{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,25]],"date-time":"2026-10-25T01:23:58Z","timestamp":1792891438913,"version":"4.5.0"},"reference-count":44,"publisher":"Oxford University Press (OUP)","issue":"1","license":[{"start":{"date-parts":[[2020,6,8]],"date-time":"2020-06-08T00:00:00Z","timestamp":1591574400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/journals\/pages\/open_access\/funder_policies\/chorus\/standard_publication_model"}],"funder":[{"DOI":"10.13039\/501100007807","name":"Japan Science Society","doi-asserted-by":"publisher","award":["#28-403"],"award-info":[{"award-number":["#28-403"]}],"id":[{"id":"10.13039\/501100007807","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100012331","name":"LEO Foundation","doi-asserted-by":"publisher","award":["LF16038"],"award-info":[{"award-number":["LF16038"]}],"id":[{"id":"10.13039\/501100012331","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2020,9,14]]},"abstract":"<jats:title>Summary<\/jats:title><jats:p>Psoriasis is characterized by excessive growth and aberrant differentiation of epidermal keratinocytes due to persistent inflammation. However, the underlying mechanism that triggers immune activation in psoriasis is not clear. In this study, we explored excessive DNA as a potential trigger of psoriasis using cultured human keratinocytes and psoriatic skin tissues. We demonstrated that human genomic DNA fragments induced tumour necrosis factor (TNF)-\u03b1 expression, hyperproliferation and over-expression of heparin-binding epidermal-like growth factor (HB-EGF) and transforming growth factor (TGF)-\u03b1, accompanied by defective expression of keratins 1 and 10 in cultured normal human epidermal keratinocytes, which have a similar phenotype to that of keratinocytes in psoriatic skin lesions. In psoriatic lesions, we found high levels of double-stranded (ds)DNA fragments, accompanying keratinocytes expressing Ki-67, HB-EGF and TNF-\u03b1. In addition, we showed that 1,25-dihydroxyvitamin D3 inhibited genomic DNA fragment-induced TNFA and interleukin-1\u03b2 (IFNB) expression in human keratinocytes, and an intact function of cathelicidin anti-microbial peptide (CAMP) was required for this effect. These results suggest that excessive dsDNA fragments probably act as a risk factor for immune activation in psoriasis, and the active form of vitamin D can prevent genomic DNA-mediated skin inflammation via CAMP.<\/jats:p>","DOI":"10.1111\/cei.13455","type":"journal-article","created":{"date-parts":[[2020,5,16]],"date-time":"2020-05-16T19:33:57Z","timestamp":1589657637000},"page":"1-10","source":"Crossref","is-referenced-by-count":19,"title":["Pathological role of excessive DNA as a trigger of keratinocyte proliferation in psoriasis"],"prefix":"10.1093","volume":"202","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2792-488X","authenticated-orcid":false,"given":"Y","family":"Luo","sequence":"first","affiliation":[{"name":"Department of Clinical Laboratory Science, Faculty of Medical Technology, Teikyo University , Tokyo, Japan"},{"name":"Leprosy Research Center, National Institute of Infectious Diseases , Tokyo, Japan"},{"name":"Department of Laboratory Medicine, Nanjing Drum Tower Hospital and Jiangsu Key Laboratory for Molecular Medicine, Nanjing University Medical School , Nanjing, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"T","family":"Hara","sequence":"additional","affiliation":[{"name":"Leprosy Research Center, National Institute of Infectious Diseases , Tokyo, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"A","family":"Kawashima","sequence":"additional","affiliation":[{"name":"Department of Clinical Laboratory Science, Faculty of Medical Technology, Teikyo University , Tokyo, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Y","family":"Ishido","sequence":"additional","affiliation":[{"name":"Department of Clinical Laboratory Science, Faculty of Medical Technology, Teikyo University , Tokyo, Japan"},{"name":"Leprosy Research Center, National Institute of Infectious Diseases , Tokyo, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"S","family":"Suzuki","sequence":"additional","affiliation":[{"name":"Emergency and Critical Care Medicine, Keio University of School of Medicine , Tokyo, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"N","family":"Ishii","sequence":"additional","affiliation":[{"name":"Leprosy Research Center, National Institute of Infectious Diseases , Tokyo, Japan"},{"name":"National Sanatorium Tamazenshoen , Tokyo, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"T","family":"Kambara","sequence":"additional","affiliation":[{"name":"Department of Dermatology, Yokohama City University Medical Center , Yokohama, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"K","family":"Suzuki","sequence":"additional","affiliation":[{"name":"Department of Clinical Laboratory Science, Faculty of Medical Technology, Teikyo University , Tokyo, Japan"},{"name":"Leprosy Research Center, National Institute of Infectious Diseases , Tokyo, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2020,6,8]]},"reference":[{"key":"2023081612584751500_cei13455-bib-0001","doi-asserted-by":"crossref","first-page":"496","DOI":"10.1056\/NEJMra0804595","article-title":"Psoriasis","volume":"361","author":"Nestle","year":"2009","journal-title":"N Engl J Med"},{"key":"2023081612584751500_cei13455-bib-0002","doi-asserted-by":"crossref","first-page":"1497","DOI":"10.1038\/sj.cdd.4401722","article-title":"Death penalty for keratinocytes: apoptosis versus cornification","volume":"12","author":"Lippens","year":"2005","journal-title":"Cell Death Diff"},{"key":"2023081612584751500_cei13455-bib-0003","doi-asserted-by":"crossref","first-page":"463","DOI":"10.2340\/0001555562463470","article-title":"Corneocyte morphology and formation rate in lichen planus and experimental parakeratosis in subjects with and without psoriasis","volume":"62","author":"Johannesson","year":"1982","journal-title":"Acta Derm Venereol"},{"key":"2023081612584751500_cei13455-bib-0004","doi-asserted-by":"crossref","first-page":"342","DOI":"10.1016\/j.cyto.2014.12.014","article-title":"Cytokines in psoriasis","volume":"73","author":"Baliwag","year":"2015","journal-title":"Cytokine"},{"key":"2023081612584751500_cei13455-bib-0005","doi-asserted-by":"crossref","first-page":"135","DOI":"10.1084\/jem.20050500","article-title":"Plasmacytoid predendritic cells initiate psoriasis through interferon-alpha production","volume":"202","author":"Nestle","year":"2005","journal-title":"J Exp Med"},{"key":"2023081612584751500_cei13455-bib-0006","doi-asserted-by":"crossref","first-page":"866","DOI":"10.1038\/nature05663","article-title":"Pathogenesis and therapy of psoriasis","volume":"445","author":"Lowes","year":"2007","journal-title":"Nature"},{"key":"2023081612584751500_cei13455-bib-0007","doi-asserted-by":"crossref","first-page":"52ra72","DOI":"10.1126\/scitranslmed.3001107","article-title":"Effects of AIN457, a fully human antibody to interleukin-17A, on psoriasis, rheumatoid arthritis, and uveitis","volume":"2","author":"Hueber","year":"2010","journal-title":"Sci Transl Med"},{"key":"2023081612584751500_cei13455-bib-0008","first-page":"613086","article-title":"Genetics of psoriasis and pharmacogenetics of biological drugs","volume":"2013","author":"Prieto-Perez","year":"2013","journal-title":"Autoimmune Dis"},{"key":"2023081612584751500_cei13455-bib-0009","doi-asserted-by":"crossref","first-page":"40","DOI":"10.1038\/ni1282","article-title":"A Toll-like receptor-independent antiviral response induced by double-stranded B-form DNA","volume":"7","author":"Ishii","year":"2006","journal-title":"Nat Immunol"},{"key":"2023081612584751500_cei13455-bib-0010","doi-asserted-by":"crossref","first-page":"2602","DOI":"10.4049\/jimmunol.167.5.2602","article-title":"Genomic DNA released by dying cells induces the maturation of APCs","volume":"167","author":"Ishii","year":"2001","journal-title":"J Immunol"},{"key":"2023081612584751500_cei13455-bib-0011","doi-asserted-by":"crossref","first-page":"1702","DOI":"10.1210\/en.2010-1132","article-title":"Fragments of genomic DNA released by injured cells activate innate immunity and suppress endocrine function in the thyroid","volume":"152","author":"Kawashima","year":"2011","journal-title":"Endocrinology"},{"key":"2023081612584751500_cei13455-bib-0012","doi-asserted-by":"crossref","first-page":"2285","DOI":"10.1073\/pnas.96.5.2285","article-title":"Activation of target-tissue immune-recognition molecules by double-stranded polynucleotides","volume":"96","author":"Suzuki","year":"1999","journal-title":"Proc Natl Acad Sci USA"},{"key":"2023081612584751500_cei13455-bib-0013","doi-asserted-by":"crossref","first-page":"177","DOI":"10.1038\/76032","article-title":"Features of systemic lupus erythematosus in Dnase1-deficient mice","volume":"25","author":"Napirei","year":"2000","journal-title":"Nat Genet"},{"key":"2023081612584751500_cei13455-bib-0014","doi-asserted-by":"crossref","first-page":"313","DOI":"10.1038\/91070","article-title":"Mutation of DNASE1 in people with systemic lupus erythematosus","volume":"28","author":"Yasutomo","year":"2001","journal-title":"Nat Genet"},{"key":"2023081612584751500_cei13455-bib-0015","doi-asserted-by":"crossref","first-page":"3661","DOI":"10.1210\/jc.2011-1568","article-title":"Innate immune activation and thyroid autoimmunity","volume":"96","author":"Kawashima","year":"2011","journal-title":"J Clin Endocrinol Metab"},{"key":"2023081612584751500_cei13455-bib-0016","doi-asserted-by":"crossref","first-page":"564","DOI":"10.1038\/nature06116","article-title":"Plasmacytoid dendritic cells sense self-DNA coupled with antimicrobial peptide","volume":"449","author":"Lande","year":"2007","journal-title":"Nature"},{"key":"2023081612584751500_cei13455-bib-0017","doi-asserted-by":"crossref","first-page":"1983","DOI":"10.1084\/jem.20090480","article-title":"Self-RNA-antimicrobial peptide complexes activate human dendritic cells through TLR7 and TLR8","volume":"206","author":"Ganguly","year":"2009","journal-title":"J Exp Med"},{"key":"2023081612584751500_cei13455-bib-0018","doi-asserted-by":"crossref","first-page":"2281","DOI":"10.1038\/nprot.2013.143","article-title":"Genome engineering using the CRISPR-Cas9 system","volume":"8","author":"Ran","year":"2013","journal-title":"Nat Protoc"},{"key":"2023081612584751500_cei13455-bib-0019","doi-asserted-by":"crossref","first-page":"E694","DOI":"10.1210\/jc.2013-3682","article-title":"Thyroglobulin suppresses thyroid-specific gene expression in cultures of normal but not neoplastic human thyroid follicular cells","volume":"99","author":"Ishido","year":"2014","journal-title":"J Clin Endocrinol Metab"},{"key":"2023081612584751500_cei13455-bib-0020","doi-asserted-by":"crossref","first-page":"437","DOI":"10.1016\/j.det.2004.03.011","article-title":"Psoriasis and its treatment with infliximab-mediated tumor necrosis factor alpha blockade","volume":"22","author":"Winterfield","year":"2004","journal-title":"Dermatol Clin"},{"key":"2023081612584751500_cei13455-bib-0021","doi-asserted-by":"crossref","first-page":"811","DOI":"10.1126\/science.2916128","article-title":"Overexpression of transforming growth factor alpha in psoriatic epidermis","volume":"243","author":"Elder","year":"1989","journal-title":"Science"},{"key":"2023081612584751500_cei13455-bib-0022","doi-asserted-by":"crossref","first-page":"328","DOI":"10.1111\/1523-1747.ep12465223","article-title":"TGF-alpha is widely expressed in differentiated as well as hyperproliferative skin epithelium","volume":"96","author":"Finzi","year":"1991","journal-title":"J Invest Dermatol"},{"key":"2023081612584751500_cei13455-bib-0023","doi-asserted-by":"crossref","first-page":"303","DOI":"10.1016\/S0002-9440(10)63654-1","article-title":"Blockade of the EGF receptor induces a deranged chemokine expression in keratinocytes leading to enhanced skin inflammation","volume":"163","author":"Mascia","year":"2003","journal-title":"Am J Pathol"},{"key":"2023081612584751500_cei13455-bib-0024","doi-asserted-by":"crossref","first-page":"110","DOI":"10.1038\/sj.jid.5700943","article-title":"PPARdelta enhances keratinocyte proliferation in psoriasis and induces heparin-binding EGF-like growth factor","volume":"128","author":"Romanowska","year":"2008","journal-title":"J Invest Dermatol"},{"key":"2023081612584751500_cei13455-bib-0025","doi-asserted-by":"crossref","first-page":"37","DOI":"10.1007\/s00403-007-0809-y","article-title":"The role of heparin-binding EGF-like growth factor and amphiregulin in the epidermal proliferation of psoriasis in cooperation with TNFalpha","volume":"300","author":"Yoshida","year":"2008","journal-title":"Arch Dermatol Res"},{"key":"2023081612584751500_cei13455-bib-0026","doi-asserted-by":"crossref","first-page":"1329","DOI":"10.1038\/ng1894","article-title":"Irf6 is a key determinant of the keratinocyte proliferation-differentiation switch","volume":"38","author":"Richardson","year":"2006","journal-title":"Nat Genet"},{"key":"2023081612584751500_cei13455-bib-0027","doi-asserted-by":"crossref","first-page":"1181","DOI":"10.1038\/ncb1960","article-title":"C\/EBPalpha and beta couple interfollicular keratinocyte proliferation arrest to commitment and terminal differentiation","volume":"11","author":"Lopez","year":"2009","journal-title":"Nat Cell Biol"},{"key":"2023081612584751500_cei13455-bib-0028","doi-asserted-by":"crossref","first-page":"e157","DOI":"10.1038\/cddis.2011.40","article-title":"PKCeta promotes a proliferation to differentiation switch in keratinocytes via upregulation of p27Kip1 mRNA through suppression of JNK\/c-Jun signaling under stress conditions","volume":"2","author":"Hara","year":"2011","journal-title":"Cell Death Dis"},{"key":"2023081612584751500_cei13455-bib-0029","doi-asserted-by":"crossref","first-page":"271","DOI":"10.1111\/1523-1747.ep12612810","article-title":"Cell density and culture factors regulate keratinocyte commitment to differentiation and expression of suprabasal K1\/K10 keratins","volume":"104","author":"Poumay","year":"1995","journal-title":"J Invest Dermatol"},{"key":"2023081612584751500_cei13455-bib-0030","doi-asserted-by":"crossref","first-page":"225","DOI":"10.1111\/j.1346-8138.2011.01483.x","article-title":"Antimicrobial peptides in the pathogenesis of psoriasis","volume":"39","author":"Morizane","year":"2012","journal-title":"J Dermatol"},{"key":"2023081612584751500_cei13455-bib-0031","doi-asserted-by":"crossref","first-page":"321","DOI":"10.1111\/j.1365-2133.2010.09767.x","article-title":"Narrowband ultraviolet B treatment improves vitamin D balance and alters antimicrobial peptide expression in skin lesions of psoriasis and atopic dermatitis","volume":"163","author":"Vahavihu","year":"2010","journal-title":"Br J Dermatol"},{"key":"2023081612584751500_cei13455-bib-0032","doi-asserted-by":"crossref","first-page":"e6340","DOI":"10.1371\/journal.pone.0006340","article-title":"Vitamin D analogs differentially control antimicrobial peptide\/\u2018alarmin\u2019 expression in psoriasis","volume":"4","author":"Peric","year":"2009","journal-title":"PLOS ONE"},{"key":"2023081612584751500_cei13455-bib-0033","doi-asserted-by":"crossref","first-page":"51","DOI":"10.1046\/j.0022-202X.2003.22113.x","article-title":"In psoriasis lesional skin the type I interferon signaling pathway is activated, whereas interferon-alpha sensitivity is unaltered","volume":"122","author":"van der Fits","year":"2004","journal-title":"J Invest Dermatol"},{"key":"2023081612584751500_cei13455-bib-0034","doi-asserted-by":"crossref","first-page":"564","DOI":"10.1038\/nature06116","article-title":"Plasmacytoid dendritic cells sense self-DNA coupled with antimicrobial peptide","volume":"449","author":"Lande","year":"2007","journal-title":"Nature"},{"key":"2023081612584751500_cei13455-bib-0035","doi-asserted-by":"crossref","first-page":"415","DOI":"10.1016\/j.tig.2010.06.006","article-title":"Psoriasis genetics: breaking the barrier","volume":"26","author":"Roberson","year":"2010","journal-title":"Trends Genet"},{"key":"2023081612584751500_cei13455-bib-0036","doi-asserted-by":"crossref","first-page":"323","DOI":"10.1016\/j.clindermatol.2011.08.022","article-title":"Abnormal epidermal barrier in the pathogenesis of psoriasis","volume":"30","author":"Wolf","year":"2012","journal-title":"Clin Dermatol"},{"key":"2023081612584751500_cei13455-bib-0037","doi-asserted-by":"crossref","first-page":"817","DOI":"10.1038\/328817a0","article-title":"Production and auto-induction of transforming growth factor-alpha in human keratinocytes","volume":"328","author":"Coffey","year":"1987","journal-title":"Nature"},{"key":"2023081612584751500_cei13455-bib-0038","doi-asserted-by":"crossref","first-page":"715","DOI":"10.1046\/j.1523-1747.1998.00390.x","article-title":"Autocrine regulation of keratinocytes: the emerging role of heparin-binding, epidermal growth factor-related growth factors","volume":"111","author":"Piepkorn","year":"1998","journal-title":"J Invest Dermatol"},{"key":"2023081612584751500_cei13455-bib-0039","doi-asserted-by":"crossref","first-page":"73","DOI":"10.1111\/j.1600-0765.2007.01081.x","article-title":"Tumor necrosis factor-alpha-stimulated membrane type 1-matrix metalloproteinase production is modulated by epidermal growth factor receptor signaling in human gingival fibroblasts","volume":"44","author":"Smith","year":"2009","journal-title":"J Periodont Res"},{"key":"2023081612584751500_cei13455-bib-0040","doi-asserted-by":"crossref","first-page":"350","DOI":"10.1111\/1523-1747.ep12616672","article-title":"Cytokine-induced expression of transforming growth factor-alpha and the epidermal growth factor receptor in neonatal skin explants","volume":"99","author":"Valyi-Nagy","year":"1992","journal-title":"J Invest Dermatol"},{"key":"2023081612584751500_cei13455-bib-0041","doi-asserted-by":"crossref","first-page":"9467","DOI":"10.1016\/S0021-9258(19)50112-0","article-title":"Tumor necrosis factor increases transcription of the heparin-binding epidermal growth factor-like growth factor gene in vascular endothelial cells","volume":"267","author":"Yoshizumi","year":"1992","journal-title":"J Biol Chem"},{"key":"2023081612584751500_cei13455-bib-0042","doi-asserted-by":"crossref","first-page":"283","DOI":"10.1111\/cei.13370","article-title":"Evidence for a role of autoinflammation in early-phase psoriasis","volume":"198","author":"Fanoni","year":"2019","journal-title":"Clin Exp Immunol"},{"key":"2023081612584751500_cei13455-bib-0043","doi-asserted-by":"crossref","first-page":"327","DOI":"10.1111\/j.1600-0625.2012.01459.x","article-title":"Cathelicidin LL-37: a defense molecule with a potential role in psoriasis pathogenesis","volume":"21","author":"Dombrowski","year":"2012","journal-title":"Exp Dermatol"},{"key":"2023081612584751500_cei13455-bib-0044","first-page":"91","article-title":"Antimicrobial peptides: an essential component of the skin defensive barrier","volume":"306","author":"Braff","year":"2006","journal-title":"Curr Top Microbiol Immunol"}],"container-title":["Clinical &amp; Experimental Immunology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.wiley.com\/onlinelibrary\/tdm\/v1\/articles\/10.1111%2Fcei.13455","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/cei.13455","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1111\/cei.13455","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/academic.oup.com\/cei\/article-pdf\/202\/1\/1\/51116355\/cei13455.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/cei\/article-pdf\/202\/1\/1\/51116355\/cei13455.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,10,1]],"date-time":"2023-10-01T05:56:23Z","timestamp":1696139783000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/cei\/article\/202\/1\/1\/6403171"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,6,8]]},"references-count":44,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2020,6,8]]},"published-print":{"date-parts":[[2020,9,14]]}},"URL":"https:\/\/doi.org\/10.1111\/cei.13455","relation":{},"ISSN":["0009-9104","1365-2249"],"issn-type":[{"value":"0009-9104","type":"print"},{"value":"1365-2249","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2020,10]]},"published":{"date-parts":[[2020,6,8]]}}}