The Cag pathogenicity island and interaction between TLR2/NOD2 and NLRP3 regulate IL‐1β production in Helicobacter pylori infected dendritic cells
Helicobacter pylori colonization of the stomach affects about half of the world population and is associated with the development of gastritis, ulcers, and cancer. Polymorphisms in the IL1B gene are linked to an increased risk of H. pylori associated cancer, but the bacterial and host factors that r...
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Veröffentlicht in: | European journal of immunology 2013-10, Vol.43 (10), p.2650-2658 |
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description | Helicobacter pylori colonization of the stomach affects about half of the world population and is associated with the development of gastritis, ulcers, and cancer. Polymorphisms in the IL1B gene are linked to an increased risk of H. pylori associated cancer, but the bacterial and host factors that regulate interleukin (IL)‐1β production in response to H. pylori infection remain unknown. Using murine BM‐derived DCs, we show that the bacterial virulence factors cytotoxin‐associated genes pathogenicity island and CagL, but not vacuolating cytotoxin A or CagA, regulate the induction of pro‐IL‐1β and the production of mature IL‐1β in response to H. pylori infection. We further show that the host receptors, Toll‐like receptor 2 (TLR2) and nucleotide‐binding oligomerization domain 2 (NOD2), but not NOD1, are required for induction of pro‐IL‐1β and NOD‐like receptor pyrin domain containing 3 (NLRP3) in H. pylori infected DCs. In contrast, NLRP3 and the adaptor ASC were essential for the activation of caspase‐1, processing of pro‐IL‐1β into IL‐1β, and IL‐1β secretion. Finally, we show that mice deficient in caspase‐1, IL‐1β, and IL‐1 receptor, but not NLRP3, are impaired in the clearance of CagA‐positive H. pylori from the stomach when compared with WT mice. These studies identify bacterial cag pathogenicity island and the cooperative interaction among host innate receptors TLR2, NOD2, and NLRP3 as important regulators of IL‐1β production in H. pylori infected DCs. |
doi_str_mv | 10.1002/eji.201243281 |
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Polymorphisms in the IL1B gene are linked to an increased risk of H. pylori associated cancer, but the bacterial and host factors that regulate interleukin (IL)‐1β production in response to H. pylori infection remain unknown. Using murine BM‐derived DCs, we show that the bacterial virulence factors cytotoxin‐associated genes pathogenicity island and CagL, but not vacuolating cytotoxin A or CagA, regulate the induction of pro‐IL‐1β and the production of mature IL‐1β in response to H. pylori infection. We further show that the host receptors, Toll‐like receptor 2 (TLR2) and nucleotide‐binding oligomerization domain 2 (NOD2), but not NOD1, are required for induction of pro‐IL‐1β and NOD‐like receptor pyrin domain containing 3 (NLRP3) in H. pylori infected DCs. In contrast, NLRP3 and the adaptor ASC were essential for the activation of caspase‐1, processing of pro‐IL‐1β into IL‐1β, and IL‐1β secretion. Finally, we show that mice deficient in caspase‐1, IL‐1β, and IL‐1 receptor, but not NLRP3, are impaired in the clearance of CagA‐positive H. pylori from the stomach when compared with WT mice. These studies identify bacterial cag pathogenicity island and the cooperative interaction among host innate receptors TLR2, NOD2, and NLRP3 as important regulators of IL‐1β production in H. pylori infected DCs.</description><identifier>ISSN: 0014-2980</identifier><identifier>EISSN: 1521-4141</identifier><identifier>DOI: 10.1002/eji.201243281</identifier><identifier>PMID: 23818043</identifier><language>eng</language><publisher>Germany</publisher><subject>Animals ; Antigens, Bacterial - metabolism ; Bacterial Load ; Bacterial Proteins - metabolism ; Carrier Proteins - genetics ; Carrier Proteins - metabolism ; Dendritic Cells - immunology ; Dendritic Cells - microbiology ; Gene Expression Regulation - genetics ; Genomic Islands ; Helicobacter Infections - immunology ; Helicobacter pylori ; Helicobacter pylori - pathogenicity ; IL‐1β ; Immunity, Innate - genetics ; Inflammasome ; Interleukin-1beta - genetics ; Interleukin-1beta - metabolism ; Mice ; Mice, Inbred C57BL ; Mice, Knockout ; NLR Family, Pyrin Domain-Containing 3 Protein ; NLRP3 ; NOD2 ; Nod2 Signaling Adaptor Protein - genetics ; Nod2 Signaling Adaptor Protein - metabolism ; Toll-Like Receptor 2 - genetics ; Toll-Like Receptor 2 - metabolism ; Virulence - genetics</subject><ispartof>European journal of immunology, 2013-10, Vol.43 (10), p.2650-2658</ispartof><rights>2013 The Authors. published by Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.</rights><rights>2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://onlinelibrary.wiley.com/doi/pdf/10.1002%2Feji.201243281$$EPDF$$P50$$Gwiley$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://onlinelibrary.wiley.com/doi/full/10.1002%2Feji.201243281$$EHTML$$P50$$Gwiley$$Hfree_for_read</linktohtml><link.rule.ids>314,780,784,1417,1433,27924,27925,45574,45575,46409,46833</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/23818043$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Kim, Dong‐Jae</creatorcontrib><creatorcontrib>Park, Jong‐Hwan</creatorcontrib><creatorcontrib>Franchi, Luigi</creatorcontrib><creatorcontrib>Backert, Steffen</creatorcontrib><creatorcontrib>Núñez, Gabriel</creatorcontrib><title>The Cag pathogenicity island and interaction between TLR2/NOD2 and NLRP3 regulate IL‐1β production in Helicobacter pylori infected dendritic cells</title><title>European journal of immunology</title><addtitle>Eur J Immunol</addtitle><description>Helicobacter pylori colonization of the stomach affects about half of the world population and is associated with the development of gastritis, ulcers, and cancer. Polymorphisms in the IL1B gene are linked to an increased risk of H. pylori associated cancer, but the bacterial and host factors that regulate interleukin (IL)‐1β production in response to H. pylori infection remain unknown. Using murine BM‐derived DCs, we show that the bacterial virulence factors cytotoxin‐associated genes pathogenicity island and CagL, but not vacuolating cytotoxin A or CagA, regulate the induction of pro‐IL‐1β and the production of mature IL‐1β in response to H. pylori infection. We further show that the host receptors, Toll‐like receptor 2 (TLR2) and nucleotide‐binding oligomerization domain 2 (NOD2), but not NOD1, are required for induction of pro‐IL‐1β and NOD‐like receptor pyrin domain containing 3 (NLRP3) in H. pylori infected DCs. In contrast, NLRP3 and the adaptor ASC were essential for the activation of caspase‐1, processing of pro‐IL‐1β into IL‐1β, and IL‐1β secretion. Finally, we show that mice deficient in caspase‐1, IL‐1β, and IL‐1 receptor, but not NLRP3, are impaired in the clearance of CagA‐positive H. pylori from the stomach when compared with WT mice. These studies identify bacterial cag pathogenicity island and the cooperative interaction among host innate receptors TLR2, NOD2, and NLRP3 as important regulators of IL‐1β production in H. pylori infected DCs.</description><subject>Animals</subject><subject>Antigens, Bacterial - metabolism</subject><subject>Bacterial Load</subject><subject>Bacterial Proteins - metabolism</subject><subject>Carrier Proteins - genetics</subject><subject>Carrier Proteins - metabolism</subject><subject>Dendritic Cells - immunology</subject><subject>Dendritic Cells - microbiology</subject><subject>Gene Expression Regulation - genetics</subject><subject>Genomic Islands</subject><subject>Helicobacter Infections - immunology</subject><subject>Helicobacter pylori</subject><subject>Helicobacter pylori - pathogenicity</subject><subject>IL‐1β</subject><subject>Immunity, Innate - genetics</subject><subject>Inflammasome</subject><subject>Interleukin-1beta - genetics</subject><subject>Interleukin-1beta - metabolism</subject><subject>Mice</subject><subject>Mice, Inbred C57BL</subject><subject>Mice, Knockout</subject><subject>NLR Family, Pyrin Domain-Containing 3 Protein</subject><subject>NLRP3</subject><subject>NOD2</subject><subject>Nod2 Signaling Adaptor Protein - genetics</subject><subject>Nod2 Signaling Adaptor Protein - metabolism</subject><subject>Toll-Like Receptor 2 - genetics</subject><subject>Toll-Like Receptor 2 - metabolism</subject><subject>Virulence - genetics</subject><issn>0014-2980</issn><issn>1521-4141</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2013</creationdate><recordtype>article</recordtype><sourceid>24P</sourceid><sourceid>WIN</sourceid><sourceid>EIF</sourceid><recordid>eNo9kc1O3EAMx0cVCJaPY6_VHLkEPB5nmRyrBcpWESC0nKNJxrMMyiYhH0J76yP00hfhQfoQfZJmWeBgWbZ__svyX4ivCk4VAJ7xUzhFUEgajfoiJipGFZEitSMmAIoiTAzsi4OuewKAZBone2IftVEGSE_En8Ujy5ldysb2j_WSq1CEfi1DV9rKyU2EqufWFn2oK5lz_8JcyUV6j2c3txf4Rtyk93datrwcStuznKf_fv1Wf19l09Zu2C6GSl5zGYo6H5W4lc26rNswtj2PtZOOK9eGPhSy4LLsjsSut2XHx-_5UDxcXS5m11F6-2M--55GDSZaR-dFDJoA2JOLtaNpMiVvtKcYyLD1Fr31aBLrCeKi0DnFecy5Q0XI1hp9KE62uuOpzwN3fbYK3eYCW3E9dJki0joxhGpEv72jQ75ilzVtWNl2nX28cgRwC7yEktefcwXZxqds9Cn79Cm7_DnHc9T6P_59h1A</recordid><startdate>201310</startdate><enddate>201310</enddate><creator>Kim, Dong‐Jae</creator><creator>Park, Jong‐Hwan</creator><creator>Franchi, Luigi</creator><creator>Backert, Steffen</creator><creator>Núñez, Gabriel</creator><scope>24P</scope><scope>WIN</scope><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>7X8</scope></search><sort><creationdate>201310</creationdate><title>The Cag pathogenicity island and interaction between TLR2/NOD2 and NLRP3 regulate IL‐1β production in Helicobacter pylori infected dendritic cells</title><author>Kim, Dong‐Jae ; Park, Jong‐Hwan ; Franchi, Luigi ; Backert, Steffen ; Núñez, Gabriel</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-p2933-7c503400ef4d53d46964f83f45048eafa2faf289af405cc3b45b5ebd2142eaa83</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2013</creationdate><topic>Animals</topic><topic>Antigens, Bacterial - metabolism</topic><topic>Bacterial Load</topic><topic>Bacterial Proteins - metabolism</topic><topic>Carrier Proteins - genetics</topic><topic>Carrier Proteins - metabolism</topic><topic>Dendritic Cells - immunology</topic><topic>Dendritic Cells - microbiology</topic><topic>Gene Expression Regulation - genetics</topic><topic>Genomic Islands</topic><topic>Helicobacter Infections - immunology</topic><topic>Helicobacter pylori</topic><topic>Helicobacter pylori - pathogenicity</topic><topic>IL‐1β</topic><topic>Immunity, Innate - genetics</topic><topic>Inflammasome</topic><topic>Interleukin-1beta - genetics</topic><topic>Interleukin-1beta - metabolism</topic><topic>Mice</topic><topic>Mice, Inbred C57BL</topic><topic>Mice, Knockout</topic><topic>NLR Family, Pyrin Domain-Containing 3 Protein</topic><topic>NLRP3</topic><topic>NOD2</topic><topic>Nod2 Signaling Adaptor Protein - genetics</topic><topic>Nod2 Signaling Adaptor Protein - metabolism</topic><topic>Toll-Like Receptor 2 - genetics</topic><topic>Toll-Like Receptor 2 - metabolism</topic><topic>Virulence - genetics</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Kim, Dong‐Jae</creatorcontrib><creatorcontrib>Park, Jong‐Hwan</creatorcontrib><creatorcontrib>Franchi, Luigi</creatorcontrib><creatorcontrib>Backert, Steffen</creatorcontrib><creatorcontrib>Núñez, Gabriel</creatorcontrib><collection>Wiley Online Library Open Access</collection><collection>Wiley Online Library (Open Access Collection)</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>MEDLINE - Academic</collection><jtitle>European journal of immunology</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Kim, Dong‐Jae</au><au>Park, Jong‐Hwan</au><au>Franchi, Luigi</au><au>Backert, Steffen</au><au>Núñez, Gabriel</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>The Cag pathogenicity island and interaction between TLR2/NOD2 and NLRP3 regulate IL‐1β production in Helicobacter pylori infected dendritic cells</atitle><jtitle>European journal of immunology</jtitle><addtitle>Eur J Immunol</addtitle><date>2013-10</date><risdate>2013</risdate><volume>43</volume><issue>10</issue><spage>2650</spage><epage>2658</epage><pages>2650-2658</pages><issn>0014-2980</issn><eissn>1521-4141</eissn><abstract>Helicobacter pylori colonization of the stomach affects about half of the world population and is associated with the development of gastritis, ulcers, and cancer. Polymorphisms in the IL1B gene are linked to an increased risk of H. pylori associated cancer, but the bacterial and host factors that regulate interleukin (IL)‐1β production in response to H. pylori infection remain unknown. Using murine BM‐derived DCs, we show that the bacterial virulence factors cytotoxin‐associated genes pathogenicity island and CagL, but not vacuolating cytotoxin A or CagA, regulate the induction of pro‐IL‐1β and the production of mature IL‐1β in response to H. pylori infection. We further show that the host receptors, Toll‐like receptor 2 (TLR2) and nucleotide‐binding oligomerization domain 2 (NOD2), but not NOD1, are required for induction of pro‐IL‐1β and NOD‐like receptor pyrin domain containing 3 (NLRP3) in H. pylori infected DCs. In contrast, NLRP3 and the adaptor ASC were essential for the activation of caspase‐1, processing of pro‐IL‐1β into IL‐1β, and IL‐1β secretion. Finally, we show that mice deficient in caspase‐1, IL‐1β, and IL‐1 receptor, but not NLRP3, are impaired in the clearance of CagA‐positive H. pylori from the stomach when compared with WT mice. These studies identify bacterial cag pathogenicity island and the cooperative interaction among host innate receptors TLR2, NOD2, and NLRP3 as important regulators of IL‐1β production in H. pylori infected DCs.</abstract><cop>Germany</cop><pmid>23818043</pmid><doi>10.1002/eji.201243281</doi><tpages>9</tpages><oa>free_for_read</oa></addata></record> |
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subjects | Animals Antigens, Bacterial - metabolism Bacterial Load Bacterial Proteins - metabolism Carrier Proteins - genetics Carrier Proteins - metabolism Dendritic Cells - immunology Dendritic Cells - microbiology Gene Expression Regulation - genetics Genomic Islands Helicobacter Infections - immunology Helicobacter pylori Helicobacter pylori - pathogenicity IL‐1β Immunity, Innate - genetics Inflammasome Interleukin-1beta - genetics Interleukin-1beta - metabolism Mice Mice, Inbred C57BL Mice, Knockout NLR Family, Pyrin Domain-Containing 3 Protein NLRP3 NOD2 Nod2 Signaling Adaptor Protein - genetics Nod2 Signaling Adaptor Protein - metabolism Toll-Like Receptor 2 - genetics Toll-Like Receptor 2 - metabolism Virulence - genetics |
title | The Cag pathogenicity island and interaction between TLR2/NOD2 and NLRP3 regulate IL‐1β production in Helicobacter pylori infected dendritic cells |
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