The NLRP3 inflammasome functions as a negative regulator of tumorigenesis during colitis-associated cancer
Colitis-associated cancer (CAC) is a major complication of inflammatory bowel diseases. We show that components of the inflammasome are protective during acute and recurring colitis and CAC in the dextran sulfate sodium (DSS) and azoxymethane + DSS models. Mice lacking the inflammasome adaptor prote...
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Veröffentlicht in: | The Journal of experimental medicine 2010-05, Vol.207 (5), p.1045-1056 |
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description | Colitis-associated cancer (CAC) is a major complication of inflammatory bowel diseases. We show that components of the inflammasome are protective during acute and recurring colitis and CAC in the dextran sulfate sodium (DSS) and azoxymethane + DSS models. Mice lacking the inflammasome adaptor protein PYCARD (ASC) and caspase-1 demonstrate increased disease outcome, morbidity, histopathology, and polyp formation. The increased tumor burden is correlated with attenuated levels of IL-1beta and IL-18 at the tumor site. To decipher the nucleotide-binding domain, leucine-rich-repeat-containing (NLR) component that is involved in colitis and CAC, we assessed Nlrp3 and Nlrc4 deficient mice. Nlrp3(-/-) mice showed an increase in acute and recurring colitis and CAC, although the disease outcome was less severe in Nlrp3(-/-) mice than in Pycard(-/-) or Casp1(-/-) animals. No significant differences were observed in disease progression or outcome in Nlrc4(-/-) mice compared with similarly treated wild-type animals. Bone marrow reconstitution experiments show that Nlrp3 gene expression and function in hematopoietic cells, rather than intestinal epithelial cells or stromal cells, is responsible for protection against increased tumorigenesis. These data suggest that the inflammasome functions as an attenuator of colitis and CAC. |
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We show that components of the inflammasome are protective during acute and recurring colitis and CAC in the dextran sulfate sodium (DSS) and azoxymethane + DSS models. Mice lacking the inflammasome adaptor protein PYCARD (ASC) and caspase-1 demonstrate increased disease outcome, morbidity, histopathology, and polyp formation. The increased tumor burden is correlated with attenuated levels of IL-1beta and IL-18 at the tumor site. To decipher the nucleotide-binding domain, leucine-rich-repeat-containing (NLR) component that is involved in colitis and CAC, we assessed Nlrp3 and Nlrc4 deficient mice. Nlrp3(-/-) mice showed an increase in acute and recurring colitis and CAC, although the disease outcome was less severe in Nlrp3(-/-) mice than in Pycard(-/-) or Casp1(-/-) animals. No significant differences were observed in disease progression or outcome in Nlrc4(-/-) mice compared with similarly treated wild-type animals. Bone marrow reconstitution experiments show that Nlrp3 gene expression and function in hematopoietic cells, rather than intestinal epithelial cells or stromal cells, is responsible for protection against increased tumorigenesis. These data suggest that the inflammasome functions as an attenuator of colitis and CAC.</description><identifier>ISSN: 0022-1007</identifier><identifier>EISSN: 1540-9538</identifier><identifier>DOI: 10.1084/jem.20100050</identifier><identifier>PMID: 20385749</identifier><language>eng</language><publisher>United States: The Rockefeller University Press</publisher><subject>Animals ; Apoptosis Regulatory Proteins ; CARD Signaling Adaptor Proteins ; Carrier Proteins - genetics ; Colitis - complications ; Colon - metabolism ; Colon - pathology ; Cytoskeletal Proteins - deficiency ; Cytoskeletal Proteins - genetics ; Euthanasia ; Gene Expression Regulation, Neoplastic ; Humans ; Inflammatory Bowel Diseases - complications ; Interleukin-18 - metabolism ; Interleukin-1beta - metabolism ; Mice ; Mice, Knockout ; Neoplasms - etiology ; Neoplasms - pathology ; Neoplasms - prevention & control ; NLR Family, Pyrin Domain-Containing 3 Protein ; Tumor Burden</subject><ispartof>The Journal of experimental medicine, 2010-05, Vol.207 (5), p.1045-1056</ispartof><rights>2010 Allen et al. 2010</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c449t-bfb6470b3d3d2296bd7838e1d8c26d8926802abfb4dc93de461647a0c94666da3</citedby><cites>FETCH-LOGICAL-c449t-bfb6470b3d3d2296bd7838e1d8c26d8926802abfb4dc93de461647a0c94666da3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>230,314,776,780,881,27901,27902</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/20385749$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Allen, Irving C</creatorcontrib><creatorcontrib>TeKippe, Erin McElvania</creatorcontrib><creatorcontrib>Woodford, Rita-Marie T</creatorcontrib><creatorcontrib>Uronis, Joshua M</creatorcontrib><creatorcontrib>Holl, Eda K</creatorcontrib><creatorcontrib>Rogers, Arlin B</creatorcontrib><creatorcontrib>Herfarth, Hans H</creatorcontrib><creatorcontrib>Jobin, Christian</creatorcontrib><creatorcontrib>Ting, Jenny P-Y</creatorcontrib><title>The NLRP3 inflammasome functions as a negative regulator of tumorigenesis during colitis-associated cancer</title><title>The Journal of experimental medicine</title><addtitle>J Exp Med</addtitle><description>Colitis-associated cancer (CAC) is a major complication of inflammatory bowel diseases. We show that components of the inflammasome are protective during acute and recurring colitis and CAC in the dextran sulfate sodium (DSS) and azoxymethane + DSS models. Mice lacking the inflammasome adaptor protein PYCARD (ASC) and caspase-1 demonstrate increased disease outcome, morbidity, histopathology, and polyp formation. The increased tumor burden is correlated with attenuated levels of IL-1beta and IL-18 at the tumor site. To decipher the nucleotide-binding domain, leucine-rich-repeat-containing (NLR) component that is involved in colitis and CAC, we assessed Nlrp3 and Nlrc4 deficient mice. Nlrp3(-/-) mice showed an increase in acute and recurring colitis and CAC, although the disease outcome was less severe in Nlrp3(-/-) mice than in Pycard(-/-) or Casp1(-/-) animals. No significant differences were observed in disease progression or outcome in Nlrc4(-/-) mice compared with similarly treated wild-type animals. Bone marrow reconstitution experiments show that Nlrp3 gene expression and function in hematopoietic cells, rather than intestinal epithelial cells or stromal cells, is responsible for protection against increased tumorigenesis. These data suggest that the inflammasome functions as an attenuator of colitis and CAC.</description><subject>Animals</subject><subject>Apoptosis Regulatory Proteins</subject><subject>CARD Signaling Adaptor Proteins</subject><subject>Carrier Proteins - genetics</subject><subject>Colitis - complications</subject><subject>Colon - metabolism</subject><subject>Colon - pathology</subject><subject>Cytoskeletal Proteins - deficiency</subject><subject>Cytoskeletal Proteins - genetics</subject><subject>Euthanasia</subject><subject>Gene Expression Regulation, Neoplastic</subject><subject>Humans</subject><subject>Inflammatory Bowel Diseases - complications</subject><subject>Interleukin-18 - metabolism</subject><subject>Interleukin-1beta - metabolism</subject><subject>Mice</subject><subject>Mice, Knockout</subject><subject>Neoplasms - etiology</subject><subject>Neoplasms - pathology</subject><subject>Neoplasms - prevention & control</subject><subject>NLR Family, Pyrin Domain-Containing 3 Protein</subject><subject>Tumor Burden</subject><issn>0022-1007</issn><issn>1540-9538</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2010</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNpVkU1rFTEUhoMo9ra6cy3ZuXHqycdkMhtBilbhUkup65BJzkxzmUlqkin03zvSDxQOnMX78J4DDyHvGJwy0PLTAZdTDgwAWnhBdqyV0PSt0C_JDoDzZku6I3JcygGASdmq1-SIg9BtJ_sdOVzfIL3YX10KGuI422WxJS1IxzW6GlIs1G5DI062hjukGad1tjVlmkZa1yXlMGHEEgr1aw5xoi7NoYbS2FKSC7aip85Gh_kNeTXaueDbx31Cfn37en32vdn_PP9x9mXfOCn72gzjoGQHg_DCc96rwXdaaGReO6687rnSwO1GSe964VEqtvEWXC-VUt6KE_L5ofd2HRb0DmPNdja3OSw235tkg_k_ieHGTOnOcK06rrut4MNjQU6_VyzVLKE4nGcbMa3FdEIwzXmnNvLjA-lyKiXj-HyFgflrx2x2zJOdDX__72fP8JMO8Qf2kY2v</recordid><startdate>20100510</startdate><enddate>20100510</enddate><creator>Allen, Irving C</creator><creator>TeKippe, Erin McElvania</creator><creator>Woodford, Rita-Marie T</creator><creator>Uronis, Joshua M</creator><creator>Holl, Eda K</creator><creator>Rogers, Arlin B</creator><creator>Herfarth, Hans H</creator><creator>Jobin, Christian</creator><creator>Ting, Jenny P-Y</creator><general>The Rockefeller University Press</general><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>20100510</creationdate><title>The NLRP3 inflammasome functions as a negative regulator of tumorigenesis during colitis-associated cancer</title><author>Allen, Irving C ; TeKippe, Erin McElvania ; Woodford, Rita-Marie T ; Uronis, Joshua M ; Holl, Eda K ; Rogers, Arlin B ; Herfarth, Hans H ; Jobin, Christian ; Ting, Jenny P-Y</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c449t-bfb6470b3d3d2296bd7838e1d8c26d8926802abfb4dc93de461647a0c94666da3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2010</creationdate><topic>Animals</topic><topic>Apoptosis Regulatory Proteins</topic><topic>CARD Signaling Adaptor Proteins</topic><topic>Carrier Proteins - genetics</topic><topic>Colitis - complications</topic><topic>Colon - metabolism</topic><topic>Colon - pathology</topic><topic>Cytoskeletal Proteins - deficiency</topic><topic>Cytoskeletal Proteins - genetics</topic><topic>Euthanasia</topic><topic>Gene Expression Regulation, Neoplastic</topic><topic>Humans</topic><topic>Inflammatory Bowel Diseases - complications</topic><topic>Interleukin-18 - metabolism</topic><topic>Interleukin-1beta - metabolism</topic><topic>Mice</topic><topic>Mice, Knockout</topic><topic>Neoplasms - etiology</topic><topic>Neoplasms - pathology</topic><topic>Neoplasms - prevention & control</topic><topic>NLR Family, Pyrin Domain-Containing 3 Protein</topic><topic>Tumor Burden</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Allen, Irving C</creatorcontrib><creatorcontrib>TeKippe, Erin McElvania</creatorcontrib><creatorcontrib>Woodford, Rita-Marie T</creatorcontrib><creatorcontrib>Uronis, Joshua M</creatorcontrib><creatorcontrib>Holl, Eda K</creatorcontrib><creatorcontrib>Rogers, Arlin B</creatorcontrib><creatorcontrib>Herfarth, Hans H</creatorcontrib><creatorcontrib>Jobin, Christian</creatorcontrib><creatorcontrib>Ting, Jenny P-Y</creatorcontrib><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>The Journal of experimental medicine</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Allen, Irving C</au><au>TeKippe, Erin McElvania</au><au>Woodford, Rita-Marie T</au><au>Uronis, Joshua M</au><au>Holl, Eda K</au><au>Rogers, Arlin B</au><au>Herfarth, Hans H</au><au>Jobin, Christian</au><au>Ting, Jenny P-Y</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>The NLRP3 inflammasome functions as a negative regulator of tumorigenesis during colitis-associated cancer</atitle><jtitle>The Journal of experimental medicine</jtitle><addtitle>J Exp Med</addtitle><date>2010-05-10</date><risdate>2010</risdate><volume>207</volume><issue>5</issue><spage>1045</spage><epage>1056</epage><pages>1045-1056</pages><issn>0022-1007</issn><eissn>1540-9538</eissn><abstract>Colitis-associated cancer (CAC) is a major complication of inflammatory bowel diseases. We show that components of the inflammasome are protective during acute and recurring colitis and CAC in the dextran sulfate sodium (DSS) and azoxymethane + DSS models. Mice lacking the inflammasome adaptor protein PYCARD (ASC) and caspase-1 demonstrate increased disease outcome, morbidity, histopathology, and polyp formation. The increased tumor burden is correlated with attenuated levels of IL-1beta and IL-18 at the tumor site. To decipher the nucleotide-binding domain, leucine-rich-repeat-containing (NLR) component that is involved in colitis and CAC, we assessed Nlrp3 and Nlrc4 deficient mice. Nlrp3(-/-) mice showed an increase in acute and recurring colitis and CAC, although the disease outcome was less severe in Nlrp3(-/-) mice than in Pycard(-/-) or Casp1(-/-) animals. No significant differences were observed in disease progression or outcome in Nlrc4(-/-) mice compared with similarly treated wild-type animals. 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subjects | Animals Apoptosis Regulatory Proteins CARD Signaling Adaptor Proteins Carrier Proteins - genetics Colitis - complications Colon - metabolism Colon - pathology Cytoskeletal Proteins - deficiency Cytoskeletal Proteins - genetics Euthanasia Gene Expression Regulation, Neoplastic Humans Inflammatory Bowel Diseases - complications Interleukin-18 - metabolism Interleukin-1beta - metabolism Mice Mice, Knockout Neoplasms - etiology Neoplasms - pathology Neoplasms - prevention & control NLR Family, Pyrin Domain-Containing 3 Protein Tumor Burden |
title | The NLRP3 inflammasome functions as a negative regulator of tumorigenesis during colitis-associated cancer |
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