Journal article 1119 views
RNA interference of STAT6 rapidly attenuates ongoing interleukin-13-mediated events in lung epithelial cells
Immunology, Volume: 127, Pages: 256 - 266
Swansea University Authors: William Walker , Gareth Healey
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DOI (Published version): 10.1111/j.1365-2567.2008.02951.x
Abstract
Signal transducer and activator of transcription 6 (STAT6) expression in lung epithelial cells plays a central role in asthma pathogenesis, with its activation driving the development of airway hyper-reactivity and local inflammation. Therefore, inhibition of local STAT6 expression provides a ration...
Published in: | Immunology |
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Immunology
2009
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URI: | https://cronfa.swan.ac.uk/Record/cronfa10002 |
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<?xml version="1.0"?><rfc1807><datestamp>2013-09-20T11:18:38.6126405</datestamp><bib-version>v2</bib-version><id>10002</id><entry>2012-03-21</entry><title>RNA interference of STAT6 rapidly attenuates ongoing interleukin-13-mediated events in lung epithelial cells</title><swanseaauthors><author><sid>1f736d4178747b6082940868d069894f</sid><ORCID>0000-0002-1940-5329</ORCID><firstname>William</firstname><surname>Walker</surname><name>William Walker</name><active>true</active><ethesisStudent>false</ethesisStudent></author><author><sid>5926519f89187489cfd5e1478aa188b1</sid><ORCID>0000-0001-9531-1220</ORCID><firstname>Gareth</firstname><surname>Healey</surname><name>Gareth Healey</name><active>true</active><ethesisStudent>false</ethesisStudent></author></swanseaauthors><date>2012-03-21</date><deptcode>BMS</deptcode><abstract>Signal transducer and activator of transcription 6 (STAT6) expression in lung epithelial cells plays a central role in asthma pathogenesis, with its activation driving the development of airway hyper-reactivity and local inflammation. Therefore, inhibition of local STAT6 expression provides a rationale for therapeutic intervention in bronchial asthma. Given the absence of specific inhibitory drugs, we tested the ability of small interfering RNAs (siRNAs) to target STAT6 gene expression through the molecular process of RNA interference (RNAi). At pico-molar concentrations, STAT6-specific siRNAs potently inhibited STAT6 mRNA expression in lung epithelial cells (50% inhibitory concentration range = 134-861 pm) without inducing cellular interferon responses. Detectable STAT6 protein expression was rapidly abolished within 48 hr of treatment (t(1/2) range = or < 12-37 hr) and this was unaffected by pretreatment with STAT6-activating cytokines. Furthermore, STAT6 suppression by RNAi produced downstream functional inhibitory effects in that interleukin (IL)-13- or IL-4-driven eotaxin chemokine family [chemokine (C-C motif) ligand 11 (CCL11), CCL24 and CCL26] mRNA expression was markedly inhibited. Induction of detectable CCL26 protein synthesis was completely ablated by pretreating cells with STAT6-specific siRNA. The therapeutic potential of this approach is further demonstrated by novel findings that cells pre-exposed to IL-13 or IL-4 and subsequently treated with STAT6-targeting siRNA exhibited a rapid and significant attenuation of ongoing CCL26 protein expression, suggesting that chronic asthma-associated lung inflammation will be responsive to this approach.</abstract><type>Journal Article</type><journal>Immunology</journal><volume>127</volume><journalNumber></journalNumber><paginationStart>256</paginationStart><paginationEnd>266</paginationEnd><publisher>Immunology</publisher><placeOfPublication/><issnPrint/><issnElectronic/><keywords>asthma, epithelium, RNAi, STAT6</keywords><publishedDay>31</publishedDay><publishedMonth>12</publishedMonth><publishedYear>2009</publishedYear><publishedDate>2009-12-31</publishedDate><doi>10.1111/j.1365-2567.2008.02951.x</doi><url/><notes/><college>COLLEGE NANME</college><department>Biomedical Sciences</department><CollegeCode>COLLEGE CODE</CollegeCode><DepartmentCode>BMS</DepartmentCode><institution>Swansea University</institution><apcterm/><lastEdited>2013-09-20T11:18:38.6126405</lastEdited><Created>2012-03-21T16:17:30.0000000</Created><path><level id="1">Faculty of Medicine, Health and Life Sciences</level><level id="2">Swansea University Medical School - Medicine</level></path><authors><author><firstname>W</firstname><surname>Walker</surname><order>1</order></author><author><firstname>GD</firstname><surname>Healey</surname><order>2</order></author><author><firstname>JM</firstname><surname>Hopkin</surname><order>3</order></author><author><firstname>William</firstname><surname>Walker</surname><orcid>0000-0002-1940-5329</orcid><order>4</order></author><author><firstname>Gareth</firstname><surname>Healey</surname><orcid>0000-0001-9531-1220</orcid><order>5</order></author></authors><documents/><OutputDurs/></rfc1807> |
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2013-09-20T11:18:38.6126405 v2 10002 2012-03-21 RNA interference of STAT6 rapidly attenuates ongoing interleukin-13-mediated events in lung epithelial cells 1f736d4178747b6082940868d069894f 0000-0002-1940-5329 William Walker William Walker true false 5926519f89187489cfd5e1478aa188b1 0000-0001-9531-1220 Gareth Healey Gareth Healey true false 2012-03-21 BMS Signal transducer and activator of transcription 6 (STAT6) expression in lung epithelial cells plays a central role in asthma pathogenesis, with its activation driving the development of airway hyper-reactivity and local inflammation. Therefore, inhibition of local STAT6 expression provides a rationale for therapeutic intervention in bronchial asthma. Given the absence of specific inhibitory drugs, we tested the ability of small interfering RNAs (siRNAs) to target STAT6 gene expression through the molecular process of RNA interference (RNAi). At pico-molar concentrations, STAT6-specific siRNAs potently inhibited STAT6 mRNA expression in lung epithelial cells (50% inhibitory concentration range = 134-861 pm) without inducing cellular interferon responses. Detectable STAT6 protein expression was rapidly abolished within 48 hr of treatment (t(1/2) range = or < 12-37 hr) and this was unaffected by pretreatment with STAT6-activating cytokines. Furthermore, STAT6 suppression by RNAi produced downstream functional inhibitory effects in that interleukin (IL)-13- or IL-4-driven eotaxin chemokine family [chemokine (C-C motif) ligand 11 (CCL11), CCL24 and CCL26] mRNA expression was markedly inhibited. Induction of detectable CCL26 protein synthesis was completely ablated by pretreating cells with STAT6-specific siRNA. The therapeutic potential of this approach is further demonstrated by novel findings that cells pre-exposed to IL-13 or IL-4 and subsequently treated with STAT6-targeting siRNA exhibited a rapid and significant attenuation of ongoing CCL26 protein expression, suggesting that chronic asthma-associated lung inflammation will be responsive to this approach. Journal Article Immunology 127 256 266 Immunology asthma, epithelium, RNAi, STAT6 31 12 2009 2009-12-31 10.1111/j.1365-2567.2008.02951.x COLLEGE NANME Biomedical Sciences COLLEGE CODE BMS Swansea University 2013-09-20T11:18:38.6126405 2012-03-21T16:17:30.0000000 Faculty of Medicine, Health and Life Sciences Swansea University Medical School - Medicine W Walker 1 GD Healey 2 JM Hopkin 3 William Walker 0000-0002-1940-5329 4 Gareth Healey 0000-0001-9531-1220 5 |
title |
RNA interference of STAT6 rapidly attenuates ongoing interleukin-13-mediated events in lung epithelial cells |
spellingShingle |
RNA interference of STAT6 rapidly attenuates ongoing interleukin-13-mediated events in lung epithelial cells William Walker Gareth Healey |
title_short |
RNA interference of STAT6 rapidly attenuates ongoing interleukin-13-mediated events in lung epithelial cells |
title_full |
RNA interference of STAT6 rapidly attenuates ongoing interleukin-13-mediated events in lung epithelial cells |
title_fullStr |
RNA interference of STAT6 rapidly attenuates ongoing interleukin-13-mediated events in lung epithelial cells |
title_full_unstemmed |
RNA interference of STAT6 rapidly attenuates ongoing interleukin-13-mediated events in lung epithelial cells |
title_sort |
RNA interference of STAT6 rapidly attenuates ongoing interleukin-13-mediated events in lung epithelial cells |
author_id_str_mv |
1f736d4178747b6082940868d069894f 5926519f89187489cfd5e1478aa188b1 |
author_id_fullname_str_mv |
1f736d4178747b6082940868d069894f_***_William Walker 5926519f89187489cfd5e1478aa188b1_***_Gareth Healey |
author |
William Walker Gareth Healey |
author2 |
W Walker GD Healey JM Hopkin William Walker Gareth Healey |
format |
Journal article |
container_title |
Immunology |
container_volume |
127 |
container_start_page |
256 |
publishDate |
2009 |
institution |
Swansea University |
doi_str_mv |
10.1111/j.1365-2567.2008.02951.x |
publisher |
Immunology |
college_str |
Faculty of Medicine, Health and Life Sciences |
hierarchytype |
|
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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 |
document_store_str |
0 |
active_str |
0 |
description |
Signal transducer and activator of transcription 6 (STAT6) expression in lung epithelial cells plays a central role in asthma pathogenesis, with its activation driving the development of airway hyper-reactivity and local inflammation. Therefore, inhibition of local STAT6 expression provides a rationale for therapeutic intervention in bronchial asthma. Given the absence of specific inhibitory drugs, we tested the ability of small interfering RNAs (siRNAs) to target STAT6 gene expression through the molecular process of RNA interference (RNAi). At pico-molar concentrations, STAT6-specific siRNAs potently inhibited STAT6 mRNA expression in lung epithelial cells (50% inhibitory concentration range = 134-861 pm) without inducing cellular interferon responses. Detectable STAT6 protein expression was rapidly abolished within 48 hr of treatment (t(1/2) range = or < 12-37 hr) and this was unaffected by pretreatment with STAT6-activating cytokines. Furthermore, STAT6 suppression by RNAi produced downstream functional inhibitory effects in that interleukin (IL)-13- or IL-4-driven eotaxin chemokine family [chemokine (C-C motif) ligand 11 (CCL11), CCL24 and CCL26] mRNA expression was markedly inhibited. Induction of detectable CCL26 protein synthesis was completely ablated by pretreating cells with STAT6-specific siRNA. The therapeutic potential of this approach is further demonstrated by novel findings that cells pre-exposed to IL-13 or IL-4 and subsequently treated with STAT6-targeting siRNA exhibited a rapid and significant attenuation of ongoing CCL26 protein expression, suggesting that chronic asthma-associated lung inflammation will be responsive to this approach. |
published_date |
2009-12-31T03:10:37Z |
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1763749959953285120 |
score |
11.026015 |