https://scholars.lib.ntu.edu.tw/handle/123456789/550440
標題: | Syk mediates IL-17-induced CCL20 expression by targeting Act1-dependent K63-linked ubiquitination of TRAF6 | 作者: | Wu N.-L. Huang D.-Y. Tsou H.-N. Lin Y.-C. WAN-WAN LIN |
公開日期: | 2015 | 卷: | 135 | 期: | 2 | 起(迄)頁: | 490-498 | 來源出版物: | Journal of Investigative Dermatology | 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. ? 2015 The Society for Investigative Dermatology. |
URI: | 2-s2.0-84925351140 https://scholars.lib.ntu.edu.tw/handle/123456789/550440 |
ISSN: | 0022202X | DOI: | 10.1038/jid.2014.383 | SDG/關鍵字: | act1 adaptor protein; adaptor protein; adenosine triphosphatase; I kappa B kinase; immunoglobulin enhancer binding protein; interleukin 17; interleukin 17 receptor; macrophage inflammatory protein 3alpha; messenger RNA; protein kinase Syk; small interfering RNA; stress activated protein kinase; tumor necrosis factor receptor associated factor 6; unclassified drug; CCL20 protein, human; immunoglobulin enhancer binding protein; interleukin 17; macrophage inflammatory protein 3alpha; MAP kinase kinase kinase 7; messenger RNA; mitogen activated protein kinase kinase kinase; protein kinase Syk; protein tyrosine kinase; signal peptide; TRAF3IP2 protein, human; tumor necrosis factor receptor associated factor; tumor necrosis factor receptor associated factor 6; Article; complex formation; controlled study; enzyme activity; gene expression; gene silencing; human; human cell; immunoprecipitation; investigative procedures; keratinocyte; normal human; priority journal; protein expression; protein interaction; protein phosphorylation; psoriasis; real time polymerase chain reaction; RNA interference; signal transduction; site directed mutagenesis; ubiquitination; upregulation; cell culture; genetics; metabolism; physiology; Cells, Cultured; Chemokine CCL20; Humans; Interleukin-17; Intracellular Signaling Peptides and Proteins; MAP Kinase Kinase Kinases; NF-kappa B; Protein-Tyrosine Kinases; RNA, Messenger; Signal Transduction; TNF Receptor-Associated Factor 6; Tumor Necrosis Factor Receptor-Associated Peptides and Proteins; Ubiquitination |
顯示於: | 藥理學科所 |
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