Browse

Endoplasmic Reticulum Stress–Induced IRE1α Activation Mediates Cross-Talk of GSK-3β and XBP-1 To Regulate Inflammatory Cytokine Production

Cited 73 time in Web of Science Cited 72 time in Scopus
Authors
Kim, Sena; Joe, Yeonsoo; Kim, Hyo Jeong; Kim, You-Sun; Jeong, Sun Oh; Pae, Hyun-Ock; Ryter, Stefan W.; Surh, Young-Joon; Chung, Hun Taeg
Issue Date
2015-05
Citation
Journal of Immunology, Vol.194 No.9, pp.4498-4506
Abstract
IL-1 beta and TNF-alpha are important proinflammatory cytokines that respond to mutated self-antigens of tissue damage and exogenous pathogens. The endoplasmic reticulum (ER) stress and unfolded protein responses are related to the induction of proinflammatory cytokines. However, the detailed molecular pathways by which ER stress mediates cytokine gene expression have not been investigated. In this study, we found that ER stress-induced inositol-requiring enzyme (IRE) 1a activation differentially regulates proinflammatory cytokine gene expression via activation of glycogen synthase kinase (GSK)-3 beta and X-box binding protein (XBP)-1. Surprisingly, IL-1 beta gene expression was modulated by IRE1 alpha-mediated GSK-3 beta activation, but not by XBP-1. However, IRE1 alpha-mediated XBP-1 splicing regulated TNF-alpha gene expression. SB216763, a GSK-3 inhibitor, selectively inhibited IL-1 beta gene expression, whereas the IRE1 alpha RNase inhibitor STF083010 suppressed only TNF-alpha production. Additionally, inhibition of GSK-3 beta greatly increased IRE1 alpha-dependent XBP-1 splicing. Our results identify an unsuspected differential role of downstream mediators GSK-3 beta and XBP-1 in ER stress-induced IRE1 alpha activation that regulates cytokine production through signaling cross-talk. These results have important implications in the regulation of inflammatory pathways during ER stress, and they suggest novel therapeutic targets for diseases in which meta-inflammation plays a key role.
ISSN
0022-1767
URI
http://hdl.handle.net/10371/172618
DOI
https://doi.org/10.4049/jimmunol.1401399
Files in This Item:
There are no files associated with this item.
Appears in Collections:
Graduate School of Convergence Science and Technology (융합과학기술대학원)Dept. of Molecular and Biopharmaceutical Sciences (분자의학 및 바이오제약학과)Journal Papers (저널논문_분자의학 및 바이오제약학과)
  • mendeley

Items in S-Space are protected by copyright, with all rights reserved, unless otherwise indicated.

Browse