Skip Navigation
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

National Institute of Environmental Health Sciences

Use this QR code to view the newest version of this document
Use this QR code to view the newest version of this document

Your Environment. Your Health.

Publication Detail

Title: Toll-like receptor-mediated IRE1α activation as a therapeutic target for inflammatory arthritis.

Authors: Qiu, Quan; Zheng, Ze; Chang, Lin; Zhao, Yuan-Si; Tan, Can; Dandekar, Aditya; Zhang, Zheng; Lin, Zhenghong; Gui, Ming; Li, Xiu; Zhang, Tongshuai; Kong, Qingfei; Li, Hulun; Chen, Sha; Chen, An; Kaufman, Randal J; Yang, Wei-Lei; Lin, Hui-Kuan; Zhang, Donna; Perlman, Harris; Thorp, Edward; Zhang, Kezhong; Fang, Deyu

Published In EMBO J, (2013 Sep 11)

Abstract: In rheumatoid arthritis (RA), macrophage is one of the major sources of inflammatory mediators. Macrophages produce inflammatory cytokines through toll-like receptor (TLR)-mediated signalling during RA. Herein, we studied macrophages from the synovial fluid of RA patients and observed a significant increase in activation of inositol-requiring enzyme 1α (IRE1α), a primary unfolded protein response (UPR) transducer. Myeloid-specific deletion of the IRE1α gene protected mice from inflammatory arthritis, and treatment with the IRE1α-specific inhibitor 4U8C attenuated joint inflammation in mice. IRE1α was required for optimal production of pro-inflammatory cytokines as evidenced by impaired TLR-induced cytokine production in IRE1α-null macrophages and neutrophils. Further analyses demonstrated that tumour necrosis factor (TNF) receptor-associated factor 6 (TRAF6) plays a key role in TLR-mediated IRE1α activation by catalysing IRE1α ubiquitination and blocking the recruitment of protein phosphatase 2A (PP2A), a phosphatase that inhibits IRE1α phosphorylation. In summary, we discovered a novel regulatory axis through TRAF6-mediated IRE1α ubiquitination in regulating TLR-induced IRE1α activation in pro-inflammatory cytokine production, and demonstrated that IRE1α is a potential therapeutic target for inflammatory arthritis.

PubMed ID: 23942232 Exiting the NIEHS site

MeSH Terms: Animals; Arthritis, Rheumatoid/drug therapy*; Blotting, Western; Cell Line; Cytokines/metabolism*; Drug Delivery Systems; Endoribonucleases/antagonists & inhibitors; Endoribonucleases/metabolism*; Enzyme Activation/physiology*; Enzyme-Linked Immunosorbent Assay; Gene Expression Profiling; Immunoprecipitation; Macrophages/cytology; Macrophages/metabolism; Mice; Phosphorylation; Protein Kinase Inhibitors/pharmacology; Protein-Serine-Threonine Kinases/antagonists & inhibitors; Protein-Serine-Threonine Kinases/metabolism*; Real-Time Polymerase Chain Reaction; Synovial Fluid/cytology; TNF Receptor-Associated Factor 6/pharmacology; Toll-Like Receptors/metabolism*; Unfolded Protein Response/physiology*

Back
to Top