{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,24]],"date-time":"2026-09-24T09:27:32Z","timestamp":1790242052502,"version":"4.1.0"},"reference-count":51,"publisher":"Oxford University Press (OUP)","issue":"5","license":[{"start":{"date-parts":[[2009,11,1]],"date-time":"2009-11-01T00:00:00Z","timestamp":1257033600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2009,11,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Interleukin-13 (IL-13) is one of the central mediators for development of airway hyperresponsiveness in asthma. The signal transducer and activation of transcription 6 (STAT6) is one of the major signal transducers activated by IL-13, and a possible involvement of IL-13\/STAT6 pathway in the augmented bronchial smooth muscle (BSM) contraction has been suggested. In the present study, the effect of a novel STAT6 inhibitor, AS1517499, on the development of antigen-induced BSM hyperresponsiveness was investigated. In cultured human BSM cells, IL-13 (100 ng\/ml) caused a phosphorylation of STAT6 and an up-regulation of RhoA, a monomeric GTPase responsible for Ca2+ sensitization of smooth muscle contraction: both events were inhibited by co-incubation with AS1517499 (100 nM). In BALB\/c mice that were actively sensitized and repeatedly challenged with ovalbumin antigen, an increased IL-13 level in bronchoalveolar lavage fluids and a phosphorylation of STAT6 in bronchial tissues were observed after the last antigen challenge. These mice had an augmented BSM contractility to acetylcholine together with an up-regulation of RhoA in bronchial tissues. Intraperitoneal injections of AS1517499 (10 mg\/kg) 1 hour before each ovalbumin exposure inhibited both the antigen-induced up-regulation of RhoA and BSM hyperresponsiveness, almost completely. A partial but significant inhibition of antigen-induced production of IL-13 was also found. These findings suggest that the inhibitory effects of STAT6 inhibitory agents, such as AS1517499, both on RhoA and IL-13 up-regulations might be useful for asthma treatment.<\/jats:p>","DOI":"10.1165\/rcmb.2008-0163oc","type":"journal-article","created":{"date-parts":[[2009,2,7]],"date-time":"2009-02-07T04:03:16Z","timestamp":1233979396000},"page":"516-524","source":"Crossref","is-referenced-by-count":115,"title":["A Novel STAT6 Inhibitor AS1517499 Ameliorates Antigen-Induced Bronchial Hypercontractility in Mice"],"prefix":"10.1093","volume":"41","author":[{"given":"Yoshihiko","family":"Chiba","sequence":"first","affiliation":[{"name":"Department of Pharmacology, School of Pharmacy, Hoshi University, Tokyo, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michiko","family":"Todoroki","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, School of Pharmacy, Hoshi University, Tokyo, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuichi","family":"Nishida","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, School of Pharmacy, Hoshi University, Tokyo, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Miki","family":"Tanabe","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, School of Pharmacy, Hoshi University, Tokyo, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Miwa","family":"Misawa","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, School of Pharmacy, Hoshi University, Tokyo, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2009,11,1]]},"reference":[{"key":"2026030623281167600_bib1","first-page":"389","volume":"121","year":"1980","journal-title":"Am Rev Respir Dis"},{"key":"2026030623281167600_bib2","year":"1993"},{"key":"2026030623281167600_bib3","doi-asserted-by":"crossref","first-page":"849","DOI":"10.1152\/jappl.1990.69.3.849","volume":"69","year":"1990","journal-title":"J Appl Physiol"},{"key":"2026030623281167600_bib4","doi-asserted-by":"crossref","first-page":"S179","DOI":"10.1164\/ajrccm.158.supplement_2.13tac160","volume":"158","year":"1998","journal-title":"Am J Respir Crit Care Med"},{"key":"2026030623281167600_bib5","doi-asserted-by":"crossref","first-page":"349","DOI":"10.1034\/j.1399-3003.2000.16b25.x","volume":"16","year":"2000","journal-title":"Eur Respir J"},{"key":"2026030623281167600_bib6","doi-asserted-by":"crossref","first-page":"1190","DOI":"10.1165\/ajrcmb.20.6.3441","volume":"20","year":"1999","journal-title":"Am J Respir Cell Mol Biol"},{"key":"2026030623281167600_bib7","doi-asserted-by":"crossref","first-page":"597","DOI":"10.1038\/sj.bjp.0702585","volume":"127","year":"1999","journal-title":"Br J Pharmacol"},{"key":"2026030623281167600_bib8","doi-asserted-by":"crossref","first-page":"4","DOI":"10.1186\/1465-9921-6-4","volume":"6","year":"2005","journal-title":"Respir Res"},{"key":"2026030623281167600_bib9","doi-asserted-by":"crossref","first-page":"221","DOI":"10.1540\/jsmr.39.221","volume":"39","year":"2003","journal-title":"J Smooth Muscle Res"},{"key":"2026030623281167600_bib10","doi-asserted-by":"crossref","first-page":"339","DOI":"10.2174\/138955706776073402","volume":"6","year":"2006","journal-title":"Mini Rev Med Chem"},{"key":"2026030623281167600_bib11","doi-asserted-by":"crossref","first-page":"2258","DOI":"10.1126\/science.282.5397.2258","volume":"282","year":"1998","journal-title":"Science"},{"key":"2026030623281167600_bib12","doi-asserted-by":"crossref","first-page":"2261","DOI":"10.1126\/science.282.5397.2261","volume":"282","year":"1998","journal-title":"Science"},{"key":"2026030623281167600_bib13","doi-asserted-by":"crossref","first-page":"4668","DOI":"10.4049\/jimmunol.167.8.4668","volume":"167","year":"2001","journal-title":"J Immunol"},{"key":"2026030623281167600_bib14","doi-asserted-by":"crossref","first-page":"425","DOI":"10.1146\/annurev.immunol.21.120601.141142","volume":"21","year":"2003","journal-title":"Annu Rev Immunol"},{"key":"2026030623281167600_bib15","doi-asserted-by":"crossref","first-page":"1678","DOI":"10.1126\/science.1095336","volume":"304","year":"2004","journal-title":"Science"},{"key":"2026030623281167600_bib16","doi-asserted-by":"crossref","first-page":"175","DOI":"10.1111\/j.0105-2896.2004.00215.x","volume":"202","year":"2004","journal-title":"Immunol Rev"},{"key":"2026030623281167600_bib17","doi-asserted-by":"crossref","first-page":"224","DOI":"10.1016\/j.cyto.2004.08.007","volume":"28","year":"2004","journal-title":"Cytokine"},{"key":"2026030623281167600_bib18","doi-asserted-by":"crossref","first-page":"8","DOI":"10.1124\/jpet.104.076133","volume":"313","year":"2005","journal-title":"J Pharmacol Exp Ther"},{"key":"2026030623281167600_bib19","doi-asserted-by":"crossref","first-page":"L576","DOI":"10.1152\/ajplung.00380.2003","volume":"288","year":"2005","journal-title":"Am J Physiol Lung Cell Mol Physiol"},{"key":"2026030623281167600_bib20","doi-asserted-by":"crossref","first-page":"1106","DOI":"10.1016\/j.jaci.2004.08.032","volume":"114","year":"2004","journal-title":"J Allergy Clin Immunol"},{"key":"2026030623281167600_bib21","doi-asserted-by":"crossref","first-page":"685","DOI":"10.1016\/j.jaci.2008.01.005","volume":"121","year":"2008","journal-title":"J Allergy Clin Immunol"},{"key":"2026030623281167600_bib22","doi-asserted-by":"crossref","first-page":"779","DOI":"10.1172\/JCI5909","volume":"103","year":"1999","journal-title":"J Clin Invest"},{"key":"2026030623281167600_bib23","doi-asserted-by":"crossref","first-page":"522","DOI":"10.1165\/ajrcmb.25.4.4620","volume":"25","year":"2001","journal-title":"Am J Respir Cell Mol Biol"},{"key":"2026030623281167600_bib24","doi-asserted-by":"crossref","first-page":"1624","DOI":"10.1172\/JCI26150","volume":"116","year":"2006","journal-title":"J Clin Invest"},{"key":"2026030623281167600_bib25","doi-asserted-by":"crossref","first-page":"141","DOI":"10.1164\/ajrccm.164.1.2008060","volume":"164","year":"2001","journal-title":"Am J Respir Crit Care Med"},{"key":"2026030623281167600_bib26","doi-asserted-by":"crossref","first-page":"159","DOI":"10.1165\/rcmb.2008-0162OC","volume":"40","year":"2009","journal-title":"Am J Respir Cell Mol Biol"},{"key":"2026030623281167600_bib27","doi-asserted-by":"crossref","first-page":"948","DOI":"10.4049\/jimmunol.171.2.948","volume":"171","year":"2003","journal-title":"J Immunol"},{"key":"2026030623281167600_bib28","doi-asserted-by":"crossref","first-page":"G226","DOI":"10.1152\/ajpgi.2002.282.2.G226","volume":"282","year":"2002","journal-title":"Am J Physiol Gastrointest Liver Physiol"},{"key":"2026030623281167600_bib29","doi-asserted-by":"crossref","first-page":"474","DOI":"10.1165\/ajrcmb.25.4.4522","volume":"25","year":"2001","journal-title":"Am J Respir Cell Mol Biol"},{"key":"2026030623281167600_bib30","doi-asserted-by":"crossref","first-page":"G609","DOI":"10.1152\/ajpgi.00273.2004","volume":"288","year":"2005","journal-title":"Am J Physiol Gastrointest Liver Physiol"},{"key":"2026030623281167600_bib31","doi-asserted-by":"crossref","first-page":"1537","DOI":"10.1084\/jem.187.9.1537","volume":"187","year":"1998","journal-title":"J Exp Med"},{"key":"2026030623281167600_bib32","doi-asserted-by":"crossref","first-page":"939","DOI":"10.1084\/jem.187.6.939","volume":"187","year":"1998","journal-title":"J Exp Med"},{"key":"2026030623281167600_bib33","doi-asserted-by":"crossref","first-page":"1283","DOI":"10.1164\/ajrccm.160.4.9809065","volume":"160","year":"1999","journal-title":"Am J Respir Crit Care Med"},{"key":"2026030623281167600_bib34","doi-asserted-by":"crossref","first-page":"2556","DOI":"10.4049\/jimmunol.179.4.2556","volume":"179","year":"2007","journal-title":"J Immunol"},{"key":"2026030623281167600_bib35","doi-asserted-by":"crossref","first-page":"63","DOI":"10.1016\/j.ejphar.2007.10.061","volume":"580","year":"2008","journal-title":"Eur J Pharmacol"},{"key":"2026030623281167600_bib36","doi-asserted-by":"crossref","first-page":"1159","DOI":"10.1124\/mol.107.043505","volume":"73","year":"2008","journal-title":"Mol Pharmacol"},{"key":"2026030623281167600_bib37","doi-asserted-by":"crossref","first-page":"1044","DOI":"10.1016\/j.bmc.2006.10.015","volume":"15","year":"2007","journal-title":"Bioorg Med Chem"},{"key":"2026030623281167600_bib38","doi-asserted-by":"crossref","first-page":"7470","DOI":"10.4049\/jimmunol.162.12.7470","volume":"162","year":"1999","journal-title":"J Immunol"},{"key":"2026030623281167600_bib39","doi-asserted-by":"crossref","first-page":"958","DOI":"10.1164\/rccm.200503-456OC","volume":"173","year":"2006","journal-title":"Am J Respir Crit Care Med"},{"key":"2026030623281167600_bib40","doi-asserted-by":"crossref","first-page":"L1193","DOI":"10.1152\/ajplung.00263.2004","volume":"287","year":"2004","journal-title":"Am J Physiol Lung Cell Mol Physiol"},{"key":"2026030623281167600_bib41","doi-asserted-by":"crossref","first-page":"39","DOI":"10.1097\/00130832-200202000-00007","volume":"2","year":"2002","journal-title":"Curr Opin Allergy Clin Immunol"},{"key":"2026030623281167600_bib42","doi-asserted-by":"crossref","first-page":"636","DOI":"10.1007\/s00011-004-1305-x","volume":"53","year":"2004","journal-title":"Inflamm Res"},{"key":"2026030623281167600_bib43","doi-asserted-by":"crossref","first-page":"1325","DOI":"10.1152\/physrev.00023.2003","volume":"83","year":"2003","journal-title":"Physiol Rev"},{"key":"2026030623281167600_bib44","doi-asserted-by":"crossref","first-page":"155","DOI":"10.1540\/jsmr.40.155","volume":"40","year":"2004","journal-title":"J Smooth Muscle Res"},{"key":"2026030623281167600_bib45","doi-asserted-by":"crossref","first-page":"1083","DOI":"10.1021\/ol034125v","volume":"5","year":"2003","journal-title":"Org Lett"},{"key":"2026030623281167600_bib46","doi-asserted-by":"crossref","first-page":"513","DOI":"10.7164\/antibiotics.56.513","volume":"56","year":"2003","journal-title":"J Antibiot (Tokyo)"},{"key":"2026030623281167600_bib47","doi-asserted-by":"crossref","first-page":"886","DOI":"10.1038\/sj.bjp.0704137","volume":"133","year":"2001","journal-title":"Br J Pharmacol"},{"key":"2026030623281167600_bib48","doi-asserted-by":"crossref","first-page":"751","DOI":"10.1093\/jb\/mvi091","volume":"137","year":"2005","journal-title":"J Biochem"},{"key":"2026030623281167600_bib49","doi-asserted-by":"crossref","first-page":"L705","DOI":"10.1152\/ajplung.00531.2007","volume":"294","year":"2008","journal-title":"Am J Physiol Lung Cell Mol Physiol"},{"key":"2026030623281167600_bib50","doi-asserted-by":"crossref","first-page":"1749","DOI":"10.1084\/jem.20062456","volume":"204","year":"2007","journal-title":"J Exp Med"},{"key":"2026030623281167600_bib51","doi-asserted-by":"crossref","first-page":"1316","DOI":"10.1128\/MCB.23.4.1316-1333.2003","volume":"23","year":"2003","journal-title":"Mol Cell Biol"}],"container-title":["American Journal of Respiratory Cell and Molecular Biology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/ajrcmb\/article-pdf\/41\/5\/516\/67068943\/ajrcmb_41_5_516.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/ajrcmb\/article-pdf\/41\/5\/516\/67068943\/ajrcmb_41_5_516.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,3,7]],"date-time":"2026-03-07T04:30:27Z","timestamp":1772857827000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/ajrcmb\/article\/41\/5\/516\/8494004"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2009,11,1]]},"references-count":51,"journal-issue":{"issue":"5","published-online":{"date-parts":[[2009,11,1]]},"published-print":{"date-parts":[[2009,11,1]]}},"URL":"https:\/\/doi.org\/10.1165\/rcmb.2008-0163oc","relation":{},"ISSN":["1044-1549","1535-4989"],"issn-type":[{"value":"1044-1549","type":"print"},{"value":"1535-4989","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2009,11]]},"published":{"date-parts":[[2009,11,1]]}}}