ER stress and its regulator X-box-binding protein-1 enhance polyIC-induced innate immune response in dendritic cells.

Abstract

Multiple physiological and pathological conditions interfere with the function of the endoplasmic reticulum (ER). However, much remains unknown regarding the impact of ER stress on inflammatory responses in dendritic cells (DCs) upon the recognition of pathogen molecules. We show that ER stress greatly potentiates the expression of inflammatory cytokines and IFN-β in murine DCs stimulated by polyIC, a synthetic mimic of virus dsRNA. Both toll-like receptor 3 and melanoma differentiation-associated gene-5 are involved in the enhanced IFN-β production, which is associated with increased activation of NF-κB and IRF3 signaling as well as the splicing of X-box-binding protein-1 (XBP-1), an important regulator involved in ER stress response. Surprisingly, silencing of XBP-1 reduces polyIC-stimulated IFN-β expression in the presence or absence of ER stress, indicating that XBP-1 may be essential for polyIC signaling and ER stress-amplified IFN-β production. Overexpression of a spliced form of XBP-1 (XBP-1s) synergistically augments polyIC-induced inflammatory response. For the first time, we show that XBP-1s overexpression-enhanced IFN-β production in DCs markedly suppresses vesicular stomatitis virus infection, revealing a previously unrecognized role for XBP-1 in an antiviral response. Our findings suggest that evolutionarily conserved ER stress response and XBP-1 may function collaboratively with innate immunity to maintain cellular homeostasis.

• Authors: Fanlei Hu, Xiaofei Yu, Hongxia Wang, Daming Zuo, Chunqing Guo, Huanfa Yi, Boaz Tirosh, John R Subjeck, Xiaoyan Qiu, Xiang-Yang Wang
• Journal: European journal of immunology (Eur J Immunol) Vol. 41 Issue 4 Pg. 1086-97 (Apr 2011) ISSN: 1521-4141 [Electronic] Germany
• PMID: 21400498 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2011 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Chemical References

• DNA-Binding Proteins
• Ligands
• Regulatory Factor X Transcription Factors
• Toll-Like Receptors
• Transcription Factors
• X-Box Binding Protein 1
• XBP1 protein, human
• Xbp1 protein, mouse
• Interferon-beta
• DEAD-box RNA Helicases
• Poly I-C

Topics

• Animals
• Cells, Cultured
• Cricetinae
• DEAD-box RNA Helicases (immunology)
• DNA-Binding Proteins (immunology)
• Dendritic Cells (immunology)
• Endoplasmic Reticulum (immunology)
• Immunity, Innate (immunology)
• Interferon-beta (biosynthesis, immunology)
• Ligands
• Mice
• Poly I-C (immunology)
• Regulatory Factor X Transcription Factors
• Signal Transduction
• Toll-Like Receptors (immunology)
• Transcription Factors (immunology)
• X-Box Binding Protein 1