NEDD4 Is Involved in Inflammation Development during Keloid Formation

作     者：Fujita, Munezumi Yamamoto, Yuhei Jiang, Jing-Jing Atsumi, Toru Tanaka, Yuki Ohki, Takuto Murao, Naoki Funayama, Emi Hayashi, Toshihiko Osawa, Masayuki Maeda, Taku Kamimura, Daisuke Murakami, Masaaki 

作者机构：Hokkaido Univ Inst Genet Med Div Mol Psychoimmunol Sapporo Hokkaido 0600815 Japan Hokkaido Univ Grad Sch Med Sapporo Hokkaido Japan Hokkaido Univ Fac Med Dept Plast & Reconstruct Surg Sapporo Hokkaido Japan 

出 版 物：《JOURNAL OF INVESTIGATIVE DERMATOLOGY》 (皮肤病学研究杂志)

年 卷 期：2019年第139卷第2期

页      面：333-341页

核心收录：

学科分类：1002[医学-临床医学] 100206[医学-皮肤病与性病学] 10[医学] 

基　　金：JSPS KAKENHI Joint Usage/Research Center Institute for Genetic Medicine, Hokkaido University Takeda Science Foundation Institute for Fermentation Osaka Mitsubishi Foundation Mochida Memorial Foundation for Medical and Pharmaceutical Research Tokyo Medical Research Foundation 

主　　题：F phenylalanine GWAS genome-wide association study phospho- phosphorylated siRNA small interfering RNA SNP single-nucleotide polymorphism TNF-α tumor necrosis factor-α TV transcript variant 

摘      要：Keloids mark a chronic inflammatory disease characterized by a fibroproliferative disorder of the skin. A genome-wide association study showed that single-nucleotide polymorphism rs8032158 in the neural precursor cell-expressed NEDD4 gene, which has six protein-coding transcript variants (TVs), is genetically linked to keloids. Here, we show that the high frequency of risk allele C in rs8032158 in keloid patients is associated with a selectively higher expression of TV3 of NEDD4 to activate the NF-kB pathway. Comparisons of keloid scars with normal skin samples that do not have the single-nucleotide polymorphism allele and were derived from different anatomical sites showed stronger expressions of NEDD4 TV3 and activated forms of NF-kB and STAT3 in keloid scars. Forced expression or selective knockdown of NEDD4 TV3 increased or decreased NF-kB activation in vitro. Furthermore, NEDD4 knockdown suppressed NF-kBedependent inflammation development in vivo. Mechanistic analysis showed that NEDD4 TV3 is involved in NF-kB activation through its association with the adaptor protein RIP. These results suggest that NEDD4 TV3 is a potential diagnostic marker and therapeutic target for chronic skin diseases, including keloid.