Wu NL, Huang DY, Tsou HN, Lin YC, Lin WW

IL-17 plays an important role in the immunopathogenesis of autoimmune diseases, and Syk has been implicated as a critical molecule in the signaling pathways of various immunoreceptors. CCL20 interacts with CCR6 to recruit IL-17-producing cells into skin to promote progression of psoriasis. Herein we investigate how Syk regulates IL-17 signaling ...

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to affect CCL20 expression in primary human epidermal keratinocytes. We found that IL-17 can induce CCL20 expression, and activate TAK, IKK, NF-κB, JNK and Syk. Data of TAK inhibitor and Syk 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 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 highlight Syk as a potential therapeutic target for inflammatory skin diseases such as psoriasis.Journal of Investigative Dermatology accepted article preview online, 09 September 2014. doi:10.1038/jid.2014.383.

Date: Sep. 09, 2014

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