{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,27]],"date-time":"2026-09-27T09:29:38Z","timestamp":1790501378983,"version":"4.1.0"},"reference-count":39,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2016,4,26]],"date-time":"2016-04-26T00:00:00Z","timestamp":1461628800000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2016,4,26]],"date-time":"2016-04-26T00:00:00Z","timestamp":1461628800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Sci Rep"],"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Systemic sclerosis is an autoimmune connective tissue disease in which T cells play a prominent role. We and others have previously demonstrated a role for T cell-derived IL-13 in mediating the induction of collagen in dermal fibroblasts and that blockade with IL-13 antibodies attenuates this increase. In this study we want to probe the signalling that underpins IL-13 mediated matrix deposition. Isolated dermal fibroblasts were incubated with recombinant IL-13 and gene expression by qRT-PCR was performed for collagen1A1 and TGF-\u03b21. Small interfering RNA (siRNA) was used to knock down STAT6 and a small molecule inhibitor was also used to block this pathway. MiR-135b was transfected into fibroblasts plus and minus IL-13 to see if this miR plays a role. miR-135b was measured in systemic sclerosis fibroblasts isolated from patients and also in serum. Results showed that IL-13 increased collagen expression and that this is independent from TGF-\u03b21. This is dependent on STAT6 as targeting this blocked induction. MiR-135b reduces collagen induction in fibroblasts and scleroderma fibroblasts have lower constitutive levels of the miR. We further demonstrate that miR135b is repressed by methylation and may include MeCP2. In conclusion we show that STAT6 and miR-135b regulate IL-13-mediated collagen production by fibroblasts.<\/jats:p>","DOI":"10.1038\/srep25066","type":"journal-article","created":{"date-parts":[[2016,4,26]],"date-time":"2016-04-26T05:22:01Z","timestamp":1461648121000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":74,"title":["IL-13 mediates collagen deposition via STAT6 and microRNA-135b: a role for epigenetics"],"prefix":"10.1038","volume":"6","author":[{"given":"Steven","family":"O\u2019Reilly","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marzena","family":"Ciechomska","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nicola","family":"Fullard","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stefan","family":"Przyborski","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jacob M.","family":"van Laar","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2016,4,26]]},"reference":[{"key":"BFsrep25066_CR1","doi-asserted-by":"publisher","first-page":"1989","DOI":"10.1056\/NEJMra0806188","volume":"360","author":"A Gabrielli","year":"2009","unstructured":"Gabrielli, A., Avvedimento, E. V. & Krieg, T. Scleroderma. N. Engl. J. Med. 360, 1989\u20132003 (2009).","journal-title":"N. Engl. J. Med."},{"key":"BFsrep25066_CR2","doi-asserted-by":"publisher","first-page":"1233","DOI":"10.1136\/ard.2004.027094","volume":"64","author":"A Kalogerou","year":"2005","unstructured":"Kalogerou, A. et al. Early T cell activation in the skin from patients with systemic sclerosis. Ann. Rheum. Dis. 64, 1233\u20131235 (2005).","journal-title":"Ann. Rheum. Dis."},{"key":"BFsrep25066_CR3","first-page":"328","volume":"24","author":"M Hasegawa","year":"1997","unstructured":"Hasegawa, M., Fujimoto, M., Kikuchi, K. & Takehara, K. Elevated serum levels of interleukin 4 (IL-4), IL-10, and IL-13 in patients with systemic sclerosis. J. Rheumatol. 24, 328\u2013332 (1997).","journal-title":"J. Rheumatol."},{"key":"BFsrep25066_CR4","doi-asserted-by":"publisher","first-page":"1168","DOI":"10.1002\/1529-0131(199906)42:6<1168::AID-ANR13>3.0.CO;2-L","volume":"42","author":"SP Atamas","year":"1999","unstructured":"Atamas, S. P. et al. Production of type 2 cytokines by CD8+ lung cells is associated with greater decline in pulmonary function in patients with systemic sclerosis. Arthritis Rheumatol. 42, 1168\u20131178 (1999).","journal-title":"Arthritis Rheumatol."},{"key":"BFsrep25066_CR5","doi-asserted-by":"publisher","first-page":"102","DOI":"10.1007\/s10067-002-0684-z","volume":"22","author":"V Riccieri","year":"2003","unstructured":"Riccieri, V. et al. Interleukin-13 in systemic sclerosis: relationship to nailfold capillaroscopy abnormalities. Clin. Rheumatol. 22, 102\u2013106 (2003).","journal-title":"Clin. Rheumatol."},{"key":"BFsrep25066_CR6","doi-asserted-by":"publisher","first-page":"481","DOI":"10.1002\/art.37738","volume":"65","author":"T H\u00fcgle","year":"2013","unstructured":"H\u00fcgle, T. et al. Tumor necrosis factor\u2013costimulated T lymphocytes from patients with systemic sclerosis trigger collagen production in fibroblasts. Arthritis Rheumatol 65, 481\u2013491 (2013).","journal-title":"Arthritis Rheumatol"},{"key":"BFsrep25066_CR7","doi-asserted-by":"publisher","first-page":"313","DOI":"10.1016\/S1074-7613(00)80439-2","volume":"4","author":"MH Kaplan","year":"1996","unstructured":"Kaplan, M. H., Schindler, U., Smiley, S. T. & Grusby, M. J. Stat6 Is Required for Mediating Responses to IL-4 and for the Development of Th2 Cells. Immunity 4, 313\u2013319 (1996).","journal-title":"Immunity"},{"key":"BFsrep25066_CR8","doi-asserted-by":"publisher","first-page":"587","DOI":"10.1016\/S0092-8674(00)80240-8","volume":"89","author":"W-p Zheng","year":"1997","unstructured":"Zheng, W.-p. & Flavell, R. A. The Transcription Factor GATA-3 Is Necessary and Sufficient for Th2 Cytokine Gene Expression in CD4 T Cells. Cell 89, 587\u2013596 (1997).","journal-title":"Cell"},{"key":"BFsrep25066_CR9","doi-asserted-by":"publisher","first-page":"1049","DOI":"10.1152\/ajplung.00321.2001","volume":"282","author":"X Liu","year":"2002","unstructured":"Liu, X. et al. Th2 cytokine regulation of type I collagen gel contraction mediated by human lung mesenchymal cells Am. J. Physiol. Lung Cell Mol. Physiol. 282, 1049\u20131056 (2002).","journal-title":"Am. J. Physiol. Lung Cell Mol. Physiol."},{"key":"BFsrep25066_CR10","doi-asserted-by":"publisher","first-page":"779","DOI":"10.1172\/JCI5909","volume":"103","author":"Z Zhu","year":"1999","unstructured":"Zhu, Z. et al. Pulmonary expression of interleukin-13 causes inflammation, mucus hypersecretion, subepithelial fibrosis, physiologic abnormalities, and eotaxin production. J. Clin. Invest. 103, 779\u2013788 (1999).","journal-title":"J. Clin. Invest."},{"key":"BFsrep25066_CR11","doi-asserted-by":"publisher","first-page":"777","DOI":"10.1172\/JCI7325","volume":"104","author":"M Chiaramonte","year":"1999","unstructured":"Chiaramonte, M. et al. An IL-13 inhibitor blocks the development of hepatic fibrosis during a T-helper type 2\u2013dominated inflammatory response. J. Clin. Invest. 104, 777\u2013785 (1999).","journal-title":"J. Clin. Invest."},{"key":"BFsrep25066_CR12","doi-asserted-by":"publisher","first-page":"3800","DOI":"10.1073\/pnas.052709999","volume":"99","author":"T Kodera","year":"2002","unstructured":"Kodera, T., McGaha, T. L., Phelps, R., Paul, W. E. & Bona, C. A. Disrupting the IL-4 gene rescues mice homozygous for the tight-skin mutation from embryonic death and diminishes TGF-\u03b2 production by fibroblasts. Proc. Natl. Acad. Sci. USA 99, 3800\u20133805 (2002).","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"BFsrep25066_CR13","doi-asserted-by":"publisher","first-page":"215","DOI":"10.1016\/j.cell.2009.01.002","volume":"136","author":"DP Bartel","year":"2009","unstructured":"Bartel, D. P. MicroRNAs: Target Recognition and Regulatory Functions. Cell 136, 215\u2013233 (2009).","journal-title":"Cell"},{"key":"BFsrep25066_CR14","doi-asserted-by":"publisher","first-page":"83","DOI":"10.1126\/science.1091903","volume":"303","author":"C-Z Chen","year":"2004","unstructured":"Chen, C.-Z., Li, L., Lodish, H. F. & Bartel, D. P. MicroRNAs Modulate Hematopoietic Lineage Differentiation. Science 303, 83\u201386 (2004).","journal-title":"Science"},{"key":"BFsrep25066_CR15","doi-asserted-by":"publisher","first-page":"1733","DOI":"10.1002\/art.27443","volume":"62","author":"B Maurer","year":"2010","unstructured":"Maurer, B. et al. MicroRNA-29, a key regulator of collagen expression in systemic sclerosis. Arthritis Rheumatol. 62, 1733\u20131743 (2010).","journal-title":"Arthritis Rheumatol"},{"key":"BFsrep25066_CR16","doi-asserted-by":"publisher","first-page":"13027","DOI":"10.1073\/pnas.0805038105","volume":"105","author":"E van Rooij","year":"2008","unstructured":"van Rooij, E. et al. Dysregulation of microRNAs after myocardial infarction reveals a role of miR-29 in cardiac fibrosis. Proc. Natl. Acad. Sci. USA 105, 13027\u201313032 (2008).","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"BFsrep25066_CR17","doi-asserted-by":"publisher","first-page":"809","DOI":"10.1084\/jem.194.6.809","volume":"194","author":"CG Lee","year":"2001","unstructured":"Lee, C. G. et al. Interleukin-13 Induces Tissue Fibrosis by Selectively Stimulating and Activating Transforming Growth Factor \u03b21. J. Exp. Med. 194, 809\u2013822 (2001).","journal-title":"J. Exp. Med."},{"key":"BFsrep25066_CR18","doi-asserted-by":"publisher","first-page":"13586","DOI":"10.1074\/jbc.274.19.13586","volume":"274","author":"SMF Ribeiro","year":"1999","unstructured":"Ribeiro, S. M. F., Poczatek, M., Schultz-Cherry, S., Villain, M. & Murphy-Ullrich, J. E. The Activation Sequence of Thrombospondin-1 Interacts with the Latency-associated Peptide to Regulate Activation of Latent Transforming Growth Factor-\u03b2. J. Biol. Chem. 274, 13586\u201313593 (1999).","journal-title":"J. Biol. Chem"},{"key":"BFsrep25066_CR19","doi-asserted-by":"publisher","first-page":"99","DOI":"10.1016\/S0923-1811(02)00150-0","volume":"31","author":"K Sakai","year":"2003","unstructured":"Sakai, K. et al. Thrombospondin-1 promotes fibroblast-mediated collagen gel contraction caused by activation of latent transforming growth factor \u03b2-1. J. Dermatol. Sci. 31, 99\u2013109 (2003).","journal-title":"J. Dermatol. Sci."},{"key":"BFsrep25066_CR20","doi-asserted-by":"publisher","first-page":"516","DOI":"10.1165\/rcmb.2008-0163OC","volume":"41","author":"Y Chiba","year":"2009","unstructured":"Chiba, Y., Todoroki, M., Nishida, Y., Tanabe, M. & Misawa, M. A Novel STAT6 Inhibitor AS1517499 Ameliorates Antigen-Induced Bronchial Hypercontractility in Mice. Am. J. Respir. Cell Mol. Biol. 41, 516\u2013524 (2009).","journal-title":"Am. J. Respir. Cell Mol. Biol."},{"key":"BFsrep25066_CR21","doi-asserted-by":"publisher","first-page":"15536","DOI":"10.1073\/pnas.242566899","volume":"99","author":"M Tudor","year":"2002","unstructured":"Tudor, M., Akbarian, S., Chen, R. Z. & Jaenisch, R. Transcriptional profiling of a mouse model for Rett syndrome reveals subtle transcriptional changes in the brain. Proc. Natl. Acad. Sci. USA 99, 15536\u201315541 (2002).","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"BFsrep25066_CR22","doi-asserted-by":"publisher","first-page":"621","DOI":"10.1136\/annrheumdis-2012-202476","volume":"72","author":"C Beyer","year":"2013","unstructured":"Beyer, C. et al. Activation of pregnane X receptor inhibits experimental dermal fibrosis. Ann. Rheum. Dis. 72, 621\u2013625 (2013).","journal-title":"Ann. Rheum. Dis."},{"key":"BFsrep25066_CR23","doi-asserted-by":"publisher","first-page":"655","DOI":"10.1038\/jid.2010.361","volume":"131","author":"C Moriya","year":"2011","unstructured":"Moriya, C. et al. Expression of Matrix Metalloproteinase-13 Is Controlled by IL-13 via PI3K\/Akt3 and PKC-[delta] in Normal Human Dermal Fibroblasts. J. Invest. Dermatol. 131, 655\u2013661 (2011).","journal-title":"J. Invest. Dermatol."},{"key":"BFsrep25066_CR24","doi-asserted-by":"publisher","first-page":"4141","DOI":"10.4049\/jimmunol.177.6.4141","volume":"177","author":"JL Ingram","year":"2006","unstructured":"Ingram, J. L. et al. Opposing Actions of Stat1 and Stat6 on IL-13-Induced Up-Regulation of Early Growth Response-1 and Platelet-Derived Growth Factor Ligands in Pulmonary Fibroblasts. J. Immunol. 177, 4141\u20134148 (2006).","journal-title":"J. Immunol."},{"key":"BFsrep25066_CR25","doi-asserted-by":"publisher","first-page":"1119","DOI":"10.1002\/art.24432","volume":"60","author":"P Fuschiotti","year":"2009","unstructured":"Fuschiotti, P., Medsger, T. A. & Morel, P. A. Effector CD8+ T cells in systemic sclerosis patients produce abnormally high levels of interleukin-13 associated with increased skin fibrosis. Arthritis Rheumatol. 60, 1119\u20131128 (2009).","journal-title":"Arthritis Rheumatol"},{"key":"BFsrep25066_CR26","doi-asserted-by":"publisher","first-page":"892","DOI":"10.4049\/jimmunol.1403046","volume":"195","author":"M Ayano","year":"2015","unstructured":"Ayano, M. et al. Increased CD226 Expression on CD8+ T Cells Is Associated with Upregulated Cytokine Production and Endothelial Cell Injury in Patients with Systemic Sclerosis. J. Immunol. 195, 892\u2013900 (2015).","journal-title":"J. Immunol."},{"key":"BFsrep25066_CR27","doi-asserted-by":"publisher","first-page":"464","DOI":"10.1183\/09031936.00068712","volume":"43","author":"R Firszt","year":"2014","unstructured":"Firszt, R. et al. Interleukin-13 induces collagen type-1 expression through matrix metalloproteinase-2 and transforming growth factor-\u03b21 in airway fibroblasts in asthma. Eur. Respir. J. 43, 464\u2013473 (2014).","journal-title":"Eur. Respir. J."},{"key":"BFsrep25066_CR28","doi-asserted-by":"publisher","first-page":"6744","DOI":"10.4049\/jimmunol.172.11.6744","volume":"172","author":"W Chen","year":"2004","unstructured":"Chen, W., Daines, M. O. & Hershey, G. K. K. Methylation of STAT6 Modulates STAT6 Phosphorylation, Nuclear Translocation, and DNA-Binding Activity. J. Immunol. 172, 6744\u20136750 (2004).","journal-title":"J. Immunol."},{"key":"BFsrep25066_CR29","doi-asserted-by":"publisher","first-page":"433","DOI":"10.1038\/gene.2014.44","volume":"15","author":"M Ciechomska","year":"2014","unstructured":"Ciechomska, M., van Laar, J. M. & O\u2019Reilly, S. Emerging role of epigenetics in systemic sclerosis pathogenesis. Genes Immun. 15, 433\u2013439 (2014).","journal-title":"Genes Immun."},{"key":"BFsrep25066_CR30","doi-asserted-by":"publisher","first-page":"3905","DOI":"10.4049\/jimmunol.1200822","volume":"190","author":"K Makino","year":"2013","unstructured":"Makino, K. et al. The Downregulation of microRNA let-7a Contributes to the Excessive Expression of Type I Collagen in Systemic and Localized Scleroderma. J. Immunol. 190, 3905\u20133915 (2013).","journal-title":"J. Immunol."},{"key":"BFsrep25066_CR31","doi-asserted-by":"publisher","first-page":"1597","DOI":"10.1038\/jid.2012.22","volume":"132","author":"K Kashiyama","year":"2012","unstructured":"Kashiyama, K. et al. miR-196a Downregulation Increases the Expression of Type I and III Collagens in Keloid Fibroblasts. J. Invest. Dermatol. 132, 1597\u20131604 (2012).","journal-title":"J. Invest. Dermatol."},{"key":"BFsrep25066_CR32","doi-asserted-by":"publisher","first-page":"185","DOI":"10.1038\/13810","volume":"23","author":"RE Amir","year":"1999","unstructured":"Amir, R. E. et al. Rett syndrome is caused by mutations in X-linked MECP2, encoding methyl-CpG-binding protein 2. Nat. Genet. 23, 185\u2013188 (1999).","journal-title":"Nat. Genet."},{"key":"BFsrep25066_CR33","doi-asserted-by":"publisher","first-page":"2032","DOI":"10.1136\/annrheumdis-2012-202742","volume":"72","author":"FD Carmona","year":"2013","unstructured":"Carmona, F. D. et al. New insight on the Xq28 association with systemic sclerosis. Ann. Rheum. Dis. 72, 2032\u20132038 (2013).","journal-title":"Ann. Rheum. Dis."},{"key":"BFsrep25066_CR34","doi-asserted-by":"publisher","first-page":"705","DOI":"10.1053\/j.gastro.2009.10.002","volume":"138","author":"J Mann","year":"2010","unstructured":"Mann, J. et al. MeCP2 Controls an Epigenetic Pathway That Promotes Myofibroblast Transdifferentiation and Fibrosis. Gastroenterol. 138, 705\u2013714.e4 (2010).","journal-title":"Gastroenterol"},{"key":"BFsrep25066_CR35","doi-asserted-by":"publisher","first-page":"e88685","DOI":"10.1371\/journal.pone.0088685","volume":"9","author":"Y Feng","year":"2014","unstructured":"Feng, Y., Huang, W., Wani, M., Yu, X. & Ashraf, M. Ischemic Preconditioning Potentiates the Protective Effect of Stem Cells through Secretion of Exosomes by Targeting Mecp2 via miR-22. PLoS ONE 9, e88685 (2014).","journal-title":"PLoS ONE"},{"key":"BFsrep25066_CR36","doi-asserted-by":"publisher","first-page":"622","DOI":"10.1161\/CIRCRESAHA.115.306721","volume":"117","author":"SC Mayer","year":"2015","unstructured":"Mayer, S. C. et al. Adrenergic Repression of the Epigenetic Reader MeCP2 Facilitates Cardiac Adaptation in Chronic Heart Failure. Circ. Res. 117, 622\u2013633 (2015).","journal-title":"Circ. Res."},{"key":"BFsrep25066_CR37","doi-asserted-by":"publisher","first-page":"1232","DOI":"10.1136\/annrheumdis-2012-203194","volume":"73","author":"C Dees","year":"2014","unstructured":"Dees, C. et al. The Wnt antagonists DKK1 and SFRP1 are downregulated by promoter hypermethylation in systemic sclerosis. Ann. Rheum. Dis. 73, 1232\u20131239 (2014).","journal-title":"Ann. Rheum. Dis."},{"key":"BFsrep25066_CR38","doi-asserted-by":"publisher","first-page":"2176","DOI":"10.1093\/hmg\/ddt614","volume":"23","author":"CJ Watson","year":"2014","unstructured":"Watson, C. J. et al. Hypoxia-induced epigenetic modifications are associated with cardiac tissue fibrosis and the development of a myofibroblast-like phenotype. Hum. Mol. Genet. 23, 2176\u20132188 (2014).","journal-title":"Hum. Mol. Genet."},{"key":"BFsrep25066_CR39","doi-asserted-by":"publisher","first-page":"4203","DOI":"10.1002\/art.23074","volume":"56","author":"JHW Distler","year":"2007","unstructured":"Distler, J. H. W. et al. Hypoxia-induced increase in the production of extracellular matrix proteins in systemic sclerosis. Arthritis Rheumatol. 56, 4203\u20134215 (2007).","journal-title":"Arthritis Rheumatol"}],"updated-by":[{"DOI":"10.1038\/srep27325","type":"correction","label":"Correction","source":"publisher","updated":{"date-parts":[[2016,6,10]],"date-time":"2016-06-10T00:00:00Z","timestamp":1465516800000}}],"container-title":["Scientific Reports"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/srep25066.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/srep25066","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/srep25066.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,1,4]],"date-time":"2023-01-04T23:18:28Z","timestamp":1672874308000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/srep25066"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2016,4,26]]},"references-count":39,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2016,4,29]]}},"alternative-id":["BFsrep25066"],"URL":"https:\/\/doi.org\/10.1038\/srep25066","relation":{},"ISSN":["2045-2322"],"issn-type":[{"value":"2045-2322","type":"electronic"}],"subject":[],"published":{"date-parts":[[2016,4,26]]},"assertion":[{"value":"16 January 2016","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"4 April 2016","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"26 April 2016","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"10 June 2016","order":4,"name":"change_date","label":"Change Date","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"Update","order":5,"name":"change_type","label":"Change Type","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"A correction has been published and is appended to both the HTML and PDF versions of this paper. The error has not been fixed in the paper.","order":6,"name":"change_details","label":"Change Details","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"The authors declare no competing financial interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"25066"}}