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

• Published in: European journal of immunology Vol. 38; no. 5; pp. 1194 - 1203
• Main Authors: Smith, Judith A, Turner, Matthew J, DeLay, Monica L, Klenk, Erin I, Sowders, Dawn P, Colbert, Robert A
• Format: Journal Article
• Language: English
• Published: Weinheim Wiley-VCH Verlag 01.05.2008; WILEY‐VCH Verlag
• Subjects: Animals; Animals, Genetically Modified; Cytokines - metabolism; DNA-Binding Proteins - physiology; Endoplasmic Reticulum - drug effects; Endoplasmic Reticulum - metabolism; Fibroblasts - cytology; Fibroblasts - drug effects; Fibroblasts - metabolism; Gene Expression - drug effects; HLA-B27 Antigen - genetics; HLA-B7 Antigen - genetics; HLA‐B27; Humans; Interferon Regulatory Factor-7 - genetics; Interferon-alpha - genetics; Interferon-beta - chemistry; Interferon-beta - genetics; Interferon-beta - metabolism; Interferons; Lipopolysaccharides - pharmacology; Macrophages - drug effects; Macrophages - metabolism; Mice; Mice, Knockout; Nuclear Proteins - physiology; Protein Folding; Protein misfolding; Rats; Rats, Inbred F344; Receptor, Interferon alpha-beta - genetics; Regulatory Factor X Transcription Factors; RNA, Small Interfering - genetics; Signal Transduction - drug effects; Signal Transduction - physiology; Thapsigargin - pharmacology; Transcription Factors; Tunicamycin - pharmacology; Unfolded protein response; X-Box Binding Protein 1
• ISSN: 0014-2980; 1521-4141
• DOI: 10.1002/eji.200737882

Type I IFN are strongly induced upon engagement of certain pattern recognition receptors 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 a 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 X-box binding protein 1 (XBP-1). Synergistic IFN-β induction also occurs in HLA-B27/human β₂m-transgenic rat macrophages exhibiting a UPR as a consequence of HLA-B27 up-regulation, 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.