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RNA interference of STAT6 rapidly attenuates ongoing interleukin-13-mediated events in lung epithelial cells

W Walker, GD Healey, JM Hopkin, William Walker Orcid Logo, Gareth Healey Orcid Logo

Immunology, Volume: 127, Pages: 256 - 266

Swansea University Authors: William Walker Orcid Logo, Gareth Healey Orcid Logo

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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...

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Published in: Immunology
Published: Immunology 2009
URI: https://cronfa.swan.ac.uk/Record/cronfa10002
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fullrecord <?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 &lt; 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>
spelling 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
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
document_store_str 0
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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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score 11.026015

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