Dupuytren's contracture-associated SNPs increase SFRP4 expression in non-immune cells including fibroblasts to enhance inflammation development.

IF 4.8 4区 医学 Q2 IMMUNOLOGY
Hiroaki Kida, Jing-Jing Jiang, Yuichiro Matsui, Ikuko Takahashi, Rie Hasebe, Daisuke Kawamura, Takeshi Endo, Hiroki Shibayama, Makoto Kondo, Yasuhiko Nishio, Kinya Nishida, Yoshihiro Matsuno, Tsukasa Oikawa, Shimpei I Kubota, Shintaro Hojyo, Norimasa Iwasaki, Shigeru Hashimoto, Yuki Tanaka, Masaaki Murakami
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引用次数: 1

Abstract

Dupuytren's contracture (DC) is an inflammatory fibrosis characterized by fibroproliferative disorders of the palmar aponeurosis, for which there is no effective treatment. Although several genome-wide association studies have identified risk alleles associated with DC, the functional linkage between these alleles and the pathogenesis remains elusive. We here focused on two single nucleotide polymorphisms (SNPs) associated with DC, rs16879765 and rs17171229, in secreted frizzled related protein 4 (SFRP4). We investigated the association of SRFP4 with the IL-6 amplifier, which amplifies the production of IL-6, growth factors and chemokines in non-immune cells and aggravates inflammatory diseases via NF-κB enhancement. Knockdown of SFRP4 suppressed activation of the IL-6 amplifier in vitro and in vivo, whereas the overexpression of SFRP4 induced the activation of NF-κB-mediated transcription activity. Mechanistically, SFRP4 induced NF-κB activation by directly binding to molecules of the ubiquitination SFC complex, such as IkBα and βTrCP, followed by IkBα degradation. Furthermore, SFRP4 expression was significantly increased in fibroblasts derived from DC patients bearing the risk alleles. Consistently, fibroblasts with the risk alleles enhanced activation of the IL-6 amplifier. These findings indicate that the IL-6 amplifier is involved in the pathogenesis of DC, particularly in patients harboring the SFRP4 risk alleles. Therefore, SFRP4 is a potential therapeutic target for various inflammatory diseases and disorders, including DC.

Dupuytren的收缩相关snp增加非免疫细胞(包括成纤维细胞)中SFRP4的表达,从而促进炎症的发展。
Dupuytren's挛缩(DC)是一种以掌腱膜纤维增生性疾病为特征的炎性纤维化,目前尚无有效的治疗方法。尽管一些全基因组关联研究已经确定了与DC相关的风险等位基因,但这些等位基因与发病机制之间的功能联系仍然难以捉摸。我们在此重点研究了与DC相关的两个单核苷酸多态性(snp), rs16879765和rs17171229,在分泌卷曲相关蛋白4 (SFRP4)中。我们研究了SRFP4与IL-6放大器的关联,IL-6放大器放大非免疫细胞中IL-6、生长因子和趋化因子的产生,并通过NF-κB增强加重炎症性疾病。在体外和体内,敲低SFRP4可抑制IL-6放大器的激活,而过表达SFRP4可诱导NF-κ b介导的转录活性的激活。机制上,SFRP4通过直接结合泛素化SFC复合体分子,如IkBα和βTrCP,诱导NF-κB活化,随后IkBα降解。此外,在携带风险等位基因的DC患者的成纤维细胞中,SFRP4的表达显著增加。具有风险等位基因的成纤维细胞一致地增强了IL-6放大器的激活。这些发现表明,IL-6放大器参与了DC的发病机制,特别是在携带SFRP4风险等位基因的患者中。因此,SFRP4是包括DC在内的各种炎症性疾病的潜在治疗靶点。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
International immunology
International immunology 医学-免疫学
CiteScore
9.30
自引率
2.30%
发文量
51
审稿时长
6-12 weeks
期刊介绍: International Immunology is an online only (from Jan 2018) journal that publishes basic research and clinical studies from all areas of immunology and includes research conducted in laboratories throughout the world.
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