Helicobacter pylori VacA Induces Programmed Necrosis in Gastric Epithelial Cells
Helicobacter pylori is a Gram-negative bacterium that colonizes the human stomach and contributes to the development of peptic ulcer disease and gastric cancer. The secreted pore-forming toxin VacA is one of the major virulence factors of H. pylori. In the current study, we show that AZ-521 human ga...
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| Veröffentlicht in: | Infection and Immunity 2011-07, Vol.79 (7), p.2535-2543 |
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| creator | Radin, Jana N González-Rivera, Christian Ivie, Susan E McClain, Mark S Cover, Timothy L |
| description | Helicobacter pylori is a Gram-negative bacterium that colonizes the human stomach and contributes to the development of peptic ulcer disease and gastric cancer. The secreted pore-forming toxin VacA is one of the major virulence factors of H. pylori. In the current study, we show that AZ-521 human gastric epithelial cells are highly susceptible to VacA-induced cell death. Wild-type VacA causes death of these cells, whereas mutant VacA proteins defective in membrane channel formation do not. Incubation of AZ-521 cells with wild-type VacA results in cell swelling, poly(ADP-ribose) polymerase (PARP) activation, decreased intracellular ATP concentration, and lactate dehydrogenase (LDH) release. VacA-induced death of these cells is a caspase-independent process that results in cellular release of histone-binding protein high mobility group box 1 (HMGB1), a proinflammatory protein. These features are consistent with the occurrence of cell death through a programmed necrosis pathway and suggest that VacA can be included among the growing number of bacterial pore-forming toxins that induce cell death through programmed necrosis. We propose that VacA augments H. pylori-induced mucosal inflammation in the human stomach by causing programmed necrosis of gastric epithelial cells and subsequent release of proinflammatory proteins and may thereby contribute to the pathogenesis of gastric cancer and peptic ulceration. |
| doi_str_mv | 10.1128/iai.01370-10 |
| format | Article |
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A.</contributor><creatorcontrib>Radin, Jana N ; González-Rivera, Christian ; Ivie, Susan E ; McClain, Mark S ; Cover, Timothy L ; McCormick, B. A.</creatorcontrib><description>Helicobacter pylori is a Gram-negative bacterium that colonizes the human stomach and contributes to the development of peptic ulcer disease and gastric cancer. The secreted pore-forming toxin VacA is one of the major virulence factors of H. pylori. In the current study, we show that AZ-521 human gastric epithelial cells are highly susceptible to VacA-induced cell death. Wild-type VacA causes death of these cells, whereas mutant VacA proteins defective in membrane channel formation do not. Incubation of AZ-521 cells with wild-type VacA results in cell swelling, poly(ADP-ribose) polymerase (PARP) activation, decreased intracellular ATP concentration, and lactate dehydrogenase (LDH) release. VacA-induced death of these cells is a caspase-independent process that results in cellular release of histone-binding protein high mobility group box 1 (HMGB1), a proinflammatory protein. These features are consistent with the occurrence of cell death through a programmed necrosis pathway and suggest that VacA can be included among the growing number of bacterial pore-forming toxins that induce cell death through programmed necrosis. We propose that VacA augments H. pylori-induced mucosal inflammation in the human stomach by causing programmed necrosis of gastric epithelial cells and subsequent release of proinflammatory proteins and may thereby contribute to the pathogenesis of gastric cancer and peptic ulceration.</description><identifier>ISSN: 0019-9567</identifier><identifier>EISSN: 1098-5522</identifier><identifier>DOI: 10.1128/iai.01370-10</identifier><identifier>PMID: 21482684</identifier><identifier>CODEN: INFIBR</identifier><language>eng</language><publisher>Washington, DC: American Society for Microbiology</publisher><subject>adenosine triphosphate ; Adenosine Triphosphate - metabolism ; Bacterial Proteins - genetics ; Bacterial Proteins - physiology ; Bacterial Toxins - metabolism ; Bacteriology ; Biological and medical sciences ; Blotting, Western ; Caspases - metabolism ; Cell Death ; Cell Line ; Cell Line, Tumor ; death ; epithelial cells ; Epithelial Cells - microbiology ; Epithelial Cells - pathology ; Fundamental and applied biological sciences. Psychology ; Gastric Mucosa - microbiology ; Gastric Mucosa - pathology ; Gastritis - microbiology ; Gram-negative bacteria ; Helicobacter pylori ; Helicobacter pylori - metabolism ; Helicobacter pylori - pathogenicity ; HMGB1 Protein - metabolism ; Humans ; inflammation ; Ion Channels ; L-Lactate Dehydrogenase - metabolism ; lactate dehydrogenase ; Microbiology ; Miscellaneous ; Molecular Pathogenesis ; mutants ; Necrosis ; pathogenesis ; Peptic Ulcer - microbiology ; peptic ulcers ; Poly(ADP-ribose) Polymerases - metabolism ; proteins ; stomach ; stomach neoplasms ; Stomach Neoplasms - microbiology ; toxins ; virulence ; Virulence Factors - physiology</subject><ispartof>Infection and Immunity, 2011-07, Vol.79 (7), p.2535-2543</ispartof><rights>2015 INIST-CNRS</rights><rights>Copyright © 2011, American Society for Microbiology 2011 American Society for Microbiology</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c572t-921d768e6016234aac3c680bb1f6ce6be8c96b823aaaa9ad9c9338176b8378b23</citedby><cites>FETCH-LOGICAL-c572t-921d768e6016234aac3c680bb1f6ce6be8c96b823aaaa9ad9c9338176b8378b23</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC3191986/pdf/$$EPDF$$P50$$Gpubmedcentral$$H</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC3191986/$$EHTML$$P50$$Gpubmedcentral$$H</linktohtml><link.rule.ids>230,314,727,780,784,885,3186,3187,27923,27924,53790,53792</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=24332800$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/21482684$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><contributor>McCormick, B. A.</contributor><creatorcontrib>Radin, Jana N</creatorcontrib><creatorcontrib>González-Rivera, Christian</creatorcontrib><creatorcontrib>Ivie, Susan E</creatorcontrib><creatorcontrib>McClain, Mark S</creatorcontrib><creatorcontrib>Cover, Timothy L</creatorcontrib><title>Helicobacter pylori VacA Induces Programmed Necrosis in Gastric Epithelial Cells</title><title>Infection and Immunity</title><addtitle>Infect Immun</addtitle><description>Helicobacter pylori is a Gram-negative bacterium that colonizes the human stomach and contributes to the development of peptic ulcer disease and gastric cancer. The secreted pore-forming toxin VacA is one of the major virulence factors of H. pylori. In the current study, we show that AZ-521 human gastric epithelial cells are highly susceptible to VacA-induced cell death. Wild-type VacA causes death of these cells, whereas mutant VacA proteins defective in membrane channel formation do not. Incubation of AZ-521 cells with wild-type VacA results in cell swelling, poly(ADP-ribose) polymerase (PARP) activation, decreased intracellular ATP concentration, and lactate dehydrogenase (LDH) release. VacA-induced death of these cells is a caspase-independent process that results in cellular release of histone-binding protein high mobility group box 1 (HMGB1), a proinflammatory protein. These features are consistent with the occurrence of cell death through a programmed necrosis pathway and suggest that VacA can be included among the growing number of bacterial pore-forming toxins that induce cell death through programmed necrosis. We propose that VacA augments H. pylori-induced mucosal inflammation in the human stomach by causing programmed necrosis of gastric epithelial cells and subsequent release of proinflammatory proteins and may thereby contribute to the pathogenesis of gastric cancer and peptic ulceration.</description><subject>adenosine triphosphate</subject><subject>Adenosine Triphosphate - metabolism</subject><subject>Bacterial Proteins - genetics</subject><subject>Bacterial Proteins - physiology</subject><subject>Bacterial Toxins - metabolism</subject><subject>Bacteriology</subject><subject>Biological and medical sciences</subject><subject>Blotting, Western</subject><subject>Caspases - metabolism</subject><subject>Cell Death</subject><subject>Cell Line</subject><subject>Cell Line, Tumor</subject><subject>death</subject><subject>epithelial cells</subject><subject>Epithelial Cells - microbiology</subject><subject>Epithelial Cells - pathology</subject><subject>Fundamental and applied biological sciences. Psychology</subject><subject>Gastric Mucosa - microbiology</subject><subject>Gastric Mucosa - pathology</subject><subject>Gastritis - microbiology</subject><subject>Gram-negative bacteria</subject><subject>Helicobacter pylori</subject><subject>Helicobacter pylori - metabolism</subject><subject>Helicobacter pylori - pathogenicity</subject><subject>HMGB1 Protein - metabolism</subject><subject>Humans</subject><subject>inflammation</subject><subject>Ion Channels</subject><subject>L-Lactate Dehydrogenase - metabolism</subject><subject>lactate dehydrogenase</subject><subject>Microbiology</subject><subject>Miscellaneous</subject><subject>Molecular Pathogenesis</subject><subject>mutants</subject><subject>Necrosis</subject><subject>pathogenesis</subject><subject>Peptic Ulcer - microbiology</subject><subject>peptic ulcers</subject><subject>Poly(ADP-ribose) Polymerases - metabolism</subject><subject>proteins</subject><subject>stomach</subject><subject>stomach neoplasms</subject><subject>Stomach Neoplasms - microbiology</subject><subject>toxins</subject><subject>virulence</subject><subject>Virulence Factors - physiology</subject><issn>0019-9567</issn><issn>1098-5522</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2011</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNpVkU1vEzEQhi0EomnhxhnMAXFhi8fe9ccFKYpKG6mCSlCu1qzjTYx218HegPrv65BQwBfL40ePZ_wS8gLYOQDX7wOGcwZCsQrYIzIDZnTVNJw_JjPGwFSmkeqEnOb8vRzrutZPyQmHWnOp6xm5ufJ9cLFFN_lEt3d9TIF-Qzeny3G1cz7TmxTXCYfBr-gn71LMIdMw0kvMUwqOXmzDtCkO7OnC931-Rp502Gf__LifkduPF18XV9X158vlYn5duUbxqTIcVkpqLxlILmpEJ5zUrG2hk87L1mtnZKu5wLIMrowzQmhQpSaUbrk4Ix8O3u2uLb05P04Je7tNYcB0ZyMG-__NGDZ2HX9aAQaMlkXw9ihI8cfO58kOIbsyAo4-7rLVSghoQKlCvjuQ--lz8t3DK8DsPgO7nC_t7wxKpeAv_-3sAf7z6QV4cwQwO-y7hKML-S9XC8E124teH7hNWG9-heQt5sGWvK0yVlneiKYwrw5Mh9HiOhXP7Rdegi5hK80NiHsB-KPf</recordid><startdate>20110701</startdate><enddate>20110701</enddate><creator>Radin, Jana N</creator><creator>González-Rivera, Christian</creator><creator>Ivie, Susan E</creator><creator>McClain, Mark S</creator><creator>Cover, Timothy L</creator><general>American Society for Microbiology</general><scope>FBQ</scope><scope>IQODW</scope><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7X8</scope><scope>5PM</scope></search><sort><creationdate>20110701</creationdate><title>Helicobacter pylori VacA Induces Programmed Necrosis in Gastric Epithelial Cells</title><author>Radin, Jana N ; González-Rivera, Christian ; Ivie, Susan E ; McClain, Mark S ; Cover, Timothy L</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c572t-921d768e6016234aac3c680bb1f6ce6be8c96b823aaaa9ad9c9338176b8378b23</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2011</creationdate><topic>adenosine triphosphate</topic><topic>Adenosine Triphosphate - metabolism</topic><topic>Bacterial Proteins - genetics</topic><topic>Bacterial Proteins - physiology</topic><topic>Bacterial Toxins - metabolism</topic><topic>Bacteriology</topic><topic>Biological and medical sciences</topic><topic>Blotting, Western</topic><topic>Caspases - metabolism</topic><topic>Cell Death</topic><topic>Cell Line</topic><topic>Cell Line, Tumor</topic><topic>death</topic><topic>epithelial cells</topic><topic>Epithelial Cells - microbiology</topic><topic>Epithelial Cells - pathology</topic><topic>Fundamental and applied biological sciences. Psychology</topic><topic>Gastric Mucosa - microbiology</topic><topic>Gastric Mucosa - pathology</topic><topic>Gastritis - microbiology</topic><topic>Gram-negative bacteria</topic><topic>Helicobacter pylori</topic><topic>Helicobacter pylori - metabolism</topic><topic>Helicobacter pylori - pathogenicity</topic><topic>HMGB1 Protein - metabolism</topic><topic>Humans</topic><topic>inflammation</topic><topic>Ion Channels</topic><topic>L-Lactate Dehydrogenase - metabolism</topic><topic>lactate dehydrogenase</topic><topic>Microbiology</topic><topic>Miscellaneous</topic><topic>Molecular Pathogenesis</topic><topic>mutants</topic><topic>Necrosis</topic><topic>pathogenesis</topic><topic>Peptic Ulcer - microbiology</topic><topic>peptic ulcers</topic><topic>Poly(ADP-ribose) Polymerases - metabolism</topic><topic>proteins</topic><topic>stomach</topic><topic>stomach neoplasms</topic><topic>Stomach Neoplasms - microbiology</topic><topic>toxins</topic><topic>virulence</topic><topic>Virulence Factors - physiology</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Radin, Jana N</creatorcontrib><creatorcontrib>González-Rivera, Christian</creatorcontrib><creatorcontrib>Ivie, Susan E</creatorcontrib><creatorcontrib>McClain, Mark S</creatorcontrib><creatorcontrib>Cover, Timothy L</creatorcontrib><collection>AGRIS</collection><collection>Pascal-Francis</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Infection and Immunity</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Radin, Jana N</au><au>González-Rivera, Christian</au><au>Ivie, Susan E</au><au>McClain, Mark S</au><au>Cover, Timothy L</au><au>McCormick, B. A.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Helicobacter pylori VacA Induces Programmed Necrosis in Gastric Epithelial Cells</atitle><jtitle>Infection and Immunity</jtitle><addtitle>Infect Immun</addtitle><date>2011-07-01</date><risdate>2011</risdate><volume>79</volume><issue>7</issue><spage>2535</spage><epage>2543</epage><pages>2535-2543</pages><issn>0019-9567</issn><eissn>1098-5522</eissn><coden>INFIBR</coden><abstract>Helicobacter pylori is a Gram-negative bacterium that colonizes the human stomach and contributes to the development of peptic ulcer disease and gastric cancer. The secreted pore-forming toxin VacA is one of the major virulence factors of H. pylori. In the current study, we show that AZ-521 human gastric epithelial cells are highly susceptible to VacA-induced cell death. Wild-type VacA causes death of these cells, whereas mutant VacA proteins defective in membrane channel formation do not. Incubation of AZ-521 cells with wild-type VacA results in cell swelling, poly(ADP-ribose) polymerase (PARP) activation, decreased intracellular ATP concentration, and lactate dehydrogenase (LDH) release. VacA-induced death of these cells is a caspase-independent process that results in cellular release of histone-binding protein high mobility group box 1 (HMGB1), a proinflammatory protein. These features are consistent with the occurrence of cell death through a programmed necrosis pathway and suggest that VacA can be included among the growing number of bacterial pore-forming toxins that induce cell death through programmed necrosis. We propose that VacA augments H. pylori-induced mucosal inflammation in the human stomach by causing programmed necrosis of gastric epithelial cells and subsequent release of proinflammatory proteins and may thereby contribute to the pathogenesis of gastric cancer and peptic ulceration.</abstract><cop>Washington, DC</cop><pub>American Society for Microbiology</pub><pmid>21482684</pmid><doi>10.1128/iai.01370-10</doi><tpages>9</tpages><oa>free_for_read</oa></addata></record> |
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| subjects | adenosine triphosphate Adenosine Triphosphate - metabolism Bacterial Proteins - genetics Bacterial Proteins - physiology Bacterial Toxins - metabolism Bacteriology Biological and medical sciences Blotting, Western Caspases - metabolism Cell Death Cell Line Cell Line, Tumor death epithelial cells Epithelial Cells - microbiology Epithelial Cells - pathology Fundamental and applied biological sciences. Psychology Gastric Mucosa - microbiology Gastric Mucosa - pathology Gastritis - microbiology Gram-negative bacteria Helicobacter pylori Helicobacter pylori - metabolism Helicobacter pylori - pathogenicity HMGB1 Protein - metabolism Humans inflammation Ion Channels L-Lactate Dehydrogenase - metabolism lactate dehydrogenase Microbiology Miscellaneous Molecular Pathogenesis mutants Necrosis pathogenesis Peptic Ulcer - microbiology peptic ulcers Poly(ADP-ribose) Polymerases - metabolism proteins stomach stomach neoplasms Stomach Neoplasms - microbiology toxins virulence Virulence Factors - physiology |
| title | Helicobacter pylori VacA Induces Programmed Necrosis in Gastric Epithelial Cells |
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