Endoplasmic reticulum stress and the unfolded protein response are linked to synergistic IFN-beta induction via X-box binding protein 1.
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-beta 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-beta induction also occurs in HLA-B27/human beta(2)m-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-beta induction by XBP-1, which has implications for the immune response and the pathogenesis of diseases involving the UPR.
Smith
Judith A
JA
William S Rowe Division of Rheumatology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229-3039, USA.
Turner
Matthew J
MJ
DeLay
Monica L
ML
Klenk
Erin I
EI
Sowders
Dawn P
DP
Colbert
Robert A
RA
D000818:Animals; D030801:Animals, Genetically Modified; D016207:Cytokines / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000502:physiology*; D004721:Endoplasmic Reticulum / Q000187:drug effects / Q000378:metabolism*; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D015870:Gene Expression / Q000187:drug effects; D015796:HLA-B27 Antigen / Q000235:genetics; D015793:HLA-B7 Antigen / Q000235:genetics; D006801:Humans; D050839:Interferon Regulatory Factor-7 / Q000235:genetics; D016898:Interferon-alpha / Q000235:genetics; D016899:Interferon-beta / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D008070:Lipopolysaccharides / Q000494:pharmacology; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D009687:Nuclear Proteins / Q000502:physiology*; D017510:Protein Folding; D034741:RNA, Small Interfering / Q000235:genetics; D051381:Rats; D011916:Rats, Inbred F344; D053633:Receptor, Interferon alpha-beta / Q000235:genetics; D000071701:Regulatory Factor X Transcription Factors; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D019284:Thapsigargin / Q000494:pharmacology; D014157:Transcription Factors; D014415:Tunicamycin / Q000494:pharmacology; D000071717:X-Box Binding Protein 1
D016207:Cytokines; D004268:DNA-Binding Proteins; D015796:HLA-B27 Antigen; D015793:HLA-B7 Antigen; C508032:Ifnar1 protein, mouse; D050839:Interferon Regulatory Factor-7; D016898:Interferon-alpha; D008070:Lipopolysaccharides; D009687:Nuclear Proteins; D034741:RNA, Small Interfering; D000071701:Regulatory Factor X Transcription Factors; D014157:Transcription Factors; D000071717:X-Box Binding Protein 1; C000605543:XBP1 protein, human; C000605544:Xbp1 protein, mouse; C000605545:Xbp1 protein, rat; D014415:Tunicamycin; D053633:Receptor, Interferon alpha-beta; D019284:Thapsigargin; D016899:Interferon-beta