{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,19]],"date-time":"2026-02-19T10:31:52Z","timestamp":1771497112501,"version":"3.50.1"},"reference-count":45,"publisher":"Oxford University Press (OUP)","issue":"4","license":[{"start":{"date-parts":[[2013,4,1]],"date-time":"2013-04-01T00:00:00Z","timestamp":1364774400000},"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":[[2013,4,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>IL-27 is involved in inflammatory reactions. CXCL10 is an important chemokine contributing to airway inflammatory disease. In this study, we investigated whether IL-27 modulated the synthesis of CXCL10 in primary human lung fibroblasts (HLFs). HLFs were activated by IL-27 alone, or in combination with other cytokines. CXCL10 synthesis was measured by real-time PCR and ELISA. An examination of transcriptional regulation was performed via the transient transfection of promoter constructs, whereas mRNA stability was assessed by actinomycin D chase and real-time PCR. The underlying signaling pathways were studied by Western blotting and intracellular staining, using flow cytometry. Our results demonstrated that IL-27 induced and synergized with TNF-\u03b1 to up-regulate CXCL10 mRNA and protein concentrations in a steroid-insensitive manner. This synergistic CXCL10 production was dependent on the transcriptional regulation of CXCL10 gene promoter activity and the enhanced stability of CXCL10 mRNA because of IL-27 and TNF-\u03b1, and this synergism was regulated by the activation of p38 mitogen\u2013activated protein kinase (MAPK) and phosphatidylinositol 3\u2013OH kinase (PI3K)\u2013Akt dominantly, and in small part via NF-\u03baB. Interestingly, IL-27 promoted the basal and enhanced TNF-\u03b1\u2013induced phosphorylation of p38 MAPK and Akt, but not I\u03baB\u03b1. Moreover, enhanced CXCL10 mRNA stability occurred via a p38 MAPK\u2013dependent pathway. Finally, clinical analysis showed that IL-27 was detected in the bronchoalveolar lavage of patients with asthma, chronic obstructive pulmonary disease (COPD), and pulmonary tuberculosis (PTB), and increased IL-27 concentrations were correlated with increased CXCL10 concentrations in patients with COPD and PTB. Our findings suggest that IL-27 has the potential to amplify airway inflammation via the induction of CXCL10 from HLFs, in combination with TNF-\u03b1.<\/jats:p>","DOI":"10.1165\/rcmb.2012-0340oc","type":"journal-article","created":{"date-parts":[[2013,1,18]],"date-time":"2013-01-18T20:16:57Z","timestamp":1358540217000},"page":"518-530","source":"Crossref","is-referenced-by-count":45,"title":["Synergy of IL-27 and TNF-\u03b1 in Regulating CXCL10 Expression in Lung Fibroblasts"],"prefix":"10.1093","volume":"48","author":[{"given":"Shanshan","family":"Dong","sequence":"first","affiliation":[{"name":"Department of Laboratory Medicine, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China"},{"name":"Key Laboratory of Diagnostic Medicine designated by the Ministry of Education, Chongqing Medical University, Chongqing, China; and"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xuemei","family":"Zhang","sequence":"additional","affiliation":[{"name":"Key Laboratory of Diagnostic Medicine designated by the Ministry of Education, Chongqing Medical University, Chongqing, China; and"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yujuan","family":"He","sequence":"additional","affiliation":[{"name":"Key Laboratory of Diagnostic Medicine designated by the Ministry of Education, Chongqing Medical University, Chongqing, China; and"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Fang","family":"Xu","sequence":"additional","affiliation":[{"name":"Department of Emergency and Intensive Care Unit, and"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Dairong","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Respiratory Disease, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"WenChun","family":"Xu","sequence":"additional","affiliation":[{"name":"Key Laboratory of Diagnostic Medicine designated by the Ministry of Education, Chongqing Medical University, Chongqing, China; and"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hong","family":"Wang","sequence":"additional","affiliation":[{"name":"Key Laboratory of Diagnostic Medicine designated by the Ministry of Education, Chongqing Medical University, Chongqing, China; and"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yibing","family":"Yin","sequence":"additional","affiliation":[{"name":"Key Laboratory of Diagnostic Medicine designated by the Ministry of Education, Chongqing Medical University, Chongqing, China; and"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ju","family":"Cao","sequence":"additional","affiliation":[{"name":"Department of Laboratory Medicine, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"286","published-online":{"date-parts":[[2013,4,1]]},"reference":[{"key":"2026021904193974400_bib1","doi-asserted-by":"crossref","first-page":"1417","DOI":"10.1378\/chest.09-1895","article-title":"Recent advances in the pathophysiology of asthma","volume":"137","author":"Murphy","year":"2010","journal-title":"Chest"},{"key":"2026021904193974400_bib2","doi-asserted-by":"crossref","first-page":"287","DOI":"10.1016\/j.jaci.2004.11.037","article-title":"Amphiregulin expression in human mast cells and its effect on the primary human lung fibroblasts","volume":"115","author":"Wang","year":"2005","journal-title":"J Allergy Clin Immunol"},{"key":"2026021904193974400_bib3","doi-asserted-by":"crossref","first-page":"534","DOI":"10.1016\/j.jaci.2004.11.051","article-title":"Airway fibroblasts exhibit a synthetic phenotype in severe asthma","volume":"115","author":"Lewis","year":"2005","journal-title":"J Allergy Clin Immunol"},{"key":"2026021904193974400_bib4","doi-asserted-by":"crossref","first-page":"520","DOI":"10.1067\/mai.2003.59","article-title":"Differential expression of thymus- and activation-regulated chemokine (CCL17) and macrophage-derived chemokine (CCL22) by human fibroblasts from cornea, skin, and lung","volume":"111","author":"Fukuda","year":"2003","journal-title":"J Allergy Clin Immunol"},{"key":"2026021904193974400_bib5","doi-asserted-by":"crossref","first-page":"664","DOI":"10.1067\/mai.2001.113524","article-title":"Expression of IFN-gamma\u2013inducible protein; monocyte chemotactic proteins 1, 3, and 4; and eotaxin in Th1- and Th2-mediated lung diseases","volume":"107","author":"Miotto","year":"2001","journal-title":"J Allergy Clin Immunol"},{"key":"2026021904193974400_bib6","doi-asserted-by":"crossref","first-page":"1404","DOI":"10.1164\/rccm.2107139","article-title":"Increased expression of the chemokine receptor CXCR3 and its ligand CXCL10 in peripheral airways of smokers with chronic obstructive pulmonary disease","volume":"165","author":"Saetta","year":"2002","journal-title":"Am J Respir Crit Care Med"},{"key":"2026021904193974400_bib7","doi-asserted-by":"crossref","first-page":"1909","DOI":"10.1378\/chest.124.5.1909","article-title":"Marked up-regulation of T lymphocytes and expression of interleukin-9 in bronchial biopsies from patients with chronic bronchitis with obstruction","volume":"124","author":"Panzner","year":"2003","journal-title":"Chest"},{"key":"2026021904193974400_bib8","doi-asserted-by":"crossref","first-page":"5278","DOI":"10.4049\/jimmunol.168.10.5278","article-title":"IFN-gamma\u2013inducible protein 10 (CXCL10) contributes to airway hyperreactivity and airway inflammation in a mouse model of asthma","volume":"168","author":"Medoff","year":"2002","journal-title":"J Immunol"},{"key":"2026021904193974400_bib9","doi-asserted-by":"crossref","first-page":"586","DOI":"10.1016\/j.jaci.2007.04.046","article-title":"IFN-gamma\u2013induced protein 10 is a novel biomarker of rhinovirus-induced asthma exacerbations","volume":"120","author":"Wark","year":"2007","journal-title":"J Allergy Clin Immunol"},{"key":"2026021904193974400_bib10","doi-asserted-by":"crossref","first-page":"812","DOI":"10.1378\/chest.09-1541","article-title":"Serum IP-10 as a biomarker of human rhinovirus infection at exacerbation of COPD","volume":"137","author":"Quint","year":"2010","journal-title":"Chest"},{"key":"2026021904193974400_bib11","doi-asserted-by":"crossref","first-page":"799","DOI":"10.1164\/rccm.200807-1089OC","article-title":"Lymphoid follicle cells in chronic obstructive pulmonary disease overexpress the chemokine receptor CXCR3","volume":"179","author":"Kelsen","year":"2009","journal-title":"Am J Respir Crit Care Med"},{"key":"2026021904193974400_bib12","doi-asserted-by":"crossref","first-page":"1103","DOI":"10.1164\/rccm.200409-1220OC","article-title":"The CXCL10\/CXCR3 axis mediates human lung mast cell migration to asthmatic airway smooth muscle","volume":"171","author":"Brightling","year":"2005","journal-title":"Am J Respir Crit Care Med"},{"key":"2026021904193974400_bib13","doi-asserted-by":"crossref","first-page":"846","DOI":"10.4049\/jimmunol.168.2.846","article-title":"CCL7 and CXCL10 orchestrate oxidative stress\u2013induced neutrophilic lung inflammation","volume":"168","author":"Michalec","year":"2002","journal-title":"J Immunol"},{"key":"2026021904193974400_bib14","doi-asserted-by":"crossref","first-page":"779","DOI":"10.1016\/S1074-7613(02)00324-2","article-title":"IL-27, a heterodimeric cytokine composed of EBI3 and p28 protein, induces proliferation of naive CD4(+) T cells","volume":"16","author":"Pflanz","year":"2002","journal-title":"Immunity"},{"key":"2026021904193974400_bib15","doi-asserted-by":"crossref","first-page":"715","DOI":"10.4049\/jimmunol.173.2.715","article-title":"Understanding the pro- and anti-inflammatory properties of IL-27","volume":"173","author":"Villarino","year":"2004","journal-title":"J Immunol"},{"key":"2026021904193974400_bib16","doi-asserted-by":"crossref","first-page":"2225","DOI":"10.4049\/jimmunol.172.4.2225","article-title":"WSX-1 and glycoprotein 130 constitute a signal-transducing receptor for IL-27","volume":"172","author":"Pflanz","year":"2004","journal-title":"J Immunol"},{"key":"2026021904193974400_bib17","doi-asserted-by":"crossref","first-page":"864","DOI":"10.4049\/jimmunol.1101912","article-title":"IL-27 enhances LPS-induced proinflammatory cytokine production via upregulation of TLR4 expression and signaling in human monocytes","volume":"188","author":"Guzzo","year":"2012","journal-title":"J Immunol"},{"key":"2026021904193974400_bib18","doi-asserted-by":"crossref","first-page":"54","DOI":"10.1016\/j.imbio.2010.03.004","article-title":"Activation of eosinophils by IL-12 family cytokine IL-27: implications of the pleiotropic roles of IL-27 in allergic responses","volume":"216","author":"Hu","year":"2011","journal-title":"Immunobiology"},{"key":"2026021904193974400_bib19","doi-asserted-by":"crossref","first-page":"788","DOI":"10.1002\/jcp.22094","article-title":"Activation of human bronchial epithelial cells by inflammatory cytokines IL-27 and TNF-alpha: implications for immunopathophysiology of airway inflammation","volume":"223","author":"Cao","year":"2010","journal-title":"J Cell Physiol"},{"key":"2026021904193974400_bib20","doi-asserted-by":"crossref","first-page":"1287","DOI":"10.1002\/eji.200738051","article-title":"IL-12, IL-23, and IL-27 enhance human beta-defensin\u20132 production in human keratinocytes","volume":"38","author":"Kanda","year":"2008","journal-title":"Eur J Immunol"},{"key":"2026021904193974400_bib21","doi-asserted-by":"crossref","first-page":"121","DOI":"10.1378\/chest.10-3297","article-title":"IL-27 is elevated in patients with COPD and patients with pulmonary TB and induces human bronchial epithelial cells to produce CXCL10","volume":"141","author":"Cao","year":"2012","journal-title":"Chest"},{"key":"2026021904193974400_bib22","doi-asserted-by":"crossref","first-page":"11899","DOI":"10.1074\/jbc.M111.308064","article-title":"Influenza A virus induces interleukin-27 through cyclooxygenase-2 and protein kinase A signaling","volume":"287","author":"Liu","year":"2012","journal-title":"J Biol Chem"},{"key":"2026021904193974400_bib23","doi-asserted-by":"crossref","first-page":"4007","DOI":"10.4049\/jimmunol.1101654","article-title":"TLR2-mediated production of IL-27 and chemokines by respiratory epithelial cells promotes bleomycin-induced pulmonary fibrosis in mice","volume":"187","author":"Kim","year":"2011","journal-title":"J Immunol"},{"key":"2026021904193974400_bib24","doi-asserted-by":"crossref","first-page":"371","DOI":"10.1378\/chest.130.2.371","article-title":"Chemokine concentrations and mast cell chemotactic activity in BAL fluid in patients with eosinophilic bronchitis and asthma, and in normal control subjects","volume":"130","author":"Woodman","year":"2006","journal-title":"Chest"},{"key":"2026021904193974400_bib25","doi-asserted-by":"crossref","first-page":"31212","DOI":"10.1016\/S0021-9258(19)84034-6","article-title":"Interferon-gamma\u2013inducible protein (IP)\u201310 mRNA stabilized by RNA-binding proteins in monocytes treated with S100b","volume":"281","author":"Shanmugam","year":"2006","journal-title":"J Biol Chem"},{"key":"2026021904193974400_bib26","doi-asserted-by":"crossref","first-page":"135","DOI":"10.1186\/1471-2334-11-135","article-title":"IP-10 response to RD1 antigens might be a useful biomarker for monitoring tuberculosis therapy","volume":"11","author":"Kabeer","year":"2011","journal-title":"BMC Infect Dis"},{"key":"2026021904193974400_bib27","doi-asserted-by":"crossref","first-page":"2333","DOI":"10.1373\/clinchem.2005.054460","article-title":"Early enhanced expression of interferon-inducible protein\u201310 (CXCL-10) and other chemokines predicts adverse outcome in severe acute respiratory syndrome","volume":"51","author":"Tang","year":"2005","journal-title":"Clin Chem"},{"key":"2026021904193974400_bib28","doi-asserted-by":"crossref","first-page":"662","DOI":"10.1164\/rccm.201104-0597OC","article-title":"Acute exacerbations of chronic obstructive pulmonary disease: identification of biologic clusters and their biomarkers","volume":"184","author":"Bafadhel","year":"2011","journal-title":"Am J Respir Crit Care Med"},{"key":"2026021904193974400_bib29","doi-asserted-by":"crossref","first-page":"592","DOI":"10.1165\/rcmb.2011-0116OC","article-title":"Long-term exposure of chemokine CXCL10 causes bronchiolitis-like inflammation","volume":"46","author":"Jiang","year":"2012","journal-title":"Am J Respir Cell Mol Biol"},{"key":"2026021904193974400_bib30","doi-asserted-by":"crossref","first-page":"193","DOI":"10.1038\/nri2275","article-title":"Dendritic cells and epithelial cells: linking innate and adaptive immunity in asthma","volume":"8","author":"Hammad","year":"2008","journal-title":"Nat Rev Immunol"},{"key":"2026021904193974400_bib31","doi-asserted-by":"crossref","first-page":"744","DOI":"10.1016\/S0140-6736(09)61342-8","article-title":"New drugs for exacerbations of chronic obstructive pulmonary disease","volume":"374","author":"Hansel","year":"2009","journal-title":"Lancet"},{"key":"2026021904193974400_bib32","doi-asserted-by":"crossref","first-page":"598","DOI":"10.1002\/ijc.20759","article-title":"The Epstein-Barr virus oncoprotein latent membrane protein 1 induces expression of the chemokine IP-10: importance of mRNA half-life regulation","volume":"114","author":"Vockerodt","year":"2005","journal-title":"Int J Cancer"},{"key":"2026021904193974400_bib33","doi-asserted-by":"crossref","first-page":"2722","DOI":"10.4049\/jimmunol.179.5.2722","article-title":"PDGF synergistically enhances IFN-gamma\u2013induced expression of CXCL10 in blood-derived macrophages: implications for HIV dementia","volume":"179","author":"Dhillon","year":"2007","journal-title":"J Immunol"},{"key":"2026021904193974400_bib34","doi-asserted-by":"crossref","first-page":"375","DOI":"10.1038\/ni1308","article-title":"MyD88-mediated stabilization of interferon-gamma\u2013induced cytokine and chemokine mRNA","volume":"7","author":"Sun","year":"2006","journal-title":"Nat Immunol"},{"key":"2026021904193974400_bib35","doi-asserted-by":"crossref","first-page":"42","DOI":"10.1097\/ACI.0b013e328334f642","article-title":"Signaling pathways critical for allergic airway inflammation","volume":"10","author":"Colgan","year":"2010","journal-title":"Curr Opin Allergy Clin Immunol"},{"key":"2026021904193974400_bib36","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1124\/jpet.106.111674","article-title":"Therapeutic potential of phosphatidylinositol 3\u2013kinase inhibitors in inflammatory respiratory disease","volume":"321","author":"Ito","year":"2007","journal-title":"J Pharmacol Exp Ther"},{"key":"2026021904193974400_bib37","doi-asserted-by":"crossref","first-page":"1045","DOI":"10.1016\/j.rmed.2007.01.004","article-title":"Mast cell infiltration of airway smooth muscle in asthma","volume":"101","author":"Bradding","year":"2007","journal-title":"Respir Med"},{"key":"2026021904193974400_bib38","doi-asserted-by":"crossref","first-page":"465","DOI":"10.1124\/jpet.110.175950","article-title":"Nortriptyline reverses corticosteroid insensitivity by inhibition of phosphoinositide-3\u2013kinase\u2013\u03b4","volume":"337","author":"Mercado","year":"2011","journal-title":"J Pharmacol Exp Ther"},{"key":"2026021904193974400_bib39","doi-asserted-by":"crossref","first-page":"1146","DOI":"10.1016\/j.jaci.2010.02.003","article-title":"A role for phosphoinositol 3\u2013kinase delta in the impairment of glucocorticoid responsiveness in patients with chronic obstructive pulmonary disease","volume":"125","author":"Marwick","year":"2010","journal-title":"J Allergy Clin Immunol"},{"key":"2026021904193974400_bib40","doi-asserted-by":"crossref","first-page":"98","DOI":"10.1007\/s12013-007-0043-4","article-title":"Impaired TNFalpha-induced VEGF expression in human airway smooth muscle cells from smokers with COPD: role of MAP kinases and histone acetylation: effect of dexamethasone","volume":"49","author":"Raidl","year":"2007","journal-title":"Cell Biochem Biophys"},{"key":"2026021904193974400_bib41","doi-asserted-by":"crossref","first-page":"1128","DOI":"10.1124\/mol.111.071993","article-title":"p38 mitogen\u2013activated protein kinase\u2013\u03b3 inhibition by long-acting \u03b22 adrenergic agonists reversed steroid insensitivity in severe asthma","volume":"80","author":"Mercado","year":"2011","journal-title":"Mol Pharmacol"},{"key":"2026021904193974400_bib42","doi-asserted-by":"crossref","first-page":"143","DOI":"10.1164\/ajrccm.159.1.9803066","article-title":"Cytokine levels correlate with a radiologic score in active pulmonary tuberculosis","volume":"159","author":"Casarini","year":"1999","journal-title":"Am J Respir Crit Care Med"},{"key":"2026021904193974400_bib43","doi-asserted-by":"crossref","first-page":"45","DOI":"10.1159\/000075648","article-title":"Leptin and TNF-alpha levels in patients with chronic obstructive pulmonary disease and their relationship to nutritional parameters","volume":"71","author":"Calikoglu","year":"2004","journal-title":"Respiration"},{"key":"2026021904193974400_bib44","doi-asserted-by":"crossref","first-page":"310","DOI":"10.1016\/j.jaci.2004.04.037","article-title":"Leukotriene D4 stimulates collagen production from myofibroblasts transformed by TGF-beta","volume":"114","author":"Asakura","year":"2004","journal-title":"J Allergy Clin Immunol"},{"key":"2026021904193974400_bib45","doi-asserted-by":"crossref","first-page":"248","DOI":"10.1164\/rccm.200706-929OC","article-title":"Lung fibroblast repair functions in patients with chronic obstructive pulmonary disease are altered by multiple mechanisms","volume":"178","author":"Togo","year":"2008","journal-title":"Am J Respir Crit Care Med"}],"container-title":["American Journal of Respiratory Cell and Molecular Biology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/ajrcmb\/article-pdf\/48\/4\/518\/66896430\/ajrcmb_48_4_518.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/ajrcmb\/article-pdf\/48\/4\/518\/66896430\/ajrcmb_48_4_518.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,2,19]],"date-time":"2026-02-19T09:22:59Z","timestamp":1771492979000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/ajrcmb\/article\/48\/4\/518\/8483377"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2013,4,1]]},"references-count":45,"journal-issue":{"issue":"4","published-online":{"date-parts":[[2013,4,1]]},"published-print":{"date-parts":[[2013,4,1]]}},"URL":"https:\/\/doi.org\/10.1165\/rcmb.2012-0340oc","relation":{},"ISSN":["1044-1549","1535-4989"],"issn-type":[{"value":"1044-1549","type":"print"},{"value":"1535-4989","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2013,4]]},"published":{"date-parts":[[2013,4,1]]}}}