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Signal transducer and activator of transcription-3 licenses Toll-like receptor 4-dependent interleukin (IL)-6 and IL-8 production via IL-6 receptor-positive feedback in endometrial cells

Cathy Thornton Orcid Logo, James Cronin Orcid Logo, Venkat Kanamarlapudi Orcid Logo, Martin Sheldon Orcid Logo

Mucosal Immunology, Volume: 9, Issue: 4, Pages: 1125 - 1136

Swansea University Authors: Cathy Thornton Orcid Logo, James Cronin Orcid Logo, Venkat Kanamarlapudi Orcid Logo, Martin Sheldon Orcid Logo

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DOI (Published version): 10.1038/mi.2015.131

Abstract

Interleukin 6 (IL-6), acting via the IL-6 receptor (IL6R) and signal transducer and activator of transcription-3 (STAT3), limits neutrophil recruitment once bacterial infections are resolved. Bovine endometritis is an exemplar mucosal disease, characterized by sustained neutrophil infiltration and e...

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Published in: Mucosal Immunology
Published: 2016
Online Access: http://www.nature.com/mi/journal/vaop/ncurrent/full/mi2015131a.html
URI: https://cronfa.swan.ac.uk/Record/cronfa25017
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Bovine endometritis is an exemplar mucosal disease, characterized by sustained neutrophil infiltration and elevated IL-6 and IL-8, a neutrophil chemoattractant, following postpartum Gram-negative bacterial infection. The present study examined the impact of the IL6R/STAT3 signaling pathway on IL-8 production by primary endometrial cells in response to short- or long-term exposure to lipopolysaccharide (LPS) from Gram-negative bacteria. Tyrosine phosphorylation of STAT3 is required for DNA binding and expression of specific targets genes. Immunoblotting indicated constitutive tyrosine phosphorylation of STAT3 in endometrial cells was impeded by acute exposure to LPS. After 24&#x2009;h exposure to LPS, STAT3 returned to a tyrosine phosphorylated state, indicating cross-talk between the Toll-like receptor 4 (TLR4) and the IL6R/STAT3 signaling pathways. This was confirmed by short interfering RNA targeting the IL6R, which abrogated the accumulation of IL-6 and IL-8, induced by LPS. Furthermore, there was a differential endometrial cell response, as the accumulation of IL-6 and IL-8 was dependent on STAT3, suppressor of cytokine signaling 3, and Src kinase signaling in stromal cells, but not epithelial cells. In conclusion, positive feedback through the IL6R amplifies LPS-induced IL-6 and IL-8 production in the endometrium. These findings provide a mechanistic insight into how elevated IL-6 concentrations in the postpartum endometrium during bacterial infection leads to marked and sustained neutrophil infiltration.</abstract><type>Journal Article</type><journal>Mucosal Immunology</journal><volume>9</volume><journalNumber>4</journalNumber><paginationStart>1125</paginationStart><paginationEnd>1136</paginationEnd><publisher/><keywords/><publishedDay>1</publishedDay><publishedMonth>9</publishedMonth><publishedYear>2016</publishedYear><publishedDate>2016-09-01</publishedDate><doi>10.1038/mi.2015.131</doi><url>http://www.nature.com/mi/journal/vaop/ncurrent/full/mi2015131a.html</url><notes>This work was funded by the United Kingdom Biotechnology and Biological Sciences Research Council (BBSRC; Grant numbers: F005121/1 and BB/1017240/1 awarded to IMS). 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spelling 2020-05-22T16:10:26.9511419 v2 25017 2015-12-10 Signal transducer and activator of transcription-3 licenses Toll-like receptor 4-dependent interleukin (IL)-6 and IL-8 production via IL-6 receptor-positive feedback in endometrial cells c71a7a4be7361094d046d312202bce0c 0000-0002-5153-573X Cathy Thornton Cathy Thornton true false 9cfd17551c0d1f7438895121e4fbb6e8 0000-0002-0590-9462 James Cronin James Cronin true false 63741801137148abfa4c00cd547dcdfa 0000-0002-8739-1483 Venkat Kanamarlapudi Venkat Kanamarlapudi true false ab0f74b794e59cc270c69e63ee1d9748 0000-0001-7902-5558 Martin Sheldon Martin Sheldon true false 2015-12-10 BMS Interleukin 6 (IL-6), acting via the IL-6 receptor (IL6R) and signal transducer and activator of transcription-3 (STAT3), limits neutrophil recruitment once bacterial infections are resolved. Bovine endometritis is an exemplar mucosal disease, characterized by sustained neutrophil infiltration and elevated IL-6 and IL-8, a neutrophil chemoattractant, following postpartum Gram-negative bacterial infection. The present study examined the impact of the IL6R/STAT3 signaling pathway on IL-8 production by primary endometrial cells in response to short- or long-term exposure to lipopolysaccharide (LPS) from Gram-negative bacteria. Tyrosine phosphorylation of STAT3 is required for DNA binding and expression of specific targets genes. Immunoblotting indicated constitutive tyrosine phosphorylation of STAT3 in endometrial cells was impeded by acute exposure to LPS. After 24 h exposure to LPS, STAT3 returned to a tyrosine phosphorylated state, indicating cross-talk between the Toll-like receptor 4 (TLR4) and the IL6R/STAT3 signaling pathways. This was confirmed by short interfering RNA targeting the IL6R, which abrogated the accumulation of IL-6 and IL-8, induced by LPS. Furthermore, there was a differential endometrial cell response, as the accumulation of IL-6 and IL-8 was dependent on STAT3, suppressor of cytokine signaling 3, and Src kinase signaling in stromal cells, but not epithelial cells. In conclusion, positive feedback through the IL6R amplifies LPS-induced IL-6 and IL-8 production in the endometrium. These findings provide a mechanistic insight into how elevated IL-6 concentrations in the postpartum endometrium during bacterial infection leads to marked and sustained neutrophil infiltration. Journal Article Mucosal Immunology 9 4 1125 1136 1 9 2016 2016-09-01 10.1038/mi.2015.131 http://www.nature.com/mi/journal/vaop/ncurrent/full/mi2015131a.html This work was funded by the United Kingdom Biotechnology and Biological Sciences Research Council (BBSRC; Grant numbers: F005121/1 and BB/1017240/1 awarded to IMS). James Cronin was a postdoctoral assistant working for Sheldon, and funded by Sheldon's BBSRC grant. COLLEGE NANME Biomedical Sciences COLLEGE CODE BMS Swansea University BBSRC 2020-05-22T16:10:26.9511419 2015-12-10T18:09:07.6727271 Faculty of Medicine, Health and Life Sciences Swansea University Medical School - Medicine Cathy Thornton 0000-0002-5153-573X 1 James Cronin 0000-0002-0590-9462 2 Venkat Kanamarlapudi 0000-0002-8739-1483 3 Martin Sheldon 0000-0001-7902-5558 4 0025017-27012016164955.pdf Cronin__MI__2016.pdf 2016-01-27T16:49:55.8100000 Output 2228497 application/pdf Version of Record true 2016-01-27T00:00:00.0000000 Open access CC-BY. This work was funded by the United Kingdom Biotechnology and Biological Sciences Research Council (BBSRC; Grant numbers: F005121/1 and BB/1017240/1 awarded to IMS). true
title Signal transducer and activator of transcription-3 licenses Toll-like receptor 4-dependent interleukin (IL)-6 and IL-8 production via IL-6 receptor-positive feedback in endometrial cells
spellingShingle Signal transducer and activator of transcription-3 licenses Toll-like receptor 4-dependent interleukin (IL)-6 and IL-8 production via IL-6 receptor-positive feedback in endometrial cells
Cathy Thornton
James Cronin
Venkat Kanamarlapudi
Martin Sheldon
title_short Signal transducer and activator of transcription-3 licenses Toll-like receptor 4-dependent interleukin (IL)-6 and IL-8 production via IL-6 receptor-positive feedback in endometrial cells
title_full Signal transducer and activator of transcription-3 licenses Toll-like receptor 4-dependent interleukin (IL)-6 and IL-8 production via IL-6 receptor-positive feedback in endometrial cells
title_fullStr Signal transducer and activator of transcription-3 licenses Toll-like receptor 4-dependent interleukin (IL)-6 and IL-8 production via IL-6 receptor-positive feedback in endometrial cells
title_full_unstemmed Signal transducer and activator of transcription-3 licenses Toll-like receptor 4-dependent interleukin (IL)-6 and IL-8 production via IL-6 receptor-positive feedback in endometrial cells
title_sort Signal transducer and activator of transcription-3 licenses Toll-like receptor 4-dependent interleukin (IL)-6 and IL-8 production via IL-6 receptor-positive feedback in endometrial cells
author_id_str_mv c71a7a4be7361094d046d312202bce0c
9cfd17551c0d1f7438895121e4fbb6e8
63741801137148abfa4c00cd547dcdfa
ab0f74b794e59cc270c69e63ee1d9748
author_id_fullname_str_mv c71a7a4be7361094d046d312202bce0c_***_Cathy Thornton
9cfd17551c0d1f7438895121e4fbb6e8_***_James Cronin
63741801137148abfa4c00cd547dcdfa_***_Venkat Kanamarlapudi
ab0f74b794e59cc270c69e63ee1d9748_***_Martin Sheldon
author Cathy Thornton
James Cronin
Venkat Kanamarlapudi
Martin Sheldon
author2 Cathy Thornton
James Cronin
Venkat Kanamarlapudi
Martin Sheldon
format Journal article
container_title Mucosal Immunology
container_volume 9
container_issue 4
container_start_page 1125
publishDate 2016
institution Swansea University
doi_str_mv 10.1038/mi.2015.131
college_str Faculty of Medicine, Health and Life Sciences
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hierarchy_top_id facultyofmedicinehealthandlifesciences
hierarchy_top_title Faculty of Medicine, Health and Life Sciences
hierarchy_parent_id facultyofmedicinehealthandlifesciences
hierarchy_parent_title Faculty of Medicine, Health and Life Sciences
department_str Swansea University Medical School - Medicine{{{_:::_}}}Faculty of Medicine, Health and Life Sciences{{{_:::_}}}Swansea University Medical School - Medicine
url http://www.nature.com/mi/journal/vaop/ncurrent/full/mi2015131a.html
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description Interleukin 6 (IL-6), acting via the IL-6 receptor (IL6R) and signal transducer and activator of transcription-3 (STAT3), limits neutrophil recruitment once bacterial infections are resolved. Bovine endometritis is an exemplar mucosal disease, characterized by sustained neutrophil infiltration and elevated IL-6 and IL-8, a neutrophil chemoattractant, following postpartum Gram-negative bacterial infection. The present study examined the impact of the IL6R/STAT3 signaling pathway on IL-8 production by primary endometrial cells in response to short- or long-term exposure to lipopolysaccharide (LPS) from Gram-negative bacteria. Tyrosine phosphorylation of STAT3 is required for DNA binding and expression of specific targets genes. Immunoblotting indicated constitutive tyrosine phosphorylation of STAT3 in endometrial cells was impeded by acute exposure to LPS. After 24 h exposure to LPS, STAT3 returned to a tyrosine phosphorylated state, indicating cross-talk between the Toll-like receptor 4 (TLR4) and the IL6R/STAT3 signaling pathways. This was confirmed by short interfering RNA targeting the IL6R, which abrogated the accumulation of IL-6 and IL-8, induced by LPS. Furthermore, there was a differential endometrial cell response, as the accumulation of IL-6 and IL-8 was dependent on STAT3, suppressor of cytokine signaling 3, and Src kinase signaling in stromal cells, but not epithelial cells. In conclusion, positive feedback through the IL6R amplifies LPS-induced IL-6 and IL-8 production in the endometrium. These findings provide a mechanistic insight into how elevated IL-6 concentrations in the postpartum endometrium during bacterial infection leads to marked and sustained neutrophil infiltration.
published_date 2016-09-01T03:29:44Z
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