh
- Department of Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee, United States of America
| | - M. Blanca Piazuelo
- Department of Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee, United States of America
| | - Thomas E. Kehl-Fie
- Department of Pathology, Microbiology and Immunology, Vanderbilt University School of Medicine, Nashville, Tennessee, United States of America
| | - Alberto G. Delgado
- Department of Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee, United States of America
| | - Florin T. Ilca
- Department of Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee, United States of America
| | - Richard M. Peek
- Department of Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee, United States of America
| | - Timothy L. Cover
- Veterans Affairs Tennessee Valley Healthcare Services, Nashville, Tennessee, United States of America
- Department of Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee, United States of America
- Department of Pathology, Microbiology and Immunology, Vanderbilt University School of Medicine, Nashville, Tennessee, United States of America
| | - Walter J. Chazin
- Department of Biochemistry, Vanderbilt University School of Medicine, Nashville, Tennessee, United States of America
- Center for Structural Biology, Vanderbilt University School of Medicine, Nashville, Tennessee, United States of America
| | - Eric P. Skaar
- Veterans Affairs Tennessee Valley Healthcare Services, Nashville, Tennessee, United States of America
- Department of Pathology, Microbiology and Immunology, Vanderbilt University School of Medicine, Nashville, Tennessee, United States of America
| | - Holly M. Scott Algood
- Veterans Affairs Tennessee Valley Healthcare Services, Nashville, Tennessee, United States of America
- Department of Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee, United States of America
- Department of Pathology, Microbiology and Immunology, Vanderbilt University School of Medicine, Nashville, Tennessee, United States of America
- * E-mail:
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11
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Yamamoto ML, Schiestl RH. Lymphoma caused by intestinal microbiota. INTERNATIONAL JOURNAL OF ENVIRONMENTAL RESEARCH AND PUBLIC HEALTH 2014; 11:9038-49. [PMID: 25257357 PMCID: PMC4199005 DOI: 10.3390/ijerph110909038] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 06/17/2014] [Revised: 08/14/2014] [Accepted: 08/15/2014] [Indexed: 12/17/2022]
Abstract
The intestinal microbiota and gut immune system must constantly communicate to maintain a balance between tolerance and activation: on the one hand, our immune system should protect us from pathogenic microbes and on the other hand, most of the millions of microbes in and on our body are innocuous symbionts and some can even be beneficial. Since there is such a close interaction between the immune system and the intestinal microbiota, it is not surprising that some lymphomas such as mucosal-associated lymphoid tissue (MALT) lymphoma have been shown to be caused by the presence of certain bacteria. Animal models played an important role in establishing causation and mechanism of bacteria-induced MALT lymphoma. In this review we discuss different ways that animal models have been applied to establish a link between the gut microbiota and lymphoma and how animal models have helped to elucidate mechanisms of microbiota-induced lymphoma. While there are not a plethora of studies demonstrating a connection between microbiota and lymphoma development, we believe that animal models are a system which can be exploited in the future to enhance our understanding of causation and improve prognosis and treatment of lymphoma.
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Affiliation(s)
- Mitsuko L Yamamoto
- Department of Pathology, Environmental Health and Radiation Oncology, University of California, Los Angeles, Schools of Medicine and Public Health, 10833 Le Conte Ave, Los Angeles, CA 90095, USA.
| | - Robert H Schiestl
- Department of Pathology, Environmental Health and Radiation Oncology, University of California, Los Angeles, Schools of Medicine and Public Health, 10833 Le Conte Ave, Los Angeles, CA 90095, USA.
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12
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Chrisment D, Dubus P, Chambonnier L, Hocès de la Guardia A, Sifré E, Giese A, Capone M, Khairallah C, Costet P, Rousseau B, Hubert C, Burlen-Defranoux O, Varon C, Bandeira A, Mégraud F, Lehours P. Neonatal thymectomy favors Helicobacter pylori-promoted gastric mucosa-associated lymphoid tissue lymphoma lesions in BALB/c mice. THE AMERICAN JOURNAL OF PATHOLOGY 2014; 184:2174-84. [PMID: 24909507 DOI: 10.1016/j.ajpath.2014.04.008] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Subscribe] [Scholar Register] [Received: 03/04/2014] [Revised: 04/16/2014] [Accepted: 04/22/2014] [Indexed: 01/26/2023]
Abstract
Neonatal thymectomy in BALB/c mice has been described as a model of gastric mucosa-associated lymphoid tissue (MALT) lymphoma (GML). By using this experimental system, we screened, for the first time to our knowledge, Helicobacter pylori GML-associated strains for their capacity to promote disease. A cohort of BALB/c mice underwent thymectomy at day 3 after birth (d3Tx). Successful thymic ablation was evaluated by the degree of lymphopenia in blood samples collected at 4 weeks of age. d3Tx and non-thymectomized controls were infected with either GML strains (B38 or B47) or control strains (SS1 or TN2GF4). Gastric samples collected at 6, 12, and 18 months after infection were studied for bacteria content, and submitted to histological, immunochemical, molecular, and immunological analyses. Severe gastric inflammation was only observed in d3Tx mice. In these animals, the gastric lamina propria was infiltrated with lymphoid cells organized in follicles composed of B cells with few infiltrating T cells. PCR of D/J IgH gene segments proved the monoclonality of infiltrating B cells, which strongly correlated with the presence of lymphoepithelial lesions. B-cell infiltrates were particularly prominent in mice infected with the B47-GML strain. No pathological changes were detected in noninfected d3Tx mice. We identified new H. pylori isolates adapted to the mouse stomach with high potential of GML development, which is only revealed in hosts rendered lymphopenic by neonatal thymic ablation.
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Affiliation(s)
- Delphine Chrisment
- Bacteriology Laboratory, University of Bordeaux, Bordeaux, France; INSERM U853, Bordeaux, France
| | - Pierre Dubus
- EA 2406, University of Bordeaux, Bordeaux, France
| | - Lucie Chambonnier
- Bacteriology Laboratory, University of Bordeaux, Bordeaux, France; INSERM U853, Bordeaux, France
| | | | - Elodie Sifré
- Bacteriology Laboratory, University of Bordeaux, Bordeaux, France; INSERM U853, Bordeaux, France
| | - Alban Giese
- EA 2406, University of Bordeaux, Bordeaux, France
| | - Myriam Capone
- National Center for Scientific Research (CNRS) UMR 5164 Innate Components of the Immune Response and Differentiation (CIRID), University of Bordeaux, Bordeaux, France
| | - Camille Khairallah
- National Center for Scientific Research (CNRS) UMR 5164 Innate Components of the Immune Response and Differentiation (CIRID), University of Bordeaux, Bordeaux, France
| | - Pierre Costet
- Animalerie Spécialisée, University of Bordeaux, Bordeaux, France
| | | | - Christophe Hubert
- Functional Genomics Center, the Genome Transcription Platform, University of Bordeaux, Bordeaux, France
| | | | - Christine Varon
- Bacteriology Laboratory, University of Bordeaux, Bordeaux, France; INSERM U853, Bordeaux, France
| | | | - Francis Mégraud
- Bacteriology Laboratory, University of Bordeaux, Bordeaux, France; INSERM U853, Bordeaux, France
| | - Philippe Lehours
- Bacteriology Laboratory, University of Bordeaux, Bordeaux, France; INSERM U853, Bordeaux, France.
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Kypriotou M, Boéchat C, Huber M, Hohl D. Spontaneous atopic dermatitis-like symptoms in a/a ma ft/ma ft/J flaky tail mice appear early after birth. PLoS One 2013; 8:e67869. [PMID: 23844115 PMCID: PMC3700905 DOI: 10.1371/journal.pone.0067869] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/27/2012] [Accepted: 05/21/2013] [Indexed: 01/27/2023] Open
Abstract
Loss-of-function mutations in human profilaggrin gene have been identified as the cause of ichthyosis vulgaris (IV), and as a major predisposition factor for atopic dermatitis (AD). Similarly, flaky tail (a/a ma ft/ma ft/J) mice were described as a model for IV, and shown to be predisposed to eczema. The aim of this study was to correlate the flaky tail mouse phenotype with human IV and AD, in order to dissect early molecular events leading to atopic dermatitis in mice and men, suffering from filaggrin deficiency. Thus, 5-days old flaky tail pups were analyzed histologically, expression of cytokines was measured in skin and signaling pathways were investigated by protein analysis. Human biopsies of IV and AD patients were analyzed histologically and by real time PCR assays. Our data show acanthosis and hyperproliferation in flaky tail epidermis, associated with increased IL1β and thymic stromal lymphopoietin (TSLP) expression, and Th2-polarization. Consequently, NFκB and Stat pathways were activated, and IL6 mRNA levels were increased. Further, quantitative analysis of late epidermal differentiation markers revealed increased Small proline-rich protein 2A (Sprr2a) synthesis. Th2-polarization and Sprr2a increase may result from high TSLP expression, as shown after analysis of 5-days old K14-TSLP tg mouse skin biopsies. Our findings in the flaky tail mouse correlate with data obtained from patient biopsies of AD, but not IV. We propose that proinflammatory cytokines are responsible for acanthosis in flaky tail epidermis, and together with the Th2-derived cytokines lead to morphological changes. Accordingly, the a/a ma ft/ma ft/J mouse model can be used as an appropriate model to study early AD onset associated with profilaggrin deficiency.
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Affiliation(s)
- Magdalini Kypriotou
- Laboratory of Cutaneous Biology, Service of Dermatology and Venereology, Beaumont Hospital CHUV, Lausanne, Switzerland
| | - Cloé Boéchat
- Laboratory of Cutaneous Biology, Service of Dermatology and Venereology, Beaumont Hospital CHUV, Lausanne, Switzerland
| | - Marcel Huber
- Laboratory of Cutaneous Biology, Service of Dermatology and Venereology, Beaumont Hospital CHUV, Lausanne, Switzerland
| | - Daniel Hohl
- Laboratory of Cutaneous Biology, Service of Dermatology and Venereology, Beaumont Hospital CHUV, Lausanne, Switzerland
- * E-mail:
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Russ AE, Peters JS, McNabb WC, Barnett MPG, Anderson RC, Park Z, Zhu S, Maclean P, Young W, Reynolds GW, Roy NC. Gene expression changes in the colon epithelium are similar to those of intact colon during late inflammation in interleukin-10 gene deficient mice. PLoS One 2013; 8:e63251. [PMID: 23700416 PMCID: PMC3659096 DOI: 10.1371/journal.pone.0063251] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2012] [Accepted: 04/01/2013] [Indexed: 01/08/2023] Open
Abstract
In addition to their role in absorption and secretion, epithelial cells play an important role in the protection of the colon mucosa from the resident microbiota and are important for the maintenance of homeostasis. Microarray analysis of intact colon samples is widely used to gain an overview of the cellular pathways and processes that are active in the colon during inflammation. Laser microdissection of colon epithelial cells allows a more targeted analysis of molecular pathways in the mucosa, preceding and during inflammation, with potentially increased sensitivity to changes in specific cell populations. The aim of this study was to investigate the molecular changes that occur in early and late inflammation stages in colon epithelium of a mouse model of inflammatory bowel diseases. Microarray analysis of intact colon samples and microdissected colon epithelial cell samples from interleukin-10 gene deficient and control mice at 6 and 12 weeks of age was undertaken. Results of gene set enrichment analysis showed that more immune-related pathways were identified between interleukin-10 gene deficient and control mice at 6 weeks of age in epithelial cells than intact colon. This suggests that targeting epithelial cells could increase sensitivity for detecting immune changes that occur early in the inflammatory process. However, in the later stages of inflammation, microarray analyses of intact colon and epithelium both provide a similar overview of gene expression changes in the colon mucosa at the pathway level.
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Affiliation(s)
- Anna E. Russ
- Food Nutrition & Health Team, Food & Bio-based Products Group, AgResearch Grasslands, Palmerston North, New Zealand
- Institute of Food Nutrition and Human Health, Massey University, Palmerston North, New Zealand
| | - Jason S. Peters
- Food Nutrition & Health Team, Food & Bio-based Products Group, AgResearch Grasslands, Palmerston North, New Zealand
| | - Warren C. McNabb
- Riddet Institute, Massey University, Palmerston North, New Zealand
- AgResearch Grasslands, Palmerston North, New Zealand
| | - Matthew P. G. Barnett
- Food Nutrition & Health Team, Food & Bio-based Products Group, AgResearch Grasslands, Palmerston North, New Zealand
| | - Rachel C. Anderson
- Food Nutrition & Health Team, Food & Bio-based Products Group, AgResearch Grasslands, Palmerston North, New Zealand
| | - Zaneta Park
- Bioinformatics & Statistics, AgResearch, Hamilton, New Zealand
| | - Shuotun Zhu
- Discipline of Nutrition, Faculty of Medicine and Health Sciences, The University of Auckland, Auckland, New Zealand
- Auckland Cancer Society Research Centre, The University of Auckland, Auckland, New Zealand
| | - Paul Maclean
- Bioinformatics & Statistics, AgResearch, Hamilton, New Zealand
| | - Wayne Young
- Food Nutrition & Health Team, Food & Bio-based Products Group, AgResearch Grasslands, Palmerston North, New Zealand
| | - Gordon W. Reynolds
- Institute of Food Nutrition and Human Health, Massey University, Palmerston North, New Zealand
| | - Nicole C. Roy
- Food Nutrition & Health Team, Food & Bio-based Products Group, AgResearch Grasslands, Palmerston North, New Zealand
- Riddet Institute, Massey University, Palmerston North, New Zealand
- * E-mail:
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15
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Ahn SH, Tsalik EL, Cyr DD, Zhang Y, van Velkinburgh JC, Langley RJ, Glickman SW, Cairns CB, Zaas AK, Rivers EP, Otero RM, Veldman T, Kingsmore SF, Lucas J, Woods CW, Ginsburg GS, Fowler VG. Gene expression-based classifiers identify Staphylococcus aureus infection in mice and humans. PLoS One 2013; 8:e48979. [PMID: 23326304 PMCID: PMC3541361 DOI: 10.1371/journal.pone.0048979] [Citation(s) in RCA: 43] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2012] [Accepted: 09/27/2012] [Indexed: 12/31/2022] Open
Abstract
Staphylococcus aureus causes a spectrum of human infection. Diagnostic delays and uncertainty lead to treatment delays and inappropriate antibiotic use. A growing literature suggests the host’s inflammatory response to the pathogen represents a potential tool to improve upon current diagnostics. The hypothesis of this study is that the host responds differently to S. aureus than to E. coli infection in a quantifiable way, providing a new diagnostic avenue. This study uses Bayesian sparse factor modeling and penalized binary regression to define peripheral blood gene-expression classifiers of murine and human S. aureus infection. The murine-derived classifier distinguished S. aureus infection from healthy controls and Escherichia coli-infected mice across a range of conditions (mouse and bacterial strain, time post infection) and was validated in outbred mice (AUC>0.97). A S. aureus classifier derived from a cohort of 94 human subjects distinguished S. aureus blood stream infection (BSI) from healthy subjects (AUC 0.99) and E. coli BSI (AUC 0.84). Murine and human responses to S. aureus infection share common biological pathways, allowing the murine model to classify S. aureus BSI in humans (AUC 0.84). Both murine and human S. aureus classifiers were validated in an independent human cohort (AUC 0.95 and 0.92, respectively). The approach described here lends insight into the conserved and disparate pathways utilized by mice and humans in response to these infections. Furthermore, this study advances our understanding of S. aureus infection; the host response to it; and identifies new diagnostic and therapeutic avenues.
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Affiliation(s)
- Sun Hee Ahn
- Division of Infectious Diseases and International Health, Department of Medicine, Duke University, Durham, North Carolina, United States of America
| | - Ephraim L. Tsalik
- Division of Infectious Diseases and International Health, Department of Medicine, Duke University, Durham, North Carolina, United States of America
- Section on Infectious Diseases, Durham Veteran’s Affairs Medical Center, Durham, North Carolina, United States of America
| | - Derek D. Cyr
- Duke Institute for Genome Sciences and Policy, Duke University, Durham, North Carolina, United States of America
| | - Yurong Zhang
- Division of Infectious Diseases and International Health, Department of Medicine, Duke University, Durham, North Carolina, United States of America
| | - Jennifer C. van Velkinburgh
- van Velkinburgh Initiative for Collaborative BioMedical Research, Santa Fe, New Mexico, United States of America
| | - Raymond J. Langley
- Immunology Division, Lovelace Respiratory Research Institute, Albuquerque, New Mexico, United States of America
| | - Seth W. Glickman
- Department of Emergency Medicine, University of North Carolina School of Medicine, Chapel Hill, North Carolina, United States of America
| | - Charles B. Cairns
- Department of Emergency Medicine, University of North Carolina School of Medicine, Chapel Hill, North Carolina, United States of America
| | - Aimee K. Zaas
- Division of Infectious Diseases and International Health, Department of Medicine, Duke University, Durham, North Carolina, United States of America
- Duke Institute for Genome Sciences and Policy, Duke University, Durham, North Carolina, United States of America
| | - Emanuel P. Rivers
- Department of Emergency Medicine, Henry Ford Hospital, Wayne State University, Detroit, Michigan, United States of America
| | - Ronny M. Otero
- Department of Emergency Medicine, Henry Ford Hospital, Wayne State University, Detroit, Michigan, United States of America
| | - Tim Veldman
- Duke Institute for Genome Sciences and Policy, Duke University, Durham, North Carolina, United States of America
| | - Stephen F. Kingsmore
- Center for Pediatric Genomic Medicine, Children’s Mercy Hospitals and Clinics, Kansas City, Missouri, United States of America
| | - Joseph Lucas
- Duke Institute for Genome Sciences and Policy, Duke University, Durham, North Carolina, United States of America
| | - Christopher W. Woods
- Division of Infectious Diseases and International Health, Department of Medicine, Duke University, Durham, North Carolina, United States of America
- Section on Infectious Diseases, Durham Veteran’s Affairs Medical Center, Durham, North Carolina, United States of America
- Duke Institute for Genome Sciences and Policy, Duke University, Durham, North Carolina, United States of America
| | - Geoffrey S. Ginsburg
- Duke Institute for Genome Sciences and Policy, Duke University, Durham, North Carolina, United States of America
- * E-mail: (GSG); (VGF)
| | - Vance G. Fowler
- Division of Infectious Diseases and International Health, Department of Medicine, Duke University, Durham, North Carolina, United States of America
- Duke Institute for Genome Sciences and Policy, Duke University, Durham, North Carolina, United States of America
- Duke Clinical Research Institute, Durham, North Carolina, United States of America
- * E-mail: (GSG); (VGF)
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16
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Walduck AK, Becher D. Leptin, CD4(+) T(reg) and the prospects for vaccination against H. pylori infection. Front Immunol 2012; 3:316. [PMID: 23087691 PMCID: PMC3470998 DOI: 10.3389/fimmu.2012.00316] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2012] [Accepted: 09/24/2012] [Indexed: 12/15/2022] Open
Abstract
Helicobacter pylori infection induces chronic inflammation which is characterized not only by infiltrations of inflammatory cells such as neutrophils and CD4+ T cells, but also significant populations of regulatory T cells (Treg). These cells are important for disease pathogenesis because they are believed to contribute to the persistence of the infection. Despite encouraging results in animal models, the prospects for an effective H. pylori vaccine are currently poor because of generally disappointing results in preclinical and phase 1 trials. As a result, a current major focus of basic research on vaccination is to better understand the mechanisms regulating the inflammatory response with the view it can inform future vaccine design. Our studies in this area have focused on gastric CD4+ Treg in vaccinated mice, and raised the hypothesis that adipokines in particular leptin are involved the establishment of a protective gastric immune response. Here we discuss the hypothesis that vaccination deregulates Treg responses in the gastric mucosa, and that this process is mediated by leptin. We propose that reduced suppression permits a protective sub population of H. pylori-specific CD4+ T cells to exert protective effects, presumably via the gastric epithelium. Evidence from the literature and experimental approaches will be discussed.
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Affiliation(s)
- Anna K Walduck
- Department of Microbiology and Immunology, University of Melbourne Parkville, VIC, Australia
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17
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Raj GD, Rajanathan TMC, Kumanan K, Elankumaran S. Changes in the Cytokine and Toll-Like Receptor Gene Expression Following Infection of Indigenous and Commercial Chickens With Infectious bursal disease virus. INDIAN JOURNAL OF VIROLOGY : AN OFFICIAL ORGAN OF INDIAN VIROLOGICAL SOCIETY 2011; 22:146-51. [PMID: 23637518 DOI: 10.1007/s13337-011-0053-0] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/16/2011] [Accepted: 08/19/2011] [Indexed: 01/04/2023]
Abstract
A comparative study of cytokine and toll-like receptor (TLR) mRNA expression in 3 weeks old indigenous and commercial chickens infected with a very virulent strain of Infectious bursal disease virus (IBDV) was performed using a custom-made microarray chip. In uninfected indigenous chickens, the basal levels of interleukin (IL) 15 were lower and IL 16 was higher than their commercial counterparts. In the IBDV infected indigenous chickens, only IL16 gene expression was down regulated, while TLR3 expression was up regulated significantly. In the IBDV infected commercial chickens IL15, IL16 and TLR3 were down regulated. But, IL1-β, IL2, IL8, IL12, IL17, interferon (IFN)-α and β were significantly increased compared with the control. In IBDV infected indigenous chickens, IL15, IFN-γ, beta-defensin and TLR3 were up regulated compared to virus-infected commercial chickens. The results suggested that up regulation of TLR3, a ligand for double-stranded (ds) RNA probably could account for the possible clinical resistance in these birds. There was a 5.2 fold difference by quantitative real-time RT-PCR between indigenous and commercial chickens in TLR3 mRNA expression. Therefore, TLR3, a receptor for dsRNA could be a putative molecule that could play a role in differential innate and adaptive immune responses to IBDV in commercial and indigenous chickens.
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Affiliation(s)
- G Dhinakar Raj
- Department of Animal Biotechnology, Madras Veterinary College, Tamil Nadu Veterinary and Animal Sciences University, Chennai, 600007 India
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18
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Craig VJ, Cogliatti SB, Rehrauer H, Wündisch T, Müller A. Epigenetic silencing of microRNA-203 dysregulates ABL1 expression and drives Helicobacter-associated gastric lymphomagenesis. Cancer Res 2011; 71:3616-24. [PMID: 21454413 DOI: 10.1158/0008-5472.can-10-3907] [Citation(s) in RCA: 83] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/24/2023]
Abstract
Gastric B-cell lymphoma of mucosa-associated lymphoid tissue (MALT lymphoma) develops in the chronically inflamed mucosa of patients infected with the bacterial pathogen Helicobacter pylori. Here we use patient material, primary gastric lymphoma cell cultures, and a preclinical model of the disease to examine the role of microRNA (miRNA)-mediated posttranscriptional regulation--focusing in particular on miR-203 and its target ABL1--in gastric MALT lymphomagenesis. Microarray-based miRNA expression profiling revealed a strong downregulation of the putative tumor suppressor miRNA miR-203 in human MALT lymphoma samples, which resulted from extensive promoter hypermethylation of the miR-203 locus and coincided with the dysregulation of the miR-203 target ABL1 in lymphoma biopsies compared with matched adjacent normal material from the same patients. Treatment of lymphoma B cells with demethylating agents led to increased miR-203 expression and the concomitant downregulation of ABL1, confirming the epigenetic regulation of this miRNA. Ectopic reexpression of miR-203 by transfection of a human lymphoma cell line or lentiviral transduction of explanted primary MALT lymphoma cells was sufficient to prevent tumor cell proliferation in vitro. Similarly, the treatment of primary MALT lymphoma cells with the ABL inhibitors imatinib and dasatinib prevented tumor cell growth. Finally, we show that the treatment of tumor-bearing mice with imatinib induces MALT lymphoma regression in a preclinical model of the disease, implicating ABL1 in MALT lymphoma progression. In summary, our results show that the transformation from gastritis to MALT lymphoma is epigenetically regulated by miR-203 promoter methylation and identify ABL1 as a novel target for the treatment of this malignancy.
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Affiliation(s)
- Vanessa J Craig
- Institute of Molecular Cancer Research, University of Zürich, Zürich, Switzerland
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19
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Kallio H, Hilvo M, Rodriguez A, Lappalainen EH, Lappalainen AM, Parkkila S. Global transcriptional response to carbonic anhydrase IX deficiency in the mouse stomach. BMC Genomics 2010; 11:397. [PMID: 20573196 PMCID: PMC2996928 DOI: 10.1186/1471-2164-11-397] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2010] [Accepted: 06/23/2010] [Indexed: 12/13/2022] Open
Abstract
Background Carbonic anhydrases (CAs) are a family of enzymes that regulate pH homeostasis in various tissues. CA IX is an exceptional member of this family because in addition to the basic CA function, it has been implicated in several other physiological and pathological processes. Functions suggested for CA IX include roles in cell adhesion and malignant cell invasion. In addition, CA IX likely regulates cell proliferation and differentiation, which was demonstrated in Car9-/- mice. These mice had gastric pit cell hyperplasia and depletion of chief cells; however, the specific molecular mechanisms behind the observed phenotypes remain unknown. Therefore, we wanted to study the effect of CA IX deficiency on whole-genome gene expression in gastric mucosa. This was done using Illumina Sentrix®Mouse-6 Expression BeadChip arrays. The expression of several genes with notable fold change values was confirmed by QRT-PCR. Results CA IX deficiency caused the induction of 86 genes and repression of 46 genes in the gastric mucosa. There was 92.9% concordance between the results obtained by microarray analysis and QRT-PCR. The differentially expressed genes included those involved in developmental processes and cell differentiation. In addition, CA IX deficiency altered the expression of genes responsible for immune responses and downregulated the expression of several digestive enzymes. Conclusions Microarray analysis identified several potential genes whose altered expression could explain the disturbed cell lineage phenotype in the Car9-/- gastric mucosa. The results also indicated a novel role for CA IX in the regulation of immunologic processes and digestion. These findings reinforce the concept that the main role of CA IX is not the regulation of pH in the stomach mucosa. Instead, it is needed for proper function of several physiological processes.
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Affiliation(s)
- Heini Kallio
- Institute of Medical Technology and School of Medicine, University of Tampere, Biokatu 6, FI-33520 Tampere, Finland.
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20
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B-cell receptor signaling and CD40 ligand-independent T cell help cooperate in Helicobacter-induced MALT lymphomagenesis. Leukemia 2010; 24:1186-96. [PMID: 20428202 DOI: 10.1038/leu.2010.76] [Citation(s) in RCA: 72] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Gastric B-cell lymphoma of mucosa-associated lymphoid tissue (MALT) develops in the context of chronic inflammation caused by Helicobacter pylori infection. Most pathophysiological features of the early stages of MALT lymphomagenesis can be reproduced by experimental infection of BALB/c mice with Helicobacter species. We have previously shown that MALT lymphomas are infiltrated by T-helper cell type 2-polarized T cells and that human and murine tumor B cells carry polyreactive surface immunoglobulins. Using the murine model of the disease, in this study we show that explanted tumor B cells proliferate upon stimulation with the same panel of self and foreign antigens that are recognized by their surface antibodies. Tumor cell proliferation is strongly enhanced by the presence of intratumoral CD4(+) T cells in a CD40/CD40L-independent manner. A large proportion of tumor-infiltrating CD4(+) T cells are CD25(+)FoxP3(+) regulatory T cells (Tregs) with highly suppressive activity, which are recruited by the tumor cells through secretion of the Treg-attracting chemokines CCL17 and CCL22. The depletion of CD25(+) cells was as efficient as CD4(+) T cell depletion in blocking tumor growth in vitro and in vivo. In conclusion, our data suggest that B-cell receptor-derived signals cooperate with T-helper cell signals in driving the progression of MALT lymphoma, providing an explanation for the unique antigen dependence of this B-cell malignancy.
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21
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Abstract
Gastric B-cell lymphoma of mucosa-associated lymphoid tissue (MALT) arises against a background of chronic inflammation caused by persistent Helicobacter pylori infection. The clinical and histopathologic features of the human tumor can be reproduced by Helicobacter infection of BALB/c mice. In this study, we have analyzed the antibody sequences and antigen specificity of a panel of murine and human MALT lymphoma-derived antibodies. We find that a majority of tumors in patients as well as experimentally infected mice are monoclonal. The tumor immunoglobulin heavy chain genes have undergone somatic hypermutation, and approximately half of all tumors show evidence of intraclonal variation and positive and/or negative selective pressure. Recombinantly expressed MALT lymphoma antibodies bind with intermediate affinity to various unrelated self- and foreign antigens, including Helicobacter sonicate, immunoglobulin G (IgG), DNA, and stomach extract; antigen binding is blocked in a dose-dependent manner in competitive enzyme-linked immunosorbent assays. A strong bias toward the use of V(H) gene segments previously linked to autoantibodies and/or polyreactive antibodies in B-cell malignancies or autoimmune pathologies supports the experimental finding of polyreactivity. Our results suggest that MALT lymphoma development may be facilitated by an array of local self- and foreign antigens, providing direct antigenic stimulation of the tumor cells via their B-cell receptor.
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22
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D'Elia R, DeSchoolmeester ML, Zeef LAH, Wright SH, Pemberton AD, Else KJ. Expulsion of Trichuris muris is associated with increased expression of angiogenin 4 in the gut and increased acidity of mucins within the goblet cell. BMC Genomics 2009; 10:492. [PMID: 19852835 PMCID: PMC2774869 DOI: 10.1186/1471-2164-10-492] [Citation(s) in RCA: 26] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2008] [Accepted: 10/24/2009] [Indexed: 01/23/2023] Open
Abstract
Background Trichuris muris in the mouse is an invaluable model for infection of man with the gastrointestinal nematode Trichuris trichiura. Three T. muris isolates have been studied, the Edinburgh (E), the Japan (J) and the Sobreda (S) isolates. The S isolate survives to chronicity within the C57BL/6 host whereas E and J are expelled prior to reaching fecundity. How the S isolate survives so successfully in its host is unclear. Results Microarray analysis was used as a tool to identify genes whose expression could determine the differences in expulsion kinetics between the E and S T. muris isolates. Clear differences in gene expression profiles were evident as early as day 7 post-infection (p.i.). 43 probe sets associated with immune and defence responses were up-regulated in gut tissue from an E isolate-infected C57BL/6 mouse compared to tissue from an S isolate infection, including the message for the anti-microbial protein, angiogenin 4 (Ang4). This led to the identification of distinct differences in the goblet cell phenotype post-infection with the two isolates. Conclusion Differences in gene expression levels identified between the S and E-infected mice early during infection have furthered our knowledge of how the S isolate persists for longer than the E isolate in the C57BL/6 mouse. Potential new targets for manipulation in order to aid expulsion have been identified. Further we provide evidence for a potential new marker involving the acidity of the mucins within the goblet cell which may predict outcome of infection within days of parasite exposure.
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Affiliation(s)
- Riccardo D'Elia
- Faculty of Life Sciences, University of Manchester, Manchester, M13 9PT, UK.
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23
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Lehours P, Zheng Z, Skoglund A, Mégraud F, Engstrand L. Is there a link between the lipopolysaccharide of Helicobacter pylori gastric MALT lymphoma associated strains and lymphoma pathogenesis? PLoS One 2009; 4:e7297. [PMID: 19806222 PMCID: PMC2752801 DOI: 10.1371/journal.pone.0007297] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2009] [Accepted: 09/10/2009] [Indexed: 01/19/2023] Open
Abstract
The aim of this study was to investigate the Lewis antigen expression in Helicobacter pylori gastric MALT lymphoma associated strains in comparison to chronic gastritis only strains. Forty MALT strains (19 cagPAI (-) and 21 cagPAI (+)) and 39 cagPAI frequency-matched gastritis strains (17 cagPAI (-) and 22 cagPAI (+)) were included in this study. The lipopolyssacharide for each strain was extracted using a hot phenol method and the expression of Le(x) and Le(y) were investigated using Western Blot. The data were analyzed according to the strains' cagPAI status and vacA genotype. Le(x) was identified in 21 (52.5%) MALT strains and 29 (74.3%) gastritis strains. Le(y) was identified in 30 (75%) MALT strains and 31 (79.5%) gastritis strains. There was an association between cagPAI positivity and Le(x) expression among MALT strains (p<0.0001), but not in gastritis strains (p = 0.64). Among cagPAI (-) strains, isolates expressing solely Le(y) were associated with MALT with an odds ratio of 64.2 (95% CI 4.9-841.0) when compared to strains expressing both Le(x) and Le(y). vacA genotypes did not modify the association between Lewis antigen expression and disease status. In conclusion, cagPAI (-) MALT strains have a particular Lewis antigen profile which could represent an adaptive mechanism to the host response or participate in MALT lymphomagenesis.
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24
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Fischer W, Prassl S, Haas R. Virulence Mechanisms and Persistence Strategies of the Human Gastric Pathogen Helicobacter pylori. Curr Top Microbiol Immunol 2009; 337:129-71. [DOI: 10.1007/978-3-642-01846-6_5] [Citation(s) in RCA: 39] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
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25
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Sayi A, Kohler E, Hitzler I, Arnold I, Schwendener R, Rehrauer H, Müller A. The CD4+ T cell-mediated IFN-gamma response to Helicobacter infection is essential for clearance and determines gastric cancer risk. THE JOURNAL OF IMMUNOLOGY 2009; 182:7085-101. [PMID: 19454706 DOI: 10.4049/jimmunol.0803293] [Citation(s) in RCA: 135] [Impact Index Per Article: 8.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/06/2023]
Abstract
Chronic infection with the bacterial pathogen Helicobacter pylori is a risk factor for the development of gastric cancer, yet remains asymptomatic in the majority of individuals. We report here that the C57BL/6 mouse model of experimental infection with the closely related Helicobacter felis recapitulates this wide range in host susceptibility. Although the majority of infected animals develop premalignant lesions such as gastric atrophy, compensatory epithelial hyperplasia, and intestinal metaplasia, a subset of mice is completely protected from preneoplasia. Protection is associated with a failure to mount an IFN-gamma response to the infection and with a concomitant high Helicobacter burden. Using a vaccine model as well as primary infection and adoptive transfer models, we demonstrate that IFN-gamma, secreted predominantly by CD4(+)CD25(-) effector T(H) cells, is essential for Helicobacter clearance, but at the same time mediates the formation of preneoplastic lesions. We further provide evidence that IFN-gamma triggers a common transcriptional program in murine gastric epithelial cells in vitro and in vivo and induces their preferential transformation to the hyperplastic phenotype. In summary, our data suggest a dual role for IFN-gamma in Helicobacter pathogenesis that could be the basis for the differential susceptibility to H. pylori-induced gastric pathology in the human population.
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Affiliation(s)
- Ayca Sayi
- Institute of Molecular Cancer Research and
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26
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Loimaranta V, Hytönen J, Pulliainen AT, Sharma A, Tenovuo J, Strömberg N, Finne J. Leucine-rich repeats of bacterial surface proteins serve as common pattern recognition motifs of human scavenger receptor gp340. J Biol Chem 2009; 284:18614-23. [PMID: 19465482 DOI: 10.1074/jbc.m900581200] [Citation(s) in RCA: 43] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022] Open
Abstract
Scavenger receptors are innate immune molecules recognizing and inducing the clearance of non-host as well as modified host molecules. To recognize a wide pattern of invading microbes, many scavenger receptors bind to common pathogen-associated molecular patterns, such as lipopolysaccharides and lipoteichoic acids. Similarly, the gp340/DMBT1 protein, a member of the human scavenger receptor cysteine-rich protein family, displays a wide ligand repertoire. The peptide motif VEVLXXXXW derived from its scavenger receptor cysteine-rich domains is involved in some of these interactions, but most of the recognition mechanisms are unknown. In this study, we used mass spectrometry sequencing, gene inactivation, and recombinant proteins to identify Streptococcus pyogenes protein Spy0843 as a recognition receptor of gp340. Antibodies against Spy0843 are shown to protect against S. pyogenes infection, but no function or host receptor have been identified for the protein. Spy0843 belongs to the leucine-rich repeat (Lrr) family of eukaryotic and prokaryotic proteins. Experiments with truncated forms of the recombinant proteins confirmed that the Lrr region is needed in the binding of Spy0843 to gp340. The same motif of two other Lrr proteins, LrrG from the Gram-positive S. agalactiae and BspA from the Gram-negative Tannerella forsythia, also mediated binding to gp340. Moreover, inhibition of Spy0843 binding occurred with peptides containing the VEVLXXXXW motif, but also peptides devoid of the XXXXW motif inhibited binding of Lrr proteins. These results thus suggest that the conserved Lrr motif in bacterial proteins serves as a novel pattern recognition motif for unique core peptides of human scavenger receptor gp340.
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Affiliation(s)
- Vuokko Loimaranta
- Departments of Medical Biochemistry and Genetics, Institute of Dentistry, University of Turku, Kiinamyllynkatu 10, FI-20520 Turku, Finland.
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Zheng L, Zhou Z, Lin L, Alber S, Watkins S, Kaminski N, Choi AMK, Morse D. Carbon monoxide modulates alpha-smooth muscle actin and small proline rich-1a expression in fibrosis. Am J Respir Cell Mol Biol 2008; 41:85-92. [PMID: 19097987 DOI: 10.1165/rcmb.2007-0401oc] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022] Open
Abstract
Carbon monoxide (CO) is a biologically active molecule produced in the body by the stress-inducible enzyme, heme oxygenase. We have previously shown that CO suppresses fibrosis in a murine bleomycin model. To investigate the mechanisms by which CO opposes fibrogenesis, we performed gene expression profiling of fibroblasts treated with transforming growth factor-beta(1) and CO. The most highly differentially expressed categories of genes included those related to muscular system development and the small proline-rich family of proteins. We confirmed in vitro, and in an in vivo bleomycin model of lung fibrosis, that CO suppresses alpha-smooth muscle actin expression and enhances small proline-rich protein-1a expression. We further show that these effects of CO depend upon signaling via the extracellular signal-regulated kinase pathway. Our results demonstrate novel transcriptional targets for CO and further elucidate the mechanism by which CO suppresses fibrosis.
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Affiliation(s)
- Liang Zheng
- Division of Pulmonary, Allergy and Critical Care Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA
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O'Rourke JL. Gene expression profiling in Helicobacter-induced MALT lymphoma with reference to antigen drive and protective immunization. J Gastroenterol Hepatol 2008; 23 Suppl 2:S151-6. [PMID: 19120889 DOI: 10.1111/j.1440-1746.2008.05553.x] [Citation(s) in RCA: 16] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/28/2022]
Abstract
We have previously shown that long-term infection of BALB/c mice with gastric Helicobacter species results in the development of histopathological lesions that resemble those seen in patients diagnosed with gastric mucosa associated lymphoid tissue (MALT) lymphoma. This paper describes analysis of this disease at the molecular level through the use of microarray technology and immunohistochemical staining. We were able to monitor the genetic changes in the gastric mucosa characterized by distinct transcriptional signatures and correlate these with histological changes as the infection progressed from a chronic inflammatory infiltrate through to MALT lymphoma. This model system also enabled us to further dissect the role of antigen presentation and prophylactic immunization in the disease process. Antimicrobial therapy to eradicate the antigen correlated with significant reduction in pathology and major changes in the gene expression profile. Subsequent reintroduction of the antigen resulted in rapid tumor development which correlated with an increase in aggressively proliferating cells and changes in the cellular composition of the tumor. The response in vaccinated animals showed that the protected animals exhibited a strikingly different transcriptional profile compared to those of non-protected or control mice, indicating that the vaccination targeted the appropriate site leaving a long-lasting signature. The genes which were most significantly up-regulated included a number of adipocyte-specific factors, such as fat-cell specific cytokines and adipocyte surface markers. This study allowed for us to highlight the significance of antigen presentation in this disease and to hypothesis mechanisms associated with protective immunity.
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Affiliation(s)
- Jani L O'Rourke
- School of Biotechnology and Biomolecular Sciences, University of New South Wales, Sydney, New South Wales, Australia.
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Vivas JR, Regnault B, Michel V, Bussière FI, Avé P, Huerre M, Labigne A, D' Elios MM, Touati E. Interferon gamma-signature transcript profiling and IL-23 upregulation in response to Helicobacter pylori infection. Int J Immunopathol Pharmacol 2008; 21:515-26. [PMID: 18831919 DOI: 10.1177/039463200802100305] [Citation(s) in RCA: 16] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/27/2023] Open
Abstract
Helicobacter pylori infection is the major cause of gastroduodenal pathologies including gastric cancer. The long persistence of bacteria and the type of immune and inflammatory response determine the clinical issue. In this study, the global gene expression profile after 6 and 12 months of H. pylori infection was investigated in the mouse stomach, using the Affymetrix GeneChip Mouse Expression Array A430. Genes related to the inflammatory and immune responses were focused. Levels of selected transcripts were confirmed by reverse transcription polymerase chain reaction. Twenty- five and nineteen percent of the differentially expressed genes observed at 6 and 12 months post-infection respectively, were related to immune response. They are characterized by an interferon (IFN)gamma-dependent expression associated to a T helper 1 (Th1) polarised response. In-depth analysis revealed that an up-regulation of IL-23p19, took place in the stomach of H. pylori infected-mice. Strong IL-23p19 levels were also confirmed in gastric biopsies from H. pylori-infected patients with chronic gastritis, as compared to healthy subjects. Our microarray analysis revealed also, a high decrease of H+K+-ATPase transcripts in the presence of the H. pylori infection. Association of gastric Th1 immune response with hypochlorhydria through the down-regulation of H+K+-ATPase contributes to the genesis of lesions upon the H. pylori infection. Our data highlight that the up-regulation of IL-23 and of many IFNgamma signature transcripts occur early on during the host response to H. pylori, and suggest that this type of immune response may promote the severity of the induced gastric lesions.
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Affiliation(s)
- J R Vivas
- Unite de Pathogénie Bacterienne des Muqueuses, Institut Pasteur, Paris, France
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Liver transcriptome profiles associated with strain-specific Ehrlichia chaffeensis-induced hepatitis in SCID mice. Infect Immun 2008; 77:245-54. [PMID: 19001077 DOI: 10.1128/iai.00979-08] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
Infection of humans with Ehrlichia chaffeensis, the etiologic agent of human monocytic ehrlichiosis, can cause hepatitis of various levels of severity. When the three human isolates of E. chaffeensis, each belonging to a different genogroup, are inoculated into severe combined immunodeficiency mice, the order of severity of clinical signs and bacterial burden detected in the liver is as follows (from greatest to least severity and highest to lowest burden): strain Wakulla, followed by strain Liberty, followed by strain Arkansas. In this article, we used microarray analysis to define transcriptional profiles characteristic of the histopathological features in the mouse liver. Cytokine and chemokine profiles and their receptor profiles were strikingly different among the three strains of E. chaffeensis: gamma interferon, CCL5, CXCL1, CXCL2, CXCL7, CXCL9, interleukin 2 receptor gamma (IL2Rgamma), IL21R, CCR2, and CXCR6 were highly upregulated with strain Arkansas; and tumor necrosis factor (TNF), CCL2, CCL3, CCL5, CCL6, CCL12, CCL20, CXCL2, CXCL7, CXCL9, CXCL13, TNF receptor superfamily 9 (TNFRSF9), TNFRSF13beta, IL1R2, IL2Rgamma, IL20Rbeta, IL21R, CCR1, CCR2, and CXCR4 were highly upregulated with strain Wakulla. With strain Liberty, only CXCL13 was highly upregulated, and IL13Ralpha2 was downregulated. In livers infected with the Arkansas strain, monocytes/macrophages and NK cells were enriched in the granulomas and an increase in NK cell marker mRNAs was detected. Livers infected with the Wakulla strain displayed infiltration of significantly more neutrophils and an increase in neutrophil marker mRNAs. Genes commonly upregulated in liver tissue infected with the three strains are other host innate immune and inflammatory response genes, including those encoding several acute-phase proteins. Genes downregulated commonly are related to host physiologic functions. The results suggest that marked modulation of host cytokine and chemokine profiles by E. chaffeensis strains underlies the distinct host liver disease.
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Huynh MQ, Wacker HH, Wündisch T, Sohlbach K, Kim TD, Krause M, Stabla K, Roth P, Fischbach W, Stolte M, Neubauer A. Expression profiling reveals specific gene expression signatures in gastric MALT lymphomas. Leuk Lymphoma 2008; 49:974-83. [PMID: 18464117 DOI: 10.1080/10428190802007734] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Abstract
The purpose of this study is to identify genes that are involved in the etiology of Helicobacter pylori induced gastric MALT lymphoma. We compared gene expression profiles of gastric MALT lymphoma with their corresponding gastric MALT (chronic gastritis with formation of follicles and aggregates). cDNA microarrays were used to compare these two tissue types from the same patient (n = 21). Quantitative PCR and immunohistochemical staining were performed to validate the microarray results. Three hundred and fifty eight out of 11,552 genes were differentially expressed between gastric MALT lymphomas and gastric MALT. Thirty eight genes are implicated in immune response, 66 in signal transduction and 36 in cell proliferation. Interestingly, chromosome 6 was the only chromosome which was significantly over-represented with 25 genes (EASE score p = 0.01254). Several surface markers of haematopoietic cells, such as CD1c, CD40, CD44, CD53, CD83, CD86 and members of the HLA-D family were up-regulated in lymphoma tissues, indicating antigen-dependent survival of lymphoma cells. We conclude that gastric MALT lymphoma shows a specific gene expression profile, which allows the differentiation from H. pylori induced lymphoid gastritis.
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Affiliation(s)
- Minh Quang Huynh
- Department of Hematology, Oncology and Immunology, University Hospital, Marburg, Germany
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Ding SZ, Olekhnovich IN, Cover TL, Peek RM, Smith MF, Goldberg JB. Helicobacter pylori and mitogen-activated protein kinases mediate activator protein-1 (AP-1) subcomponent protein expression and DNA-binding activity in gastric epithelial cells. ACTA ACUST UNITED AC 2008; 53:385-94. [PMID: 18625013 DOI: 10.1111/j.1574-695x.2008.00439.x] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Abstract
Emerging evidence has suggested a critical role for activator protein-1 (AP)-1 in regulating various cellular functions. The goal of this study was to investigate the effects of Helicobacter pylori and mitogen-activated protein kinases (MAPK) on AP-1 subcomponents expression and AP-1 DNA-binding activity in gastric epithelial cells. We found that H. pylori infection resulted in a time- and dose-dependent increase in the expression of the proteins c-Jun, JunB, JunD, Fra-1, and c-Fos, which make up the major AP-1 DNA-binding proteins in AGS and MKN45 cells, while the expression levels of Fra-2 and FosB remained unchanged. Helicobacter pylori infection and MAPK inhibition altered AP-1 subcomponent protein expression and AP-1 DNA-binding activity, but did not change the overall subcomponent composition. Different clinical isolates of H. pylori showed various abilities to induce AP-1 DNA binding. Mutation of cagA, cagPAI, or vacA, and the nonphosphorylateable CagA mutant (cagA(EPISA)) resulted in less H. pylori-induced AP-1 DNA-binding activity, while mutation of the H. pylori flagella had no effect. extracellular signal-related kinase (ERK), p38, and c-Jun N-terminal kinase (JNK) each selectively regulated AP-1 subcomponent expression and DNA-binding activity. These results provide more insight into how H. pylori and MAPK modulate AP-1 subcomponents in gastric epithelial cells to alter the expression of downstream target genes and affect cellular functions.
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Affiliation(s)
- Song-Ze Ding
- Department of Microbiology, The University of Virginia Health System, 1300 Jefferson Park Avenue, Charlottesville, VA 22908, USA
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Ferrand J, Roumanes D, Pitard V, Moreau JF, Mégraud F, Lehours P. Modulation of lymphocyte proliferation induced by gastric MALT lymphoma-associated Helicobacter pylori strains. Helicobacter 2008; 13:167-73. [PMID: 18466391 DOI: 10.1111/j.1523-5378.2008.00596.x] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
BACKGROUND Helicobacter pylori infection leads to different chronic diseases, suggesting that this bacterium can evade the host immune defense system. The ability to control lymphocyte proliferation may be a mechanism leading to the development of gastric pathologies. Our aim was to characterize the effects of mucosa-associated lymphoid tissue (MALT) associated H. pylori strains on lymphocyte proliferation. MATERIALS AND METHODS We measured the in vitro proliferation of human lymphocytes originally from blood or tonsil samples in the presence or absence of viable bacteria or lysates. RESULTS We showed that MALT lymphoma-associated strains are not likely to be directly responsible for anarchical B-cell proliferation in vitro. On the other hand, proliferation of prestimulated T lymphocytes was abolished in vitro by the presence of all H. pylori strains, whether associated with MALT lymphoma or not. CONCLUSION Inhibition of T-cell proliferation may be of major importance in the gastric colonization and in the persistence of the infection. Furthermore, this inhibition may favor anarchical B-cell proliferation in vivo and predispose the host to gastric MALT lymphoma, whereas MALT-associated H. pylori strains do not appear to possess a specific capability to directly stimulate B-lymphocyte proliferation.
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Affiliation(s)
- Jonathan Ferrand
- INSERM U853, Bordeaux, F 33076 France, and Université Victor Segalen Bordeaux 2, Bordeaux, F33076, France
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Galamb O, Gyõrffy B, Sipos F, Dinya E, Krenács T, Berczi L, Szõke D, Spisák S, Solymosi N, Németh AM, Juhász M, Molnár B, Tulassay Z. Helicobacter pylori and antrum erosion-specific gene expression patterns: the discriminative role of CXCL13 and VCAM1 transcripts. Helicobacter 2008; 13:112-126. [PMID: 18321301 DOI: 10.1111/j.1523-5378.2008.00584.x] [Citation(s) in RCA: 34] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/05/2023]
Abstract
BACKGROUND AND AIMS Chronic Helicobacter pylori infection affects approximately half of the world, leads to chronic gastritis and peptic ulceration, and is linked to gastric carcinoma. Our aims were to compare the gene expression profile (GEP) of H. pylori-positive and H. pylori-negative gastric erosions and adjacent mucosa to explain the possible role and response to H. pylori infection and to get erosion-related mRNA expression patterns. METHODS Total RNA was extracted, amplified, and biotinylated from gastric biopsies of patients with H. pylori-positive and H. pylori-negative antrum erosions (ER) (8/8) and adjacent macroscopically normal mucosae (8/8). The GEP was evaluated using HGU133plus2.0 microarrays. Two independent normalizations (MAS5.0, RMA), PAM feature selection, hierarchical cluster analysis, and discriminant analysis were done. The expression of 14 genes was also measured by real-time-polymerase chain reaction. VCAM-1 and CXCL13 immunohistochemistry (IHC) was done. RESULTS In H. pylori infection, significant overexpression of MHC class II antigen-presenting genes, interleukin-7 receptor, ubiquitin-D, CXCR4, lactoferrin immune response-related genes, CXCL-2 and -13, CCL18 chemokine ligand, and VCAM-1 genes were established. In erosive gastritis, increased proliferation (MET) and transport (UCP2, SCFD1, KPNA4) were found, while genes associated with adhesion (SIGLEC11), transcription regulation (ESRRG), and electron and ion transport (ACADM, CLIC6) were down-regulated. Discriminant analysis successfully classified all samples into four groups (HP+ER-, HP+ER+, HP-ER+, HP-ER-) using a reduced gene set (20). Significant overexpression of VCAM-1 and CXC13 protein was detected by IHC in HP+ samples (p < .05). CONCLUSIONS Whole genomic microarray analysis yielded new H. pylori infection and erosion-related gene expression changes. Discriminative genes can be used in mRNA-based diagnostic classification of gastric biopsies.
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Affiliation(s)
- Orsolya Galamb
- 2nd Department of Medicine, Semmelweis University, Budapest, Hungary.
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Li S, Nikulina K, DeVoss J, Wu AJ, Strauss EC, Anderson MS, McNamara NA. Small proline-rich protein 1B (SPRR1B) is a biomarker for squamous metaplasia in dry eye disease. Invest Ophthalmol Vis Sci 2008; 49:34-41. [PMID: 18172072 DOI: 10.1167/iovs.07-0685] [Citation(s) in RCA: 61] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/12/2023] Open
Abstract
PURPOSE Squamous metaplasia occurs in ocular surface diseases like Sjögren's syndrome (SS). It is a phenotypic change whereby epithelial cells initiate synthesis of squamous cell-specific proteins such as small proline-rich protein 1B (SPRR1B) that result in pathologic keratin formation on the ocular surface. The authors hypothesized that inflammation is a key inducer of pathologic keratinization and that SPRR1B represents an analytical biomarker for the study of the molecular mechanisms. METHODS Real-time quantitative RT-PCR and immunohistochemistry were used to examine SPRR1B mRNA and protein in two different mouse models of dry eye and patients with SS. Adoptive transfer of mature lymphocytes from mice lacking the autoimmune regulator (aire) gene was performed to examine the role of inflammation as an inducer of squamous metaplasia. SPRR1B expression in response to several cytokines was examined in vitro, whereas the expression of cytokines IL1beta and IFNgamma was quantified in ocular tissues of aire-deficient mice and patients with SS. RESULTS SPRR1B was increased across the ocular surface of mice with both desiccating stress and autoimmune-mediated, aqueous-deficient dry eye and in patients with SS. Adoptive transfer of CD4(+) T cells from aire-deficient mice to immunodeficient recipients caused advanced ocular surface keratinization. IL1alpha, IL1beta, IL6, IFNgamma, and TNFalpha induced SPRR1B expression in vitro and the local expression of IL1beta and IFNgamma was elevated in ocular tissues of patients with SS and aire-deficient mice. CONCLUSIONS SPRR1B is a valid biomarker for the study of the molecular mechanisms of squamous metaplasia. There is a definitive link between inflammation and squamous metaplasia in autoimmune-mediated dry eye disease, with IL1beta and IFNgamma likely acting as key participants.
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Affiliation(s)
- Shimin Li
- Francis I. Proctor Foundation, University of California-San Francisco, 513 Parnassus, San Francisco, CA 94143, USA
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Small proline-rich proteins (SPRR) function as SH3 domain ligands, increase resistance to injury and are associated with epithelial-mesenchymal transition (EMT) in cholangiocytes. J Hepatol 2008; 48:276-88. [PMID: 18155796 PMCID: PMC2263141 DOI: 10.1016/j.jhep.2007.09.019] [Citation(s) in RCA: 33] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/18/2007] [Revised: 09/04/2007] [Accepted: 09/05/2007] [Indexed: 12/23/2022]
Abstract
BACKGROUND/AIMS Deficient biliary epithelial cell (BEC) expression of small proline-rich protein (SPRR) 2A in IL-6(-/-) mice is associated with defective biliary barrier function after bile duct ligation. And numerous gene array expression studies show SPRR2A to commonly be among the most highly up-regulated genes in many non-squamous, stressed and remodeling barrier epithelia. Since the function of SPRR in these circumstances is unknown, we tested the exploratory hypothesis that BEC SPRR2A expression contributes to BEC barrier function and wound repair. METHODS The effect of SPRR2A expression was studied in primary mouse BEC cultures; in a BEC cell line after forced overexpression of SPRR2A; and in human livers removed at the time of liver transplantation. RESULTS Forced SPRR2A overexpression showed that it functions as a SH3 domain ligand that increases resistance to oxidative injury and promotes wound restitution by enhancing migration and acquisition of mesenchymal characteristics. Low confluency non-neoplastic mouse BEC cultures show a phenotype similar to the stable transfectants, as did spindle-shaped BEC participating in atypical ductular reactions in primary biliary cirrhosis. CONCLUSIONS These observations suggest that SPRR2A-related BEC barrier modifications represent a novel, but widely utilized and evolutionarily conserved, response to stress that is worthy of further study.
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Sousa JF, Espreafico EM. Suppression subtractive hybridization profiles of radial growth phase and metastatic melanoma cell lines reveal novel potential targets. BMC Cancer 2008; 8:19. [PMID: 18211678 PMCID: PMC2267200 DOI: 10.1186/1471-2407-8-19] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2007] [Accepted: 01/22/2008] [Indexed: 01/25/2023] Open
Abstract
BACKGROUND Melanoma progression occurs through three major stages: radial growth phase (RGP), confined to the epidermis; vertical growth phase (VGP), when the tumor has invaded into the dermis; and metastasis. In this work, we used suppression subtractive hybridization (SSH) to investigate the molecular signature of melanoma progression, by comparing a group of metastatic cell lines with an RGP-like cell line showing characteristics of early neoplastic lesions including expression of the metastasis suppressor KISS1, lack of alphavbeta3-integrin and low levels of RHOC. METHODS Two subtracted cDNA collections were obtained, one (RGP library) by subtracting the RGP cell line (WM1552C) cDNA from a cDNA pool from four metastatic cell lines (WM9, WM852, 1205Lu and WM1617), and the other (Met library) by the reverse subtraction. Clones were sequenced and annotated, and expression validation was done by Northern blot and RT-PCR. Gene Ontology annotation and searches in large-scale melanoma expression studies were done for the genes identified. RESULTS We identified 367 clones from the RGP library and 386 from the Met library, of which 351 and 368, respectively, match human mRNA sequences, representing 288 and 217 annotated genes. We confirmed the differential expression of all genes selected for validation. In the Met library, we found an enrichment of genes in the growth factors/receptor, adhesion and motility categories whereas in the RGP library, enriched categories were nucleotide biosynthesis, DNA packing/repair, and macromolecular/vesicular trafficking. Interestingly, 19% of the genes from the RGP library map to chromosome 1 against 4% of the ones from Met library. CONCLUSION This study identifies two populations of genes differentially expressed between melanoma cell lines from two tumor stages and suggests that these sets of genes represent profiles of less aggressive versus metastatic melanomas. A search for expression profiles of melanoma in available expression study databases allowed us to point to a great potential of involvement in tumor progression for several of the genes identified here. A few sequences obtained here may also contribute to extend annotated mRNAs or to the identification of novel transcripts.
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Affiliation(s)
- Josane F Sousa
- Department of Cellular and Molecular Biology and Pathogenic Bioagents of Faculty of Medicine of Ribeirão Preto - University of São Paulo, Ribeirão Preto, SP, Brazil.
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Renner M, Bergmann G, Krebs I, End C, Lyer S, Hilberg F, Helmke B, Gassler N, Autschbach F, Bikker F, Strobel-Freidekind O, Gronert-Sum S, Benner A, Blaich S, Wittig R, Hudler M, Ligtenberg AJ, Madsen J, Holmskov U, Annese V, Latiano A, Schirmacher P, Amerongen AVN, D'Amato M, Kioschis P, Hafner M, Poustka A, Mollenhauer J. DMBT1 confers mucosal protection in vivo and a deletion variant is associated with Crohn's disease. Gastroenterology 2007; 133:1499-1509. [PMID: 17983803 DOI: 10.1053/j.gastro.2007.08.007] [Citation(s) in RCA: 86] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/18/2007] [Accepted: 07/19/2007] [Indexed: 01/04/2023]
Abstract
BACKGROUND & AIMS Impaired mucosal defense plays an important role in the pathogenesis of Crohn's disease (CD), one of the main subtypes of inflammatory bowel disease (IBD). Deleted in malignant brain tumors 1 (DMBT1) is a secreted scavenger receptor cysteine-rich protein with predominant expression in the intestine and has been proposed to exert possible functions in regenerative processes and pathogen defense. Here, we aimed at analyzing the role of DMBT1 in IBD. METHODS We studied DMBT1 expression in IBD and normal tissues by quantitative reverse transcription-polymerase chain reaction, immunohistochemistry, and mRNA in situ hybridization. Genetic polymorphisms within DMBT1 were analyzed in an Italian IBD case-control sample. Dmbt1(-/-) mice were generated, characterized, and analyzed for their susceptibility to dextran sulfate sodium-induced colitis. RESULTS DMBT1 levels correlate with disease activity in inflamed IBD tissues. A highly significant fraction of the patients with IBD displayed up-regulation of DMBT1 specifically in the intestinal epithelial surface cells and Paneth cells. A deletion allele of DMBT1 with a reduced number of scavenger receptor cysteine-rich domain coding exons is associated with an increased risk of CD (P = .00056; odds ratio, 1.75) but not for ulcerative colitis. Dmbt1(-/-) mice display enhanced susceptibility to dextran sulfate sodium-induced colitis and elevated Tnf, Il6, and Nod2 expression levels during inflammation. CONCLUSIONS DMBT1 may play a role in intestinal mucosal protection and prevention of inflammation. Impaired DMBT1 function may contribute to the pathogenesis of CD.
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Affiliation(s)
- Marcus Renner
- Division of Molecular Genome Analysis, Deutsches Krebsforschungszentrum, Heidelberg, Germany
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Mollenhauer J, End C, Renner M, Lyer S, Poustka A. DMBT1 as an archetypal link between infection, inflammation, and cancer. ACTA ACUST UNITED AC 2007. [DOI: 10.1016/s0213-9626(07)70089-6] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
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Rosenstiel P, Sina C, End C, Renner M, Lyer S, Till A, Hellmig S, Nikolaus S, Fölsch UR, Helmke B, Autschbach F, Schirmacher P, Kioschis P, Hafner M, Poustka A, Mollenhauer J, Schreiber S. Regulation of DMBT1 via NOD2 and TLR4 in intestinal epithelial cells modulates bacterial recognition and invasion. THE JOURNAL OF IMMUNOLOGY 2007; 178:8203-11. [PMID: 17548659 DOI: 10.4049/jimmunol.178.12.8203] [Citation(s) in RCA: 135] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/26/2022]
Abstract
Mucosal epithelial cell layers are constantly exposed to a complex resident microflora. Deleted in malignant brain tumors 1 (DMBT1) belongs to the group of secreted scavenger receptor cysteine-rich proteins and is considered to be involved in host defense by pathogen binding. This report describes the regulation and function of DMBT1 in intestinal epithelial cells, which form the primary immunological barrier for invading pathogens. We report that intestinal epithelial cells up-regulate DMBT1 upon proinflammatory stimuli (e.g., TNF-alpha, LPS). We demonstrate that DMBT1 is a target gene for the intracellular pathogen receptor NOD2 via NF-kappaB activation. DMBT1 is strongly up-regulated in the inflamed intestinal mucosa of Crohn's disease patients with wild-type, but not with mutant NOD2. We show that DMBT1 inhibits cytoinvasion of Salmonella enterica and LPS- and muramyl dipeptide-induced NF-kappaB activation and cytokine secretion in vitro. Thus, DMBT1 may play an important role in the first line of mucosal defense conferring immune exclusion of bacterial cell wall components. Dysregulated intestinal DMBT1 expression due to mutations in the NOD2/CARD15 gene may be part of the complex pathophysiology of barrier dysfunction in Crohn's disease.
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Affiliation(s)
- Philip Rosenstiel
- Institute of Clinical Molecular Biology, University Hospital Schleswig-Holstein, Campus Kiel, Schittenhelmstrache 12, Kiel, Germany
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41
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Driemel O, Murzik U, Escher N, Melle C, Bleul A, Dahse R, Reichert T, Ernst G, von Eggeling F. Protein profiling of oral brush biopsies: S100A8 and S100A9 can differentiate between normal, premalignant, and tumor cells. Proteomics Clin Appl 2007; 1:486-93. [DOI: 10.1002/prca.200600669] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2006] [Indexed: 11/06/2022]
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Wang X, Rosa AJM, Oliverira HN, Rosa GJM, Guo X, Travnicek M, Girshick T. Transcriptome of local innate and adaptive immunity during early phase of infectious bronchitis viral infection. Viral Immunol 2007; 19:768-74. [PMID: 17201672 DOI: 10.1089/vim.2006.19.768] [Citation(s) in RCA: 46] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022] Open
Abstract
To understand the mechanistic basis of local innate and adaptive immunity against infectious bronchitis virus (IBV) at the molecular level, we examined the gene transcription profile of tracheal epithelial layers 3 d after infection of chickens with an attenuated IBV-Massachusetts strain. Results suggested that the transcription levels of 365 genes were either upregulated or downregulated (2-fold and higher) after IBV infection. Among the upregulated 250 genes, 25 were directly immune-related genes. These upregulated immune response genes included TLR2, TLR3, interferon-induced antiviral genes (Mx), and genes responsible for cytotoxic T cell killing such as Fas antigen and granzyme-A. Overall, a diversity of innate immunity and helper T cell type 1 (Th1)-biased adaptive immunity are activated in the host's early defense against IBV invasion, and they are responsible for the rapid clearance of virus from the local infection.
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Affiliation(s)
- Xiuqing Wang
- Department of Biology and Microbiology, South Dakota State University, Brookings, SD 57007, USA.
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43
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Johansen JS, Jensen BV, Roslind A, Price PA. Is YKL-40 a new therapeutic target in cancer? Expert Opin Ther Targets 2007; 11:219-34. [PMID: 17227236 DOI: 10.1517/14728222.11.2.219] [Citation(s) in RCA: 43] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
YKL-40 is produced by cancer cells and tumour-associated macrophages. YKL-40 may play a role in cancer cell proliferation, differentiation, survival, invasiveness, metastasis, in angiogenesis and the inflammation and remodelling of the extracellular matrix surrounding the tumour. Serum YKL-40 is a biomarker of prognosis, confirmed in 13 different types of cancer including > 2500 patients. Highest serum YKL-40 is found in patients with metastatic cancer with the shortest recurrence-free interval and shortest overall survival. Serum YKL-40 provides independent information compared with clinical characteristics and biomarkers, such as HER2, carcinoembryonic antigen, CA-125, prostate-specific antigen and lactate dehydrogenase. The authors hypothesise that inhibition of YKL-40 by monoclonal antibodies either directly or towards its receptor may be as efficient a cancer therapeutic as the monoclonal antibodies against HER2, HER1, vascular endothelial growth factor and CD20. Drugs inhibiting YKL-40 should be explored as new cancer therapeutics.
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Affiliation(s)
- Julia S Johansen
- Herlev Hospital, University of Copenhagen, Department of Rheumatology Q107, Herlev Ringvej 75, DK-2730 Herlev, Denmark.
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44
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Tan YF, Sun XY, Li FX, Tang S, Piao YS, Wang YL. Gene expression pattern and hormonal regulation of small proline-rich protein 2 family members in the female mouse reproductive system during the estrous cycle and pregnancy. ACTA ACUST UNITED AC 2006; 46:641-55. [PMID: 17169311 DOI: 10.1051/rnd:2006037] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2006] [Accepted: 07/07/2006] [Indexed: 01/15/2023]
Abstract
Small proline-rich proteins (SPRR) are known to construct the cornified cell envelope (CE) in the stratified squamous epithelial cell. Their functions in the simple epithelium such as the uterine epithelium are not clear hitherto. In the present study, the mRNA expression patterns of sprr2 family members in the mouse uterus and vagina during the estrous cycle and pregnancy as well as their regulation by steroids were investigated. Using semi-quantitative RT-PCR, it was revealed that the transcripts of sprr2b, 2e and 2g genes were up-regulated in the proestrous and estrous uteri, and sprr2d was up-regulated only in the estrous uterus. In the vagina, transcription of sprr2a, 2b, 2d, 2e and 2k genes were up-regulated at the metestrous stage. Northern blot analysis demonstrated that the overall expression of sprr2 was highly up-regulated in the estrous uterus and the metestrous vagina. During pregnancy, the sprr2 mRNA in the uterus was sharply repressed from day 3 postcoitus on, and began to be induced around labor time. In situ hybridization showed that the sprr2 transcripts were localized in uterine luminal and glandular epithelial cells as well as vaginal stratified epithelial cells. In ovariectomized mice, the expression of sprr2a, 2d, 2e and 2f genes in the uterus were induced by estrogen, and the effect of estrogen on sprr2d and 2e expression could be partly abolished by progesterone. The data indicate that the sprr2 genes have unique regulation patterns in different reproductive tissues under different physiological conditions, and the encoded proteins might play diverse functions in the female reproductive system.
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Affiliation(s)
- Yin-fei Tan
- State Key Laboratory of Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100080, China
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45
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Fisher SG, Fisher RI. The emerging concept of antigen-driven lymphomas: epidemiology and treatment implications. Curr Opin Oncol 2006; 18:417-24. [PMID: 16894287 DOI: 10.1097/01.cco.0000239878.31463.0b] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
PURPOSE OF REVIEW Dramatic increases in the incidence of lymphomas worldwide have stimulated considerable efforts to identify factors that contribute to the etiology of this heterogeneous group of malignancies. The treatment and, ultimately, the prevention of lymphoma depend on our understanding of the complex interaction of exogenous agents with the molecular milieu which initiates and sustains a lymphoid malignancy. This review discusses the current evidence for the role of foreign or self antigens in the initiation of lymphomagenesis. RECENT FINDINGS Recent data have demonstrated an increased risk of lymphoma among individuals with chronic inflammatory conditions, persistent infections or immunodeficient states. Common to these clinical conditions is antigenic stimulation leading to an inflammatory cascade of cellular and cytokine reactions that may tax the host immune response, provoke tissue injury and eventually result in lymphoid neoplasia. SUMMARY Efforts to detect and suppress chronic, antigen-driven inflammation have suggested that neoplastic progression may often be interrupted and controlled. Elucidation of the etiologic mechanisms critical to the survival of these malignancies would provide promising alternatives for the prevention and treatment of some lymphomas.
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Affiliation(s)
- Susan G Fisher
- Division of Epidemiology, Department of Community & Preventive Medicine and James P. Wilmot Cancer Center, University of Rochester, Rochester, New York 14642, USA.
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46
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Kobayashi M, Lee H, Schaffer L, Gilmartin TJ, Head SR, Takaishi S, Wang TC, Nakayama J, Fukuda M. A distinctive set of genes is upregulated during the inflammation-carcinoma sequence in mouse stomach infected by Helicobacter felis. J Histochem Cytochem 2006; 55:263-74. [PMID: 17101721 DOI: 10.1369/jhc.6a7097.2006] [Citation(s) in RCA: 18] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/28/2022] Open
Abstract
Helicobacter pylori infects over half the population worldwide and is a leading cause of chronic gastritis and gastric cancer. However, the mechanism by which this organism induces inflammation and carcinogenesis is not fully understood. In the present study we used insulin-gastrin (INS-GAS) transgenic mice that fully develop gastric adenocarcinoma after infection of H. pylori-related Helicobacter felis. Histological examination revealed that more than half of those mice developed invasive adenocarcinoma after 8 months of infection. These carcinomas were stained by NCC-ST-439 and HECA-452 that recognize 6-sulfated and non-sulfated sialyl Lewis X. Lymphocytic infiltration predominantly to submucosa was observed in most H. felis-infected mice, and this was associated with the formation of peripheral lymph node addressin (PNAd) on high endothelial venule (HEV)-like vessels detected by MECA-79. Time-course analysis of gene expression by using gene microarray revealed upregulation of several inflammation-associated genes including chemokines, adhesion molecules, surfactant protein D (SP-D), and CD74 in the infected stomach. Immunohistochemical analysis demonstrated that SP-D is expressed in hyperplasia and adenocarcinoma whereas CD74 is expressed in adenocarcinoma in situ and invasive carcinoma. These results as a whole indicate that H. felis induces HEV-like vessels and inflammation-associated chemokines and chemokine receptors, followed by adenocarcinoma formation.
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Affiliation(s)
- Motohiro Kobayashi
- Glycobiology Program, Cancer Research Center, Burnham Institute for Medical Research, 10901 North Torrey Pines Road, La Jolla, CA 92037, USA
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47
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Hossain H, Tchatalbachev S, Chakraborty T. Host gene expression profiling in pathogen–host interactions. Curr Opin Immunol 2006; 18:422-9. [PMID: 16782318 DOI: 10.1016/j.coi.2006.05.018] [Citation(s) in RCA: 33] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2006] [Accepted: 05/31/2006] [Indexed: 01/16/2023]
Abstract
Microarray technology is a powerful high-throughput tool for the analysis of host-pathogen interactions that permits simultaneous interrogation of the transcriptional status of thousands of genes. Emerging topics from microarray-based studies employing diverse pathogens and cell types suggest an initial common host response largely characterised by features of the innate immune response. However, specific host gene expression patterns that reflect differences between bacteria of related genera, different species of a particular genus, as well as strains within a single species can also be discerned. These differences are indicative of virulence determinant functions and suggest adaptive survival strategies. These studies have led to a more comprehensive understanding of the host response and identified new avenues of research for potential control strategies against pathogens.
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Affiliation(s)
- Hamid Hossain
- Institute for Medical Microbiology, Giessen, Germany
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48
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Demetris AJ, Fontes P, Lunz JG, Specht S, Murase N, Marcos A. Wound healing in the biliary tree of liver allografts. Cell Transplant 2006; 15 Suppl 1:S57-65. [PMID: 16826796 DOI: 10.3727/000000006783982386] [Citation(s) in RCA: 29] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
An increasing need for liver transplantation requires evaluation and triage of organs harvested from "extended criteria" donors. Although there is currently no widely accepted definition, most would agree that "extended criteria" includes organs donated by individuals that are old (>65 years), obese, infected with HBV or HCV, non-heart beating (NHBD), or had an unstable blood pressure before harvesting or the organ experienced a long cold ischemic time. These organs carry a statistical risk of dysfunction early after transplantation, but in the majority of recipients, hepatic parenchymal function recovers. Later, however, a small but significant percentage of extended criteria donors develop biliary strictures within several months after transplantation. The strictures occur primarily because of preservation injury that leads to "ischemic cholangitis" or deep wounding of the bile duct wall. Subsequent partial wound healing and wound contraction, but failed restitution of the biliary epithelial cell (BEC) lining, result in biliary tract strictures that cause progressive biliary fibrosis, increased morbidity, and decreased organ half-life. Better understanding of the pathophysiologic mechanisms that lead to biliary strictures in extended criteria donors provides an ideal proving ground for regenerative medicine; it also can provide insights into other diseases, such as extrahepatic biliary atresia and primary sclerosing cholangitis, that likely share certain pathogenic mechanisms. Possible points of therapeutic intervention include limiting cold and warm ischemic times, donor and/or donor organ treatment, ex vivo, to minimize the ischemic/preservation injury, maximize blood flow after transplantation, promote BEC wound healing, and limit myofibroblasts activation and proliferation in the bile duct wall. The pathobiology of biliary wound healing and therapeutic potential of interleukin-6 (IL-6) are highlighted.
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Affiliation(s)
- A J Demetris
- Thomas E. Starzl Transplantation Institute, University of Pittsburgh Medical Center, Pittsburgh, PA, USA.
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Demetris AJ, Lunz JG, Specht S, Nozaki I. Biliary wound healing, ductular reactions, and IL-6/gp130 signaling in the development of liver disease. World J Gastroenterol 2006; 12:3512-22. [PMID: 16773708 PMCID: PMC4087567 DOI: 10.3748/wjg.v12.i22.3512] [Citation(s) in RCA: 39] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Basic and translational wound healing research in the biliary tree lag significantly behind similar studies on the skin and gastrointestinal tract. This is at least partly attributable to lack of easy access to the biliary tract for study. But clinical relevance, more interest in biliary epithelial cell (BEC) pathophysiology, and widespread availability of BEC cultures are factors reversing this trend. In the extra-hepatic biliary tree, ineffectual wound healing, scarring and stricture development are pressing issues. In the smallest intra-hepatic bile ducts either impaired BEC proliferation or an exuberant response can contribute to liver disease. Chronic inflammation and persistent wound healing reactions in large and small bile ducts often lead to liver cancer. General concepts of wound healing as they apply to the biliary tract, importance of cellular processes dependent on IL-6/gp130/STAT3 signaling pathways, unanswered questions, and future directions are discussed.
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Affiliation(s)
- A-J Demetris
- The Thomas E. Starzl Transplantation Institute, Department of Pathology, Division of Transplantation, University of Pittsburgh Medical Center, UPMC-Montefiore E-741, 200 Lothrop Street, Pittsburgh, PA 15213-2582, USA.
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50
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Morgan TK, Montgomery K, Mason V, West RB, Wang L, van de Rijn M, Higgins JP. Upregulation of histidine decarboxylase expression in superficial cortical nephrons during pregnancy in mice and women. Kidney Int 2006; 70:306-14. [PMID: 16760908 DOI: 10.1038/sj.ki.5001553] [Citation(s) in RCA: 17] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Abstract
Mechanisms regulating pregnancy-induced changes in renal function are incompletely understood. Few candidate genes have been identified and data suggest that alternate mechanisms remain to be elucidated. Our objective was to screen thousands of genes expressed in kidneys from mice throughout gestation to identify possible key regulators of renal function during pregnancy. Mouse complementary DNA microarrays were used to screen for differences in expression during pregnancy in C57BL/6 mice. Interesting candidate genes whose expression varied with pregnancy were further analyzed by reverse transcription-PCR and Northern blot. Expression was localized by in situ hybridization and immunohistochemistry. Follow-up immunohistochemical analyses in archival human kidney sections from the fetus, non-pregnant, and pregnant women were also performed. Histidine decarboxylase (HDC), the enzyme that synthesizes histamine, was markedly upregulated in the mouse kidney during pregnancy. HDC expression localized to proximal tubule cells of fetal and adult mice. Females showed strong expression in the juxtamedullary zone before pregnancy and upregulation in the superficial cortical zone (SCZ) by mid-gestation. Histamine colocalized with HDC. Male mice showed only low HDC expression. Similar expression patterns were observed in human kidneys. Our results show that HDC expression and histamine production are increased in the SCZ during pregnancy. If histamine acts as a vasodilator, we speculate that increasing production in the SCZ may increase renal blood flow to this zone and recruit superficial cortical nephrons during pregnancy.
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Affiliation(s)
- T K Morgan
- Department of Pathology, Stanford University Medical Center, Stanford, California, USA.
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