Syk mediates IL-17-induced CCL20 expression by targeting Act1-dependent K63-linked ubiquitination of TRAF6

Nan Lin Wu, Duen Yi Huang, Hsin Ni Tsou, Ying Cing Lin, Wan Wan Lin

研究成果: 雜誌貢獻文章同行評審

33 引文 斯高帕斯(Scopus)

摘要

IL-17 has an important role in the immunopathogenesis of autoimmune diseases, and spleen tyrosine kinase (Syk) has been implicated as a critical molecule in the signaling pathways of various immunoreceptors. Chemokine (C-C motif) ligand 20 (CCL20) interacts with chemokine (C-C motif) receptor 6 to recruit IL-17-producing cells into the skin to promote progression of psoriasis. Herein we investigate how Syk regulates IL-17 signaling to affect CCL20 expression in primary human epidermal keratinocytes. We found that IL-17 can induce CCL20 expression and activate TAK, IKK, NF-κB, c-Jun N-terminal kinase, and Syk. Data of TAK inhibitor and Syk small interfering RNA (siRNA) indicate Syk being an upstream molecule of TAK in IL-17-elicited signaling. The promoter activity assay combined with site-directed mutagenesis showed that IL-17-elicited CCL20 upregulation is depending on the Syk-mediated NF-κB pathway. Immunoprecipitation also indicated the interaction of Syk with signal molecules of IL-17R, such as TRAF6 and Act1, under IL-17A stimulation. However, the essential signaling events including TRAF6 interaction with Act1 and TRAF6 polyubiquitination under IL-17A stimulation were diminished by Syk siRNA and pharmacologically inhibiting Syk. Taken together, we identify Syk as an upstream signaling molecule in IL-17A-induced Act1-TRAF6 interaction in keratinocytes, and inhibition of Syk can attenuate CCL20 production, which highlights Syk as a potential therapeutic target for inflammatory skin diseases such as psoriasis.
原文英語
頁(從 - 到)490-498
頁數9
期刊Journal of Investigative Dermatology
135
發行號2
DOIs
出版狀態已發佈 - 二月 13 2015

ASJC Scopus subject areas

  • 皮膚科
  • 生物化學
  • 細胞生物學
  • 分子生物學
  • 醫藥 (全部)

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