MyD88 adaptor-like (Mal) regulates intestinal homeostasis and colitis-associated colorectal cancer in mice
Toll-like receptors (TLRs) play a central role in the recognition and response to microbial pathogens and in the maintenance and function of the epithelial barrier integrity in the gut. The protein MyD88 adaptor-like (Mal/TIRAP) serves as a bridge between TLR2/TLR4- and MyD88-mediated signaling to o...
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| Veröffentlicht in: | American journal of physiology: Gastrointestinal and liver physiology 2014-05, Vol.306 (9), p.G769-G778 |
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| container_title | American journal of physiology: Gastrointestinal and liver physiology |
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| creator | Aviello, Gabriella Corr, Sinéad C Johnston, Daniel G W O'Neill, Luke A J Fallon, Padraic G |
| description | Toll-like receptors (TLRs) play a central role in the recognition and response to microbial pathogens and in the maintenance and function of the epithelial barrier integrity in the gut. The protein MyD88 adaptor-like (Mal/TIRAP) serves as a bridge between TLR2/TLR4- and MyD88-mediated signaling to orchestrate downstream inflammatory responses. Whereas MyD88 has an essential function in the maintenance of intestinal homeostasis, a role for Mal in this context is less well described. Colitis was induced in wild-type (WT) and Mal-deficient (Mal(-/-)) mice by administration of dextran sodium sulfate (DSS). Colitis-associated cancer was induced by DSS and azoxymethane (AOM) treatment. Chimeric mice were generated by total body gamma irradiation followed by transplantation of bone marrow cells. In the DSS model of colon epithelial injury, Mal(-/-) mice developed increased inflammation and severity of colitis relative to WT mice. Mal(-/-) mice demonstrated the presence of inflammatory cell infiltrates, increased crypt proliferation, and presence of neoformations. Furthermore, in the AOM/DSS model, Mal(-/-) mice had greater incidence of tumors. Mal(-/-) and WT bone marrow chimeras demonstrated that nonhematopoietic cell expression of Mal had an important protective role in the control of intestinal inflammation and inflammation-associated cancer. Mal is essential for the maintenance of intestinal homeostasis and expression of Mal in nonhematopoietic cells prevents chronic intestinal inflammation that may predispose to colon neoplasia. |
| doi_str_mv | 10.1152/ajpgi.00399.2013 |
| format | Article |
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The protein MyD88 adaptor-like (Mal/TIRAP) serves as a bridge between TLR2/TLR4- and MyD88-mediated signaling to orchestrate downstream inflammatory responses. Whereas MyD88 has an essential function in the maintenance of intestinal homeostasis, a role for Mal in this context is less well described. Colitis was induced in wild-type (WT) and Mal-deficient (Mal(-/-)) mice by administration of dextran sodium sulfate (DSS). Colitis-associated cancer was induced by DSS and azoxymethane (AOM) treatment. Chimeric mice were generated by total body gamma irradiation followed by transplantation of bone marrow cells. In the DSS model of colon epithelial injury, Mal(-/-) mice developed increased inflammation and severity of colitis relative to WT mice. Mal(-/-) mice demonstrated the presence of inflammatory cell infiltrates, increased crypt proliferation, and presence of neoformations. Furthermore, in the AOM/DSS model, Mal(-/-) mice had greater incidence of tumors. Mal(-/-) and WT bone marrow chimeras demonstrated that nonhematopoietic cell expression of Mal had an important protective role in the control of intestinal inflammation and inflammation-associated cancer. Mal is essential for the maintenance of intestinal homeostasis and expression of Mal in nonhematopoietic cells prevents chronic intestinal inflammation that may predispose to colon neoplasia.</description><identifier>ISSN: 0193-1857</identifier><identifier>EISSN: 1522-1547</identifier><identifier>DOI: 10.1152/ajpgi.00399.2013</identifier><identifier>PMID: 24603458</identifier><identifier>CODEN: APGPDF</identifier><language>eng</language><publisher>United States: American Physiological Society</publisher><subject>Animals ; Azoxymethane ; Bone Marrow Transplantation ; Caco-2 Cells ; Colitis - chemically induced ; Colitis - etiology ; Colitis - genetics ; Colitis - metabolism ; Colitis - pathology ; Colitis - prevention & control ; Colon - metabolism ; Colon - pathology ; Colorectal cancer ; Colorectal Neoplasms - chemically induced ; Colorectal Neoplasms - etiology ; Colorectal Neoplasms - genetics ; Colorectal Neoplasms - metabolism ; Colorectal Neoplasms - pathology ; Colorectal Neoplasms - prevention & control ; Dextran Sulfate ; Digestive system ; Disease Models, Animal ; Female ; Gastrointestinal diseases ; Homeostasis ; Humans ; Male ; Membrane Glycoproteins - deficiency ; Membrane Glycoproteins - genetics ; Membrane Glycoproteins - metabolism ; Mice ; Mice, Inbred C57BL ; Mice, Knockout ; Pathogens ; Receptors, Interleukin-1 - deficiency ; Receptors, Interleukin-1 - genetics ; Receptors, Interleukin-1 - metabolism ; Rodents ; Severity of Illness Index ; Time Factors ; Transplantation Chimera</subject><ispartof>American journal of physiology: Gastrointestinal and liver physiology, 2014-05, Vol.306 (9), p.G769-G778</ispartof><rights>Copyright American Physiological Society May 1, 2014</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c369t-bdbe4282fea3ad5f9a941bcaa8190e0aa6d50b983bcd3b1486104fcf2e33c9863</citedby><cites>FETCH-LOGICAL-c369t-bdbe4282fea3ad5f9a941bcaa8190e0aa6d50b983bcd3b1486104fcf2e33c9863</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,780,784,3039,27924,27925</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/24603458$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Aviello, Gabriella</creatorcontrib><creatorcontrib>Corr, Sinéad C</creatorcontrib><creatorcontrib>Johnston, Daniel G W</creatorcontrib><creatorcontrib>O'Neill, Luke A J</creatorcontrib><creatorcontrib>Fallon, Padraic G</creatorcontrib><title>MyD88 adaptor-like (Mal) regulates intestinal homeostasis and colitis-associated colorectal cancer in mice</title><title>American journal of physiology: Gastrointestinal and liver physiology</title><addtitle>Am J Physiol Gastrointest Liver Physiol</addtitle><description>Toll-like receptors (TLRs) play a central role in the recognition and response to microbial pathogens and in the maintenance and function of the epithelial barrier integrity in the gut. The protein MyD88 adaptor-like (Mal/TIRAP) serves as a bridge between TLR2/TLR4- and MyD88-mediated signaling to orchestrate downstream inflammatory responses. Whereas MyD88 has an essential function in the maintenance of intestinal homeostasis, a role for Mal in this context is less well described. Colitis was induced in wild-type (WT) and Mal-deficient (Mal(-/-)) mice by administration of dextran sodium sulfate (DSS). Colitis-associated cancer was induced by DSS and azoxymethane (AOM) treatment. Chimeric mice were generated by total body gamma irradiation followed by transplantation of bone marrow cells. In the DSS model of colon epithelial injury, Mal(-/-) mice developed increased inflammation and severity of colitis relative to WT mice. Mal(-/-) mice demonstrated the presence of inflammatory cell infiltrates, increased crypt proliferation, and presence of neoformations. Furthermore, in the AOM/DSS model, Mal(-/-) mice had greater incidence of tumors. Mal(-/-) and WT bone marrow chimeras demonstrated that nonhematopoietic cell expression of Mal had an important protective role in the control of intestinal inflammation and inflammation-associated cancer. Mal is essential for the maintenance of intestinal homeostasis and expression of Mal in nonhematopoietic cells prevents chronic intestinal inflammation that may predispose to colon neoplasia.</description><subject>Animals</subject><subject>Azoxymethane</subject><subject>Bone Marrow Transplantation</subject><subject>Caco-2 Cells</subject><subject>Colitis - chemically induced</subject><subject>Colitis - etiology</subject><subject>Colitis - genetics</subject><subject>Colitis - metabolism</subject><subject>Colitis - pathology</subject><subject>Colitis - prevention & control</subject><subject>Colon - metabolism</subject><subject>Colon - pathology</subject><subject>Colorectal cancer</subject><subject>Colorectal Neoplasms - chemically induced</subject><subject>Colorectal Neoplasms - etiology</subject><subject>Colorectal Neoplasms - genetics</subject><subject>Colorectal Neoplasms - metabolism</subject><subject>Colorectal Neoplasms - pathology</subject><subject>Colorectal Neoplasms - prevention & control</subject><subject>Dextran Sulfate</subject><subject>Digestive system</subject><subject>Disease Models, Animal</subject><subject>Female</subject><subject>Gastrointestinal diseases</subject><subject>Homeostasis</subject><subject>Humans</subject><subject>Male</subject><subject>Membrane Glycoproteins - deficiency</subject><subject>Membrane Glycoproteins - genetics</subject><subject>Membrane Glycoproteins - metabolism</subject><subject>Mice</subject><subject>Mice, Inbred C57BL</subject><subject>Mice, Knockout</subject><subject>Pathogens</subject><subject>Receptors, Interleukin-1 - deficiency</subject><subject>Receptors, Interleukin-1 - genetics</subject><subject>Receptors, Interleukin-1 - metabolism</subject><subject>Rodents</subject><subject>Severity of Illness Index</subject><subject>Time Factors</subject><subject>Transplantation Chimera</subject><issn>0193-1857</issn><issn>1522-1547</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2014</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNpdkb1PwzAQxS0EoqWwM6FILGVIOcdOao-ofEqtWGCOLo5TXJK42MnQ_x43FAaWO-n0e6e79wi5pDCjNE1ucbNdmxkAk3KWAGVHZBzGSUxTPj8mY6CSxVSk8xE5834DAGlC6SkZJTwDxlMxJpvV7l6ICEvcdtbFtfnU0XSF9U3k9LqvsdM-Mm2onWmxjj5so63v0BsfYVtGytamMz5G760ygR5G1mnVBVphq7QL-qgxSp-Tkwprry8OfULeHx_eFs_x8vXpZXG3jBXLZBcXZaF5IpJKI8MyrSRKTguFKKgEDYhZmUIhBStUyQrKRUaBV6pKNGNKioxNyPRn79bZrz5cnjfGK13X2Grb-zw4RBkDDjKg1__Qje1deHSgeCalFGmg4IdSznrvdJVvnWnQ7XIK-T6HfMghH3LI9zkEydVhcV80uvwT_BrPvgGQlIUX</recordid><startdate>20140501</startdate><enddate>20140501</enddate><creator>Aviello, Gabriella</creator><creator>Corr, Sinéad C</creator><creator>Johnston, Daniel G W</creator><creator>O'Neill, Luke A J</creator><creator>Fallon, Padraic G</creator><general>American Physiological Society</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></search><sort><creationdate>20140501</creationdate><title>MyD88 adaptor-like (Mal) regulates intestinal homeostasis and colitis-associated colorectal cancer in mice</title><author>Aviello, Gabriella ; Corr, Sinéad C ; Johnston, Daniel G W ; O'Neill, Luke A J ; Fallon, Padraic G</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c369t-bdbe4282fea3ad5f9a941bcaa8190e0aa6d50b983bcd3b1486104fcf2e33c9863</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2014</creationdate><topic>Animals</topic><topic>Azoxymethane</topic><topic>Bone Marrow Transplantation</topic><topic>Caco-2 Cells</topic><topic>Colitis - chemically induced</topic><topic>Colitis - etiology</topic><topic>Colitis - genetics</topic><topic>Colitis - metabolism</topic><topic>Colitis - pathology</topic><topic>Colitis - prevention & control</topic><topic>Colon - metabolism</topic><topic>Colon - pathology</topic><topic>Colorectal cancer</topic><topic>Colorectal Neoplasms - chemically induced</topic><topic>Colorectal Neoplasms - etiology</topic><topic>Colorectal Neoplasms - genetics</topic><topic>Colorectal Neoplasms - metabolism</topic><topic>Colorectal Neoplasms - pathology</topic><topic>Colorectal Neoplasms - prevention & control</topic><topic>Dextran Sulfate</topic><topic>Digestive system</topic><topic>Disease Models, Animal</topic><topic>Female</topic><topic>Gastrointestinal diseases</topic><topic>Homeostasis</topic><topic>Humans</topic><topic>Male</topic><topic>Membrane Glycoproteins - deficiency</topic><topic>Membrane Glycoproteins - genetics</topic><topic>Membrane Glycoproteins - metabolism</topic><topic>Mice</topic><topic>Mice, Inbred C57BL</topic><topic>Mice, Knockout</topic><topic>Pathogens</topic><topic>Receptors, Interleukin-1 - deficiency</topic><topic>Receptors, Interleukin-1 - genetics</topic><topic>Receptors, Interleukin-1 - metabolism</topic><topic>Rodents</topic><topic>Severity of Illness Index</topic><topic>Time Factors</topic><topic>Transplantation Chimera</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Aviello, Gabriella</creatorcontrib><creatorcontrib>Corr, Sinéad C</creatorcontrib><creatorcontrib>Johnston, Daniel G W</creatorcontrib><creatorcontrib>O'Neill, Luke A J</creatorcontrib><creatorcontrib>Fallon, Padraic G</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><jtitle>American journal of physiology: Gastrointestinal and liver physiology</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Aviello, Gabriella</au><au>Corr, Sinéad C</au><au>Johnston, Daniel G W</au><au>O'Neill, Luke A J</au><au>Fallon, Padraic G</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>MyD88 adaptor-like (Mal) regulates intestinal homeostasis and colitis-associated colorectal cancer in mice</atitle><jtitle>American journal of physiology: Gastrointestinal and liver physiology</jtitle><addtitle>Am J Physiol Gastrointest Liver Physiol</addtitle><date>2014-05-01</date><risdate>2014</risdate><volume>306</volume><issue>9</issue><spage>G769</spage><epage>G778</epage><pages>G769-G778</pages><issn>0193-1857</issn><eissn>1522-1547</eissn><coden>APGPDF</coden><abstract>Toll-like receptors (TLRs) play a central role in the recognition and response to microbial pathogens and in the maintenance and function of the epithelial barrier integrity in the gut. The protein MyD88 adaptor-like (Mal/TIRAP) serves as a bridge between TLR2/TLR4- and MyD88-mediated signaling to orchestrate downstream inflammatory responses. Whereas MyD88 has an essential function in the maintenance of intestinal homeostasis, a role for Mal in this context is less well described. Colitis was induced in wild-type (WT) and Mal-deficient (Mal(-/-)) mice by administration of dextran sodium sulfate (DSS). Colitis-associated cancer was induced by DSS and azoxymethane (AOM) treatment. Chimeric mice were generated by total body gamma irradiation followed by transplantation of bone marrow cells. In the DSS model of colon epithelial injury, Mal(-/-) mice developed increased inflammation and severity of colitis relative to WT mice. Mal(-/-) mice demonstrated the presence of inflammatory cell infiltrates, increased crypt proliferation, and presence of neoformations. Furthermore, in the AOM/DSS model, Mal(-/-) mice had greater incidence of tumors. Mal(-/-) and WT bone marrow chimeras demonstrated that nonhematopoietic cell expression of Mal had an important protective role in the control of intestinal inflammation and inflammation-associated cancer. Mal is essential for the maintenance of intestinal homeostasis and expression of Mal in nonhematopoietic cells prevents chronic intestinal inflammation that may predispose to colon neoplasia.</abstract><cop>United States</cop><pub>American Physiological Society</pub><pmid>24603458</pmid><doi>10.1152/ajpgi.00399.2013</doi><oa>free_for_read</oa></addata></record> |
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| identifier | ISSN: 0193-1857 |
| ispartof | American journal of physiology: Gastrointestinal and liver physiology, 2014-05, Vol.306 (9), p.G769-G778 |
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| source | MEDLINE; American Physiological Society Paid; EZB-FREE-00999 freely available EZB journals; Alma/SFX Local Collection |
| subjects | Animals Azoxymethane Bone Marrow Transplantation Caco-2 Cells Colitis - chemically induced Colitis - etiology Colitis - genetics Colitis - metabolism Colitis - pathology Colitis - prevention & control Colon - metabolism Colon - pathology Colorectal cancer Colorectal Neoplasms - chemically induced Colorectal Neoplasms - etiology Colorectal Neoplasms - genetics Colorectal Neoplasms - metabolism Colorectal Neoplasms - pathology Colorectal Neoplasms - prevention & control Dextran Sulfate Digestive system Disease Models, Animal Female Gastrointestinal diseases Homeostasis Humans Male Membrane Glycoproteins - deficiency Membrane Glycoproteins - genetics Membrane Glycoproteins - metabolism Mice Mice, Inbred C57BL Mice, Knockout Pathogens Receptors, Interleukin-1 - deficiency Receptors, Interleukin-1 - genetics Receptors, Interleukin-1 - metabolism Rodents Severity of Illness Index Time Factors Transplantation Chimera |
| title | MyD88 adaptor-like (Mal) regulates intestinal homeostasis and colitis-associated colorectal cancer in mice |
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