{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T05:24:08Z","timestamp":1790745848597,"version":"4.1.0"},"reference-count":49,"publisher":"Wiley","issue":"12","license":[{"start":{"date-parts":[[2015,11,25]],"date-time":"2015-11-25T00:00:00Z","timestamp":1448409600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"name":"Ministry of Health, Labor, and Welfare of Japan"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Arthritis &amp; Rheumatology"],"published-print":{"date-parts":[[2015,12]]},"abstract":"<jats:sec><jats:title>Objective<\/jats:title><jats:p>Progranulin is a growth factor that is active in wound repair and is an antagonist of tumor necrosis factor (TNF) receptors, regulating fibroblast activation, angiogenesis, and inflammation. Because long\u2010standing activation of gene programs related to wound healing is a hallmark of systemic sclerosis (SSc), we sought to investigate the role of progranulin in SSc.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Progranulin expression levels in human and murine skin samples were determined by immunohistochemical analysis and quantitative reverse transcription\u2013polymerase chain reaction. The role of progranulin in fibroblast activation was examined using a gene\u2010silencing technique. Progranulin levels in serum obtained from 60 patients with SSc and 16 healthy control subjects were determined by enzyme\u2010linked immunosorbent assay.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Progranulin expression was increased in SSc dermal fibroblasts compared with normal dermal fibroblasts, both in vivo and in vitro. Transcription factor Fli\u20101, a deficiency of which is involved in the activation of SSc dermal fibroblasts, served as a potent repressor of the progranulin gene, and Fli\u20101<jats:sup>+\/\u2212<\/jats:sup> mice and bleomycin\u2010treated wild\u2010type mice exhibited up\u2010regulated expression of progranulin in dermal fibroblasts. SSc dermal fibroblasts were resistant to the antifibrotic effect of TNF, but this resistance was reversed by gene silencing of progranulin. Serum progranulin levels were elevated in patients with early diffuse cutaneous SSc (dcSSc), especially in those with inflammatory skin symptoms, and were positively correlated with the C\u2010reactive protein level.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>Progranulin overproduction due to Fli\u20101 deficiency may contribute to the constitutive activation of SSc dermal fibroblasts by antagonizing the antifibrotic effect of TNF. Progranulin may also be involved in the inflammatory process associated with progressive skin sclerosis in early dcSSc.<\/jats:p><\/jats:sec>","DOI":"10.1002\/art.39312","type":"journal-article","created":{"date-parts":[[2015,8,5]],"date-time":"2015-08-05T20:37:28Z","timestamp":1438807048000},"page":"3245-3255","source":"Crossref","is-referenced-by-count":31,"title":["Progranulin Overproduction Due to Fli\u20101 Deficiency Contributes to the Resistance of Dermal Fibroblasts to Tumor Necrosis Factor in Systemic Sclerosis"],"prefix":"10.1002","volume":"67","author":[{"given":"Yohei","family":"Ichimura","sequence":"first","affiliation":[{"name":"University of Tokyo Graduate School of Medicine Tokyo Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yoshihide","family":"Asano","sequence":"additional","affiliation":[{"name":"University of Tokyo Graduate School of Medicine Tokyo 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