Endoplasmic reticulum stress and the unfolded protein response are linked to synergistic IFN-β induction via XBP-1

• Published in: European journal of immunology 2008-05, Vol.38 (5), p.1194-1203
• Main Authors: Smith, Judith A., Turner, Matthew J., DeLay, Monica L., Klenk, Erin I., Sowders, Dawn P., Colbert, Robert A.
• Format: Article
• Language: English
• ISSN: 0014-2980; 1521-4141
• DOI: 10.1002/eji.200737882

Type I IFN are strongly induced upon engagement of certain pattern recognition receptors (PRR) by microbial products, and play key roles in regulating innate and adaptive immunity. It has become apparent that the endoplasmic reticulum (ER) stress-induced unfolded protein response (UPR), in addition to restoring ER homeostasis, also influences the expression of certain inflammatory cytokines. However, the extent to which UPR signaling regulates type I IFN remains unclear. Here we show that cells undergoing an UPR respond to TLR4 and TLR3 ligands, and intracellular dsRNA, with log-fold greater IFN-β induction. This synergy is not dependent on autocrine type I IFN signaling, but unexpectedly requires the UPR transcription factor XBP-1. Synergistic IFN-β induction also occurs in HLA-B27/human β 2 m transgenic rat macrophages exhibiting an UPR as a consequence of HLA-B27 upregulation, where it correlates with activation of XBP-1 splicing. Together these findings indicate that the cellular response to endogenous ‘danger’ that disrupts ER homeostasis is coupled to IFN-β induction by XBP-1, which has implications for the immune response and the pathogenesis of diseases involving the UPR.