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Overexpression of TNF-α-converting enzyme in fibroblasts augments dermal fibrosis after inflammation

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Please use this identifier to cite or link to this item:http://hdl.handle.net/2115/52972

Title: Overexpression of TNF-α-converting enzyme in fibroblasts augments dermal fibrosis after inflammation
Authors: Fukaya, Shinji Browse this author
Matsui, Yuki Browse this author
Tomaru, Utano Browse this author →KAKEN DB
Kawakami, Ai Browse this author
Sogo, Sayuri Browse this author
Bohgaki, Toshiyuki Browse this author
Atsumi, Tatsuya Browse this author →KAKEN DB
Koike, Takao Browse this author →KAKEN DB
Kasahara, Masanori Browse this author →KAKEN DB
Ishizu, Akihiro Browse this author →KAKEN DB
Keywords: EGFR
fibrosis
inflammation
PMA
TACE
Issue Date: Jan-2013
Publisher: Nature Publishing Group
Journal Title: Laboratory Investigation
Volume: 93
Issue: 1
Start Page: 72
End Page: 80
Publisher DOI: 10.1038/labinvest.2012.153
PMID: 23147225
Abstract: TNF-α converting enzyme (TACE) can cleave transmembrane proteins, such as TNF-α, TNF receptors, and epidermal growth factor receptor (EGFR) ligands, to release the extracellular domains from the cell surface. Recent studies have suggested that overexpression of TACE may be associated with the pathogenesis of inflammation and fibrosis. To determine the roles of TACE in inflammation and fibrosis, TACE transgenic (TACE-Tg) mice, which overexpressed TACE systemically, were generated. Since the transgene-derived TACE was expressed as an inactive form, no spontaneous phenotype developed in TACE-Tg mice. However, the transgene-derived TACE could be converted to an active form by furin in vitro and by phorbol myristate acetate (PMA) in vivo. Subcutaneous injection of PMA into mice induced inflammatory cell infiltration 1 day later and subsequent dermal fibrosis 7 days later. Interestingly, the degree of dermal fibrosis at day 7 was significantly higher in TACE-Tg mice than in wild-type mice. Correspondingly, PMA increased the expression of type I collagen in the primary culture of dermal fibroblasts derived from TACE-Tg mice. Furthermore, phosphorylated EGFR was increased in the fibroblasts by the PMA treatment. The collective findings suggest that TACE overexpression and activation in fibroblasts could shed off putative EGFR ligands. Subsequently, the soluble EGFR ligands could bind and activate EGFR on fibroblasts, and then increase the type I collagen expression resulting in induction of dermal fibrosis. These results also suggest that TACE and EGFR on fibroblasts may be novel therapeutic targets of dermal fibrosis, which is induced after diverse inflammatory disorders of the skin.
Type: article (author version)
URI: http://hdl.handle.net/2115/52972
Appears in Collections:保健科学院・保健科学研究院 (Graduate School of Health Sciences / Faculty of Health Sciences) > 雑誌発表論文等 (Peer-reviewed Journal Articles, etc)

Submitter: 石津 明洋

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