DDX6 is involved in the pathogenesis of inflammatory diseases via NF-xB activation

The IL-6 amplifier was originally discovered as a mechanism for the enhanced activation of NF-xB in nonimmune cells. In the IL-6 amplifier, IL-6-STAT3 and NF-xB stimulation is followed by an excessive production of IL-6, chemokines, and growth factors to develop chronic inflammation preceding the development of inflammatory diseases. Previously, using a shRNA-mediated genome-wide screening, we found that DEAD-Box Helicase 6 (DDX6) is a candidate positive regulator of the amplifier. Here, we investigate whether DDX6 is involved in the pathogenesis of inflammatory diseases via the IL-6 amplifier. We found that DDX6-silencing in non-immune cells suppressed the NF-xB pathway and inhibited activation of the IL-6 amplifier, while the forced expression of DDX6 enhanced NF-xB promoter activity independent of the RNA helicase activity of DDX6. The imiquimod-mediated dermatitis model was suppressed by the siRNA-mediated gene downregulation of DDX6. Furthermore, silencing DDX6 significantly reduced the TNF-a-induced phosphorylation of p65/RelA and IxBa, nuclear localization of p65, and the protein levels of IxBa. Mechanistically, DDX6 is strongly associated with p65 and IxBa, but not TRADD, RIP, or TRAF2, suggesting a novel function of DDX6 as an adaptor protein in the NF-xB pathway. Thus, our findings demonstrate a possible role of DDX6 beyond RNA metabolism and suggest DDX6 is a therapeutic target for inflammatory diseases.