Non-hematopoietic STAT6 induces epithelial tight junction dysfunction and promotes intestinal inflammation and tumorigenesis
Enhanced gut permeability due to dysregulated epithelial tight junction is often associated with inflammatory bowel diseases (IBD), which have a greater risk for developing colorectal cancer. STAT6 activation was detected in inflamed colonic epithelium of active IBD patients, suggesting a role of ep...
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| Veröffentlicht in: | Mucosal immunology 2019-11, Vol.12 (6), p.1304-1315 |
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| creator | Lin, Yuli Li, Bingji Yang, Xuguang Liu, Ting Shi, Tiancong Deng, Bo Zhang, Yubin Jia, Lijun Jiang, Zhengfan He, Rui |
| description | Enhanced gut permeability due to dysregulated epithelial tight junction is often associated with inflammatory bowel diseases (IBD), which have a greater risk for developing colorectal cancer. STAT6 activation was detected in inflamed colonic epithelium of active IBD patients, suggesting a role of epithelial STAT6 in colitis development. Here, we demonstrated that non-hematopoietic STAT6, but not hematopoietic STAT6, triggered DSS-induced colitis and subsequent tumorigenesis. This could be due to the enhancing-effect of STAT6 on gut permeability and microbiota translocation via interruption of epithelial tight junction integrity. Mechanistically, long-myosin light-chain kinase (MLCK1) was identified as a target of STAT6, leading to epithelial tight junction dysfunction and microbiota-driven colitis. Furthermore, neutralization of IL-13, which was primarily derived from type 2 innate lymphoid cells (ILC2) in a microbiota-dependent way, inhibited epithelial STAT6 activation and improved gut permeability and DSS-induced colitis. Importantly, pharmacological inhibition of STAT6 reduces murine intestinal tumor formation, and tumoral p-STAT6 levels positively correlated to the clinical stage and poor prognosis of human colorectal cancer. Thus, our study reveals a direct role of STAT6 in the disruption of epithelial tight junction integrity and colitis development, and suggests STAT6 as a potential therapeutic and prophylactic target for IBD and colitis-associated cancer. |
| doi_str_mv | 10.1038/s41385-019-0204-y |
| format | Article |
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STAT6 activation was detected in inflamed colonic epithelium of active IBD patients, suggesting a role of epithelial STAT6 in colitis development. Here, we demonstrated that non-hematopoietic STAT6, but not hematopoietic STAT6, triggered DSS-induced colitis and subsequent tumorigenesis. This could be due to the enhancing-effect of STAT6 on gut permeability and microbiota translocation via interruption of epithelial tight junction integrity. Mechanistically, long-myosin light-chain kinase (MLCK1) was identified as a target of STAT6, leading to epithelial tight junction dysfunction and microbiota-driven colitis. Furthermore, neutralization of IL-13, which was primarily derived from type 2 innate lymphoid cells (ILC2) in a microbiota-dependent way, inhibited epithelial STAT6 activation and improved gut permeability and DSS-induced colitis. Importantly, pharmacological inhibition of STAT6 reduces murine intestinal tumor formation, and tumoral p-STAT6 levels positively correlated to the clinical stage and poor prognosis of human colorectal cancer. Thus, our study reveals a direct role of STAT6 in the disruption of epithelial tight junction integrity and colitis development, and suggests STAT6 as a potential therapeutic and prophylactic target for IBD and colitis-associated cancer.</description><identifier>ISSN: 1933-0219</identifier><identifier>EISSN: 1935-3456</identifier><identifier>DOI: 10.1038/s41385-019-0204-y</identifier><identifier>PMID: 31534167</identifier><language>eng</language><publisher>New York: Nature Publishing Group US</publisher><subject>Allergology ; Animals ; Antibodies ; Bacterial Translocation ; Biomedical and Life Sciences ; Biomedicine ; Caco-2 Cells ; Cancer ; Colitis ; Colitis - genetics ; Colitis - metabolism ; Colitis - microbiology ; Colitis - pathology ; Colon - drug effects ; Colon - metabolism ; Colon - microbiology ; Colon - pathology ; Colonic Neoplasms - metabolism ; Colonic Neoplasms - microbiology ; Colonic Neoplasms - pathology ; Colonic Neoplasms - prevention & control ; Colorectal cancer ; Colorectal carcinoma ; Digestive system ; Disease Models, Animal ; Electric Impedance ; Epithelium ; Gastroenterology ; Gastrointestinal Microbiome ; Gastrointestinal tract ; Genes, APC ; Humans ; Immunology ; Inflammatory bowel disease ; Inflammatory bowel diseases ; Interleukin 13 ; Interleukin-13 - metabolism ; Intestinal Mucosa - drug effects ; Intestinal Mucosa - metabolism ; Intestinal Mucosa - microbiology ; Intestinal Mucosa - pathology ; Intestine ; Lymphocytes - metabolism ; Lymphocytes - pathology ; Lymphoid cells ; Mice, 129 Strain ; Mice, Inbred BALB C ; Mice, Inbred C57BL ; Mice, Knockout ; Microbiota ; Myosin ; Myosin-light-chain kinase ; Myosin-Light-Chain Kinase - genetics ; Myosin-Light-Chain Kinase - metabolism ; Permeability ; Phosphorylation ; Pyrimidines - pharmacology ; Signal Transduction ; Stat6 protein ; STAT6 Transcription Factor - antagonists & inhibitors ; STAT6 Transcription Factor - deficiency ; STAT6 Transcription Factor - genetics ; STAT6 Transcription Factor - metabolism ; Tight Junctions - drug effects ; Tight Junctions - metabolism ; Tight Junctions - microbiology ; Tight Junctions - pathology ; Tissue Culture Techniques ; Tumorigenesis</subject><ispartof>Mucosal immunology, 2019-11, Vol.12 (6), p.1304-1315</ispartof><rights>The Author(s) 2019</rights><rights>2019. This work is published under http://creativecommons.org/licenses/by/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c415t-fb46f5e4b089ab6333a2b3ff9e68caf89640a1e29f6bf169ccbf82fe392c04493</citedby><cites>FETCH-LOGICAL-c415t-fb46f5e4b089ab6333a2b3ff9e68caf89640a1e29f6bf169ccbf82fe392c04493</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://www.proquest.com/docview/2310990906?pq-origsite=primo$$EHTML$$P50$$Gproquest$$H</linktohtml><link.rule.ids>314,776,780,27903,27904,64361,64363,64365,72215</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/31534167$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Lin, Yuli</creatorcontrib><creatorcontrib>Li, Bingji</creatorcontrib><creatorcontrib>Yang, Xuguang</creatorcontrib><creatorcontrib>Liu, Ting</creatorcontrib><creatorcontrib>Shi, Tiancong</creatorcontrib><creatorcontrib>Deng, Bo</creatorcontrib><creatorcontrib>Zhang, Yubin</creatorcontrib><creatorcontrib>Jia, Lijun</creatorcontrib><creatorcontrib>Jiang, Zhengfan</creatorcontrib><creatorcontrib>He, Rui</creatorcontrib><title>Non-hematopoietic STAT6 induces epithelial tight junction dysfunction and promotes intestinal inflammation and tumorigenesis</title><title>Mucosal immunology</title><addtitle>Mucosal Immunol</addtitle><addtitle>Mucosal Immunol</addtitle><description>Enhanced gut permeability due to dysregulated epithelial tight junction is often associated with inflammatory bowel diseases (IBD), which have a greater risk for developing colorectal cancer. STAT6 activation was detected in inflamed colonic epithelium of active IBD patients, suggesting a role of epithelial STAT6 in colitis development. Here, we demonstrated that non-hematopoietic STAT6, but not hematopoietic STAT6, triggered DSS-induced colitis and subsequent tumorigenesis. This could be due to the enhancing-effect of STAT6 on gut permeability and microbiota translocation via interruption of epithelial tight junction integrity. Mechanistically, long-myosin light-chain kinase (MLCK1) was identified as a target of STAT6, leading to epithelial tight junction dysfunction and microbiota-driven colitis. Furthermore, neutralization of IL-13, which was primarily derived from type 2 innate lymphoid cells (ILC2) in a microbiota-dependent way, inhibited epithelial STAT6 activation and improved gut permeability and DSS-induced colitis. Importantly, pharmacological inhibition of STAT6 reduces murine intestinal tumor formation, and tumoral p-STAT6 levels positively correlated to the clinical stage and poor prognosis of human colorectal cancer. Thus, our study reveals a direct role of STAT6 in the disruption of epithelial tight junction integrity and colitis development, and suggests STAT6 as a potential therapeutic and prophylactic target for IBD and colitis-associated cancer.</description><subject>Allergology</subject><subject>Animals</subject><subject>Antibodies</subject><subject>Bacterial Translocation</subject><subject>Biomedical and Life Sciences</subject><subject>Biomedicine</subject><subject>Caco-2 Cells</subject><subject>Cancer</subject><subject>Colitis</subject><subject>Colitis - genetics</subject><subject>Colitis - metabolism</subject><subject>Colitis - microbiology</subject><subject>Colitis - pathology</subject><subject>Colon - drug effects</subject><subject>Colon - metabolism</subject><subject>Colon - microbiology</subject><subject>Colon - pathology</subject><subject>Colonic Neoplasms - metabolism</subject><subject>Colonic Neoplasms - microbiology</subject><subject>Colonic Neoplasms - pathology</subject><subject>Colonic Neoplasms - 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genetics</subject><subject>Myosin-Light-Chain Kinase - metabolism</subject><subject>Permeability</subject><subject>Phosphorylation</subject><subject>Pyrimidines - pharmacology</subject><subject>Signal Transduction</subject><subject>Stat6 protein</subject><subject>STAT6 Transcription Factor - antagonists & inhibitors</subject><subject>STAT6 Transcription Factor - deficiency</subject><subject>STAT6 Transcription Factor - genetics</subject><subject>STAT6 Transcription Factor - metabolism</subject><subject>Tight Junctions - drug effects</subject><subject>Tight Junctions - metabolism</subject><subject>Tight Junctions - microbiology</subject><subject>Tight Junctions - pathology</subject><subject>Tissue Culture Techniques</subject><subject>Tumorigenesis</subject><issn>1933-0219</issn><issn>1935-3456</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2019</creationdate><recordtype>article</recordtype><sourceid>C6C</sourceid><sourceid>EIF</sourceid><sourceid>ABUWG</sourceid><sourceid>AFKRA</sourceid><sourceid>AZQEC</sourceid><sourceid>BENPR</sourceid><sourceid>CCPQU</sourceid><sourceid>DWQXO</sourceid><sourceid>GNUQQ</sourceid><recordid>eNp1kUFrGzEQhUVpqFMnP6CXspBLL5uMVlp5dTQhaQsmOdQ9C608smV2JWelPRj64yPHdguBXmYG5ntPIx4hXyjcUmDNXeSUNXUJVJZQAS_3H8gllawuGa_Fx7eZ5Q2VE_I5xi2AAKjZJzJhtGacitkl-fMUfLnBXqewCw6TM8Wv5XwpCudXo8FY4M6lDXZOd0Vy600qtqM3yQVfrPbRnmftV8VuCH1IWeJ8rsn5LHHedrrP7mcojX0Y3Bo9RhevyIXVXcTrU5-S348Py_sf5eL5-8_7-aI0nNaptC0XtkbeQiN1KxhjumqZtRJFY7RtpOCgKVbSitZSIY1pbVNZZLIywLlkU_Lt6JtPfBnzbap30WDXaY9hjKqqJJMzyqHJ6M07dBvGIX8lU4yClCBBZIoeKTOEGAe0aje4Xg97RUEdolHHaFSORh2iUfus-XpyHtseV38V5ywyUB2BmFd-jcO_p__v-gqAMZzX</recordid><startdate>20191101</startdate><enddate>20191101</enddate><creator>Lin, Yuli</creator><creator>Li, Bingji</creator><creator>Yang, Xuguang</creator><creator>Liu, Ting</creator><creator>Shi, Tiancong</creator><creator>Deng, Bo</creator><creator>Zhang, Yubin</creator><creator>Jia, Lijun</creator><creator>Jiang, Zhengfan</creator><creator>He, Rui</creator><general>Nature Publishing Group US</general><general>Elsevier Limited</general><scope>C6C</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>3V.</scope><scope>7T5</scope><scope>7X7</scope><scope>7XB</scope><scope>88E</scope><scope>8FE</scope><scope>8FH</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>ABUWG</scope><scope>AFKRA</scope><scope>AZQEC</scope><scope>BBNVY</scope><scope>BENPR</scope><scope>BHPHI</scope><scope>CCPQU</scope><scope>DWQXO</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>GNUQQ</scope><scope>H94</scope><scope>HCIFZ</scope><scope>K9.</scope><scope>LK8</scope><scope>M0S</scope><scope>M1P</scope><scope>M7P</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PRINS</scope><scope>7X8</scope></search><sort><creationdate>20191101</creationdate><title>Non-hematopoietic STAT6 induces epithelial tight junction dysfunction and promotes intestinal inflammation and tumorigenesis</title><author>Lin, Yuli ; Li, Bingji ; Yang, Xuguang ; Liu, Ting ; Shi, Tiancong ; Deng, Bo ; Zhang, Yubin ; Jia, Lijun ; Jiang, Zhengfan ; He, Rui</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c415t-fb46f5e4b089ab6333a2b3ff9e68caf89640a1e29f6bf169ccbf82fe392c04493</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2019</creationdate><topic>Allergology</topic><topic>Animals</topic><topic>Antibodies</topic><topic>Bacterial Translocation</topic><topic>Biomedical and Life Sciences</topic><topic>Biomedicine</topic><topic>Caco-2 Cells</topic><topic>Cancer</topic><topic>Colitis</topic><topic>Colitis - genetics</topic><topic>Colitis - metabolism</topic><topic>Colitis - microbiology</topic><topic>Colitis - pathology</topic><topic>Colon - drug effects</topic><topic>Colon - metabolism</topic><topic>Colon - microbiology</topic><topic>Colon - pathology</topic><topic>Colonic Neoplasms - metabolism</topic><topic>Colonic Neoplasms - microbiology</topic><topic>Colonic Neoplasms - pathology</topic><topic>Colonic Neoplasms - prevention & control</topic><topic>Colorectal cancer</topic><topic>Colorectal carcinoma</topic><topic>Digestive system</topic><topic>Disease Models, Animal</topic><topic>Electric Impedance</topic><topic>Epithelium</topic><topic>Gastroenterology</topic><topic>Gastrointestinal Microbiome</topic><topic>Gastrointestinal tract</topic><topic>Genes, APC</topic><topic>Humans</topic><topic>Immunology</topic><topic>Inflammatory bowel disease</topic><topic>Inflammatory bowel diseases</topic><topic>Interleukin 13</topic><topic>Interleukin-13 - metabolism</topic><topic>Intestinal Mucosa - drug effects</topic><topic>Intestinal Mucosa - metabolism</topic><topic>Intestinal Mucosa - microbiology</topic><topic>Intestinal Mucosa - pathology</topic><topic>Intestine</topic><topic>Lymphocytes - metabolism</topic><topic>Lymphocytes - pathology</topic><topic>Lymphoid cells</topic><topic>Mice, 129 Strain</topic><topic>Mice, Inbred BALB C</topic><topic>Mice, Inbred C57BL</topic><topic>Mice, Knockout</topic><topic>Microbiota</topic><topic>Myosin</topic><topic>Myosin-light-chain kinase</topic><topic>Myosin-Light-Chain Kinase - genetics</topic><topic>Myosin-Light-Chain Kinase - metabolism</topic><topic>Permeability</topic><topic>Phosphorylation</topic><topic>Pyrimidines - pharmacology</topic><topic>Signal Transduction</topic><topic>Stat6 protein</topic><topic>STAT6 Transcription Factor - antagonists & inhibitors</topic><topic>STAT6 Transcription Factor - deficiency</topic><topic>STAT6 Transcription Factor - genetics</topic><topic>STAT6 Transcription Factor - metabolism</topic><topic>Tight Junctions - drug effects</topic><topic>Tight Junctions - metabolism</topic><topic>Tight Junctions - microbiology</topic><topic>Tight Junctions - pathology</topic><topic>Tissue Culture Techniques</topic><topic>Tumorigenesis</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Lin, Yuli</creatorcontrib><creatorcontrib>Li, Bingji</creatorcontrib><creatorcontrib>Yang, Xuguang</creatorcontrib><creatorcontrib>Liu, Ting</creatorcontrib><creatorcontrib>Shi, Tiancong</creatorcontrib><creatorcontrib>Deng, Bo</creatorcontrib><creatorcontrib>Zhang, Yubin</creatorcontrib><creatorcontrib>Jia, Lijun</creatorcontrib><creatorcontrib>Jiang, Zhengfan</creatorcontrib><creatorcontrib>He, Rui</creatorcontrib><collection>Springer Nature OA Free Journals</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>ProQuest Central (Corporate)</collection><collection>Immunology Abstracts</collection><collection>Health & Medical Collection</collection><collection>ProQuest Central (purchase pre-March 2016)</collection><collection>Medical Database (Alumni Edition)</collection><collection>ProQuest SciTech Collection</collection><collection>ProQuest Natural Science Collection</collection><collection>Hospital Premium Collection</collection><collection>Hospital Premium Collection (Alumni Edition)</collection><collection>ProQuest Central (Alumni) (purchase pre-March 2016)</collection><collection>ProQuest Central (Alumni Edition)</collection><collection>ProQuest Central UK/Ireland</collection><collection>ProQuest Central Essentials</collection><collection>Biological Science Collection</collection><collection>ProQuest Central</collection><collection>Natural Science Collection</collection><collection>ProQuest One Community College</collection><collection>ProQuest Central Korea</collection><collection>Health Research Premium Collection</collection><collection>Health Research Premium Collection (Alumni)</collection><collection>ProQuest Central Student</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>SciTech Premium Collection</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>ProQuest Biological Science Collection</collection><collection>Health & Medical Collection (Alumni Edition)</collection><collection>Medical Database</collection><collection>Biological Science Database</collection><collection>ProQuest One Academic Eastern Edition (DO NOT USE)</collection><collection>ProQuest One Academic</collection><collection>ProQuest One Academic UKI Edition</collection><collection>ProQuest Central China</collection><collection>MEDLINE - Academic</collection><jtitle>Mucosal immunology</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Lin, Yuli</au><au>Li, Bingji</au><au>Yang, Xuguang</au><au>Liu, Ting</au><au>Shi, Tiancong</au><au>Deng, Bo</au><au>Zhang, Yubin</au><au>Jia, Lijun</au><au>Jiang, Zhengfan</au><au>He, Rui</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Non-hematopoietic STAT6 induces epithelial tight junction dysfunction and promotes intestinal inflammation and tumorigenesis</atitle><jtitle>Mucosal immunology</jtitle><stitle>Mucosal Immunol</stitle><addtitle>Mucosal Immunol</addtitle><date>2019-11-01</date><risdate>2019</risdate><volume>12</volume><issue>6</issue><spage>1304</spage><epage>1315</epage><pages>1304-1315</pages><issn>1933-0219</issn><eissn>1935-3456</eissn><abstract>Enhanced gut permeability due to dysregulated epithelial tight junction is often associated with inflammatory bowel diseases (IBD), which have a greater risk for developing colorectal cancer. STAT6 activation was detected in inflamed colonic epithelium of active IBD patients, suggesting a role of epithelial STAT6 in colitis development. Here, we demonstrated that non-hematopoietic STAT6, but not hematopoietic STAT6, triggered DSS-induced colitis and subsequent tumorigenesis. This could be due to the enhancing-effect of STAT6 on gut permeability and microbiota translocation via interruption of epithelial tight junction integrity. Mechanistically, long-myosin light-chain kinase (MLCK1) was identified as a target of STAT6, leading to epithelial tight junction dysfunction and microbiota-driven colitis. Furthermore, neutralization of IL-13, which was primarily derived from type 2 innate lymphoid cells (ILC2) in a microbiota-dependent way, inhibited epithelial STAT6 activation and improved gut permeability and DSS-induced colitis. Importantly, pharmacological inhibition of STAT6 reduces murine intestinal tumor formation, and tumoral p-STAT6 levels positively correlated to the clinical stage and poor prognosis of human colorectal cancer. Thus, our study reveals a direct role of STAT6 in the disruption of epithelial tight junction integrity and colitis development, and suggests STAT6 as a potential therapeutic and prophylactic target for IBD and colitis-associated cancer.</abstract><cop>New York</cop><pub>Nature Publishing Group US</pub><pmid>31534167</pmid><doi>10.1038/s41385-019-0204-y</doi><tpages>12</tpages><oa>free_for_read</oa></addata></record> |
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| subjects | Allergology Animals Antibodies Bacterial Translocation Biomedical and Life Sciences Biomedicine Caco-2 Cells Cancer Colitis Colitis - genetics Colitis - metabolism Colitis - microbiology Colitis - pathology Colon - drug effects Colon - metabolism Colon - microbiology Colon - pathology Colonic Neoplasms - metabolism Colonic Neoplasms - microbiology Colonic Neoplasms - pathology Colonic Neoplasms - prevention & control Colorectal cancer Colorectal carcinoma Digestive system Disease Models, Animal Electric Impedance Epithelium Gastroenterology Gastrointestinal Microbiome Gastrointestinal tract Genes, APC Humans Immunology Inflammatory bowel disease Inflammatory bowel diseases Interleukin 13 Interleukin-13 - metabolism Intestinal Mucosa - drug effects Intestinal Mucosa - metabolism Intestinal Mucosa - microbiology Intestinal Mucosa - pathology Intestine Lymphocytes - metabolism Lymphocytes - pathology Lymphoid cells Mice, 129 Strain Mice, Inbred BALB C Mice, Inbred C57BL Mice, Knockout Microbiota Myosin Myosin-light-chain kinase Myosin-Light-Chain Kinase - genetics Myosin-Light-Chain Kinase - metabolism Permeability Phosphorylation Pyrimidines - pharmacology Signal Transduction Stat6 protein STAT6 Transcription Factor - antagonists & inhibitors STAT6 Transcription Factor - deficiency STAT6 Transcription Factor - genetics STAT6 Transcription Factor - metabolism Tight Junctions - drug effects Tight Junctions - metabolism Tight Junctions - microbiology Tight Junctions - pathology Tissue Culture Techniques Tumorigenesis |
| title | Non-hematopoietic STAT6 induces epithelial tight junction dysfunction and promotes intestinal inflammation and tumorigenesis |
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