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Signaling via TLR7 leads to an upregulation of the transcription factor XBP1 in PBMCs and pDCs.XBP1 mRNA expression levels positively correlated with the subsequent production of IFNα.Blocking of XBP1 mRNA splicing significantly reduced mRNA transcripts of IFNα.Our data demonstrate a central role of XBP1 in TLR7-induced IFNα production.XBP1 represents a potential therapeutic target in IFNα-driven autoimmune and inflammatory diseases.The transcription factor X-box binding protein 1 (XBP1) represents a key component of the endoplasmatic reticulum (ER) stress response and is required for the production of several pro-inflammatory cytokines. XBP1 is furthermore essential for the development and survival of plasmacytoid dendritic cells (pDCs), and has recently been suggested to be involved in toll-like receptor (TLR) 2/4 signaling. Activation of TLR7 on pDCs results in an upregulation of pro-inflammatory cytokines, such as type I interferons (IFN-I), and has been implicated in several autoimmune and inflammatory diseases, but the role of XBP1 in this process remains unknown. Here, we show that signaling via TLR7 leads to an upregulation of XBP1 and IFNα-production. XBP1 mRNA expression levels positively correlated with the production of IFNα, while blocking of XBP1 mRNA splicing significantly reduced mRNA transcripts of IFNα. In conclusion, these data suggest a central role of XBP1 in TLR7-induced IFNα production and identify XBP1 as a potential novel therapeutic target in IFNα-driven autoimmune and inflammatory diseases.