Restoration of mucosal integrity and epithelial transport function by concomitant anti-TNFα treatment in chronic DSS-induced colitis
Impaired salt and water absorption is a hallmark of diarrhea in IBD. In the present study, the therapeutic effect of continuous anti-TNFα treatment on the progression of inflammation and colonic transport dysfunction during chronic dextran sulfate sodium (DSS)-induced colitis was investigated. Chron...
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| Veröffentlicht in: | Journal of molecular medicine (Berlin, Germany) Germany), 2018-08, Vol.96 (8), p.831-843 |
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| creator | Lenzen, Henrike Qian, Jiajie Manns, Michael P Seidler, Ursula Jörns, Anne |
| description | Impaired salt and water absorption is a hallmark of diarrhea in IBD. In the present study, the therapeutic effect of continuous anti-TNFα treatment on the progression of inflammation and colonic transport dysfunction during chronic dextran sulfate sodium (DSS)-induced colitis was investigated. Chronic colitis was induced by three DSS exposure cycles. Mice received TNFα monoclonal antibody treatment twice weekly after the end of the first 5-day DSS drinking period. Mice developed chronic DSS-induced colitis characterized by a typical immune cell infiltration composed of CD3
+
T cells and CD68
+
macrophages, both expressing high levels of the pro-inflammatory cytokines IL-1β and TNFα, a loss of NHE3 and PDZK1 in the brush border region of the absorptive enterocyte and a decrease of colonic fluid absorption in vivo, measured by colonic single pass perfusion. Concomitant anti-TNFα treatment resulted in a significant reduction of mucosal immune cell infiltration and expression of the pro-inflammatory cytokines IL-1β and TNFα. It also resulted in a normalization of NHE3-mediated fluid absorption and a restoration of NHE3 and PDZK1 location in the apical and subapical region of the enterocytes. Here, we show for the first time that in this chemically induced murine colitis model, anti-TNFα treatment significantly decreased inflammatory activity, improved mucosal integrity and restored transport function despite an ongoing inflammatory insult. Anti-TNFα treatment may therefore be beneficial in patients with IBD even in spite of an absence of complete mucosal healing.
Key messages
Chronic DSS treatment caused a loss of NHE3 and PDZK1 in the brush border region of the absorptive enterocyte and decreases colonic fluid absorption.
In DSS-induced colitis, anti-TNFα treatment reduced mucosal immune cell infiltration and expression of the pro-inflammatory cytokines IL-1β and TNFα.
In DSS-induced colitis, anti-TNFα treatment normalized NHE3-mediated fluid absorption and restored NHE3 and PDZK1 location in the enterocytes.
In DSS-induced colitis, anti-TNFα treatment decreased inflammatory activity, improved mucosal integrity, and restored transport function. |
| doi_str_mv | 10.1007/s00109-018-1658-1 |
| format | Article |
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+
T cells and CD68
+
macrophages, both expressing high levels of the pro-inflammatory cytokines IL-1β and TNFα, a loss of NHE3 and PDZK1 in the brush border region of the absorptive enterocyte and a decrease of colonic fluid absorption in vivo, measured by colonic single pass perfusion. Concomitant anti-TNFα treatment resulted in a significant reduction of mucosal immune cell infiltration and expression of the pro-inflammatory cytokines IL-1β and TNFα. It also resulted in a normalization of NHE3-mediated fluid absorption and a restoration of NHE3 and PDZK1 location in the apical and subapical region of the enterocytes. Here, we show for the first time that in this chemically induced murine colitis model, anti-TNFα treatment significantly decreased inflammatory activity, improved mucosal integrity and restored transport function despite an ongoing inflammatory insult. Anti-TNFα treatment may therefore be beneficial in patients with IBD even in spite of an absence of complete mucosal healing.
Key messages
Chronic DSS treatment caused a loss of NHE3 and PDZK1 in the brush border region of the absorptive enterocyte and decreases colonic fluid absorption.
In DSS-induced colitis, anti-TNFα treatment reduced mucosal immune cell infiltration and expression of the pro-inflammatory cytokines IL-1β and TNFα.
In DSS-induced colitis, anti-TNFα treatment normalized NHE3-mediated fluid absorption and restored NHE3 and PDZK1 location in the enterocytes.
In DSS-induced colitis, anti-TNFα treatment decreased inflammatory activity, improved mucosal integrity, and restored transport function.</description><identifier>ISSN: 0946-2716</identifier><identifier>EISSN: 1432-1440</identifier><identifier>DOI: 10.1007/s00109-018-1658-1</identifier><identifier>PMID: 29967942</identifier><language>eng</language><publisher>Berlin/Heidelberg: Springer Berlin Heidelberg</publisher><subject>Absorption ; Absorptivity ; Biomedical and Life Sciences ; Biomedicine ; CD3 antigen ; Colitis ; Colon ; Cytokines ; Dextran ; Dextran sulfate ; Diarrhea ; Enterocytes ; Human Genetics ; IL-1β ; Inflammation ; Inflammatory bowel disease ; Internal Medicine ; Lymphocytes ; Lymphocytes T ; Macrophages ; Molecular Medicine ; Monoclonal antibodies ; Mucosal immunity ; Original Article ; Perfusion ; Rodents ; Sodium ; Tumor necrosis factor-α ; Water absorption</subject><ispartof>Journal of molecular medicine (Berlin, Germany), 2018-08, Vol.96 (8), p.831-843</ispartof><rights>Springer-Verlag GmbH Germany, part of Springer Nature 2018</rights><rights>Journal of Molecular Medicine is a copyright of Springer, (2018). All Rights Reserved.</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c372t-2d8b3e6d7839c417774658d0f66433ea8eff218f839bcd9e06b7ed879ec807963</citedby><cites>FETCH-LOGICAL-c372t-2d8b3e6d7839c417774658d0f66433ea8eff218f839bcd9e06b7ed879ec807963</cites><orcidid>0000-0002-0903-1415</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://link.springer.com/content/pdf/10.1007/s00109-018-1658-1$$EPDF$$P50$$Gspringer$$H</linktopdf><linktohtml>$$Uhttps://link.springer.com/10.1007/s00109-018-1658-1$$EHTML$$P50$$Gspringer$$H</linktohtml><link.rule.ids>314,780,784,27924,27925,41488,42557,51319</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/29967942$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Lenzen, Henrike</creatorcontrib><creatorcontrib>Qian, Jiajie</creatorcontrib><creatorcontrib>Manns, Michael P</creatorcontrib><creatorcontrib>Seidler, Ursula</creatorcontrib><creatorcontrib>Jörns, Anne</creatorcontrib><title>Restoration of mucosal integrity and epithelial transport function by concomitant anti-TNFα treatment in chronic DSS-induced colitis</title><title>Journal of molecular medicine (Berlin, Germany)</title><addtitle>J Mol Med</addtitle><addtitle>J Mol Med (Berl)</addtitle><description>Impaired salt and water absorption is a hallmark of diarrhea in IBD. In the present study, the therapeutic effect of continuous anti-TNFα treatment on the progression of inflammation and colonic transport dysfunction during chronic dextran sulfate sodium (DSS)-induced colitis was investigated. Chronic colitis was induced by three DSS exposure cycles. Mice received TNFα monoclonal antibody treatment twice weekly after the end of the first 5-day DSS drinking period. Mice developed chronic DSS-induced colitis characterized by a typical immune cell infiltration composed of CD3
+
T cells and CD68
+
macrophages, both expressing high levels of the pro-inflammatory cytokines IL-1β and TNFα, a loss of NHE3 and PDZK1 in the brush border region of the absorptive enterocyte and a decrease of colonic fluid absorption in vivo, measured by colonic single pass perfusion. Concomitant anti-TNFα treatment resulted in a significant reduction of mucosal immune cell infiltration and expression of the pro-inflammatory cytokines IL-1β and TNFα. It also resulted in a normalization of NHE3-mediated fluid absorption and a restoration of NHE3 and PDZK1 location in the apical and subapical region of the enterocytes. Here, we show for the first time that in this chemically induced murine colitis model, anti-TNFα treatment significantly decreased inflammatory activity, improved mucosal integrity and restored transport function despite an ongoing inflammatory insult. Anti-TNFα treatment may therefore be beneficial in patients with IBD even in spite of an absence of complete mucosal healing.
Key messages
Chronic DSS treatment caused a loss of NHE3 and PDZK1 in the brush border region of the absorptive enterocyte and decreases colonic fluid absorption.
In DSS-induced colitis, anti-TNFα treatment reduced mucosal immune cell infiltration and expression of the pro-inflammatory cytokines IL-1β and TNFα.
In DSS-induced colitis, anti-TNFα treatment normalized NHE3-mediated fluid absorption and restored NHE3 and PDZK1 location in the enterocytes.
In DSS-induced colitis, anti-TNFα treatment decreased inflammatory activity, improved mucosal integrity, and restored transport function.</description><subject>Absorption</subject><subject>Absorptivity</subject><subject>Biomedical and Life Sciences</subject><subject>Biomedicine</subject><subject>CD3 antigen</subject><subject>Colitis</subject><subject>Colon</subject><subject>Cytokines</subject><subject>Dextran</subject><subject>Dextran sulfate</subject><subject>Diarrhea</subject><subject>Enterocytes</subject><subject>Human Genetics</subject><subject>IL-1β</subject><subject>Inflammation</subject><subject>Inflammatory bowel disease</subject><subject>Internal Medicine</subject><subject>Lymphocytes</subject><subject>Lymphocytes T</subject><subject>Macrophages</subject><subject>Molecular Medicine</subject><subject>Monoclonal antibodies</subject><subject>Mucosal immunity</subject><subject>Original Article</subject><subject>Perfusion</subject><subject>Rodents</subject><subject>Sodium</subject><subject>Tumor necrosis factor-α</subject><subject>Water absorption</subject><issn>0946-2716</issn><issn>1432-1440</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2018</creationdate><recordtype>article</recordtype><sourceid>ABUWG</sourceid><sourceid>AFKRA</sourceid><sourceid>BENPR</sourceid><sourceid>CCPQU</sourceid><recordid>eNp1kc9uFSEYxYnR2Gv1AdwYEjduUP5dGJamtWrSaGLrmjDwTUszA1dgFvcBfCBfxGeS9lZNTNxAwvmd8_HlIPSc0deMUv2mUsqoIZQNhKltPx6gDZOCEyYlfYg21EhFuGbqCD2p9abTemvkY3TEjVHaSL5B379Abbm4FnPCecLL6nN1M46pwVWJbY9dChh2sV3DHLvQikt1l0vD05r8nW3cY5-Tz0tsLrVuaJFcfjr7-aPD4NoC_TEm7K9LTtHj04sLElNYPYTum2OL9Sl6NLm5wrP7-xh9PXt3efKBnH9-__Hk7TnxQvNGeBhGASroQRgvmdZa9rUDnZSSQoAbYJo4G6Yujz4YoGrUEAZtwA9UGyWO0atD7q7kb2vf3C6xephnlyCv1XKqhGaCq21HX_6D3uS1pP67O4pRLqjsFDtQvuRaC0x2V-Liyt4yam87soeObO_I3nZkWfe8uE9exwXCH8fvUjrAD0DtUrqC8nf0_1N_Adionps</recordid><startdate>20180801</startdate><enddate>20180801</enddate><creator>Lenzen, Henrike</creator><creator>Qian, Jiajie</creator><creator>Manns, Michael P</creator><creator>Seidler, Ursula</creator><creator>Jörns, Anne</creator><general>Springer Berlin Heidelberg</general><general>Springer Nature B.V</general><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>3V.</scope><scope>7TK</scope><scope>7X7</scope><scope>7XB</scope><scope>88E</scope><scope>8AO</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>ABUWG</scope><scope>AFKRA</scope><scope>BENPR</scope><scope>CCPQU</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>K9.</scope><scope>M0S</scope><scope>M1P</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PRINS</scope><scope>7X8</scope><orcidid>https://orcid.org/0000-0002-0903-1415</orcidid></search><sort><creationdate>20180801</creationdate><title>Restoration of mucosal integrity and epithelial transport function by concomitant anti-TNFα treatment in chronic DSS-induced colitis</title><author>Lenzen, Henrike ; Qian, Jiajie ; Manns, Michael P ; Seidler, Ursula ; Jörns, Anne</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c372t-2d8b3e6d7839c417774658d0f66433ea8eff218f839bcd9e06b7ed879ec807963</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2018</creationdate><topic>Absorption</topic><topic>Absorptivity</topic><topic>Biomedical and Life Sciences</topic><topic>Biomedicine</topic><topic>CD3 antigen</topic><topic>Colitis</topic><topic>Colon</topic><topic>Cytokines</topic><topic>Dextran</topic><topic>Dextran sulfate</topic><topic>Diarrhea</topic><topic>Enterocytes</topic><topic>Human Genetics</topic><topic>IL-1β</topic><topic>Inflammation</topic><topic>Inflammatory bowel disease</topic><topic>Internal Medicine</topic><topic>Lymphocytes</topic><topic>Lymphocytes T</topic><topic>Macrophages</topic><topic>Molecular Medicine</topic><topic>Monoclonal antibodies</topic><topic>Mucosal immunity</topic><topic>Original Article</topic><topic>Perfusion</topic><topic>Rodents</topic><topic>Sodium</topic><topic>Tumor necrosis factor-α</topic><topic>Water absorption</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Lenzen, Henrike</creatorcontrib><creatorcontrib>Qian, Jiajie</creatorcontrib><creatorcontrib>Manns, Michael P</creatorcontrib><creatorcontrib>Seidler, Ursula</creatorcontrib><creatorcontrib>Jörns, Anne</creatorcontrib><collection>PubMed</collection><collection>CrossRef</collection><collection>ProQuest Central (Corporate)</collection><collection>Neurosciences Abstracts</collection><collection>Health & Medical Collection</collection><collection>ProQuest Central (purchase pre-March 2016)</collection><collection>Medical Database (Alumni Edition)</collection><collection>ProQuest Pharma 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</collection><collection>ProQuest One Community College</collection><collection>Health Research Premium Collection</collection><collection>Health Research Premium Collection (Alumni)</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>Health & Medical Collection (Alumni Edition)</collection><collection>Medical 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>Journal of molecular medicine (Berlin, Germany)</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Lenzen, Henrike</au><au>Qian, Jiajie</au><au>Manns, Michael P</au><au>Seidler, Ursula</au><au>Jörns, Anne</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Restoration of mucosal integrity and epithelial transport function by concomitant anti-TNFα treatment in chronic DSS-induced colitis</atitle><jtitle>Journal of molecular medicine (Berlin, Germany)</jtitle><stitle>J Mol Med</stitle><addtitle>J Mol Med (Berl)</addtitle><date>2018-08-01</date><risdate>2018</risdate><volume>96</volume><issue>8</issue><spage>831</spage><epage>843</epage><pages>831-843</pages><issn>0946-2716</issn><eissn>1432-1440</eissn><abstract>Impaired salt and water absorption is a hallmark of diarrhea in IBD. In the present study, the therapeutic effect of continuous anti-TNFα treatment on the progression of inflammation and colonic transport dysfunction during chronic dextran sulfate sodium (DSS)-induced colitis was investigated. Chronic colitis was induced by three DSS exposure cycles. Mice received TNFα monoclonal antibody treatment twice weekly after the end of the first 5-day DSS drinking period. Mice developed chronic DSS-induced colitis characterized by a typical immune cell infiltration composed of CD3
+
T cells and CD68
+
macrophages, both expressing high levels of the pro-inflammatory cytokines IL-1β and TNFα, a loss of NHE3 and PDZK1 in the brush border region of the absorptive enterocyte and a decrease of colonic fluid absorption in vivo, measured by colonic single pass perfusion. Concomitant anti-TNFα treatment resulted in a significant reduction of mucosal immune cell infiltration and expression of the pro-inflammatory cytokines IL-1β and TNFα. It also resulted in a normalization of NHE3-mediated fluid absorption and a restoration of NHE3 and PDZK1 location in the apical and subapical region of the enterocytes. Here, we show for the first time that in this chemically induced murine colitis model, anti-TNFα treatment significantly decreased inflammatory activity, improved mucosal integrity and restored transport function despite an ongoing inflammatory insult. Anti-TNFα treatment may therefore be beneficial in patients with IBD even in spite of an absence of complete mucosal healing.
Key messages
Chronic DSS treatment caused a loss of NHE3 and PDZK1 in the brush border region of the absorptive enterocyte and decreases colonic fluid absorption.
In DSS-induced colitis, anti-TNFα treatment reduced mucosal immune cell infiltration and expression of the pro-inflammatory cytokines IL-1β and TNFα.
In DSS-induced colitis, anti-TNFα treatment normalized NHE3-mediated fluid absorption and restored NHE3 and PDZK1 location in the enterocytes.
In DSS-induced colitis, anti-TNFα treatment decreased inflammatory activity, improved mucosal integrity, and restored transport function.</abstract><cop>Berlin/Heidelberg</cop><pub>Springer Berlin Heidelberg</pub><pmid>29967942</pmid><doi>10.1007/s00109-018-1658-1</doi><tpages>13</tpages><orcidid>https://orcid.org/0000-0002-0903-1415</orcidid></addata></record> |
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| subjects | Absorption Absorptivity Biomedical and Life Sciences Biomedicine CD3 antigen Colitis Colon Cytokines Dextran Dextran sulfate Diarrhea Enterocytes Human Genetics IL-1β Inflammation Inflammatory bowel disease Internal Medicine Lymphocytes Lymphocytes T Macrophages Molecular Medicine Monoclonal antibodies Mucosal immunity Original Article Perfusion Rodents Sodium Tumor necrosis factor-α Water absorption |
| title | Restoration of mucosal integrity and epithelial transport function by concomitant anti-TNFα treatment in chronic DSS-induced colitis |
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