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Endoplasmic reticulum stress-induced IRE1α activation mediates cross-talk of GSK-3β and XBP-1 to regulate inflammatory cytokine production.

Authors
Kim, S | Joe, Y | Kim, HJ | Kim, YS  | Jeong, SO | Pae, HO | Ryter, SW | Surh, YJ | Chung, HT
Citation
Journal of immunology (Baltimore, Md. : 1950), 194(9). : 4498-4506, 2015
Journal Title
Journal of immunology (Baltimore, Md. : 1950)
ISSN
0022-17671550-6606
Abstract
IL-1β and TNF-α 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)1α activation differentially regulates proinflammatory cytokine gene expression via activation of glycogen synthase kinase (GSK)-3β and X-box binding protein (XBP)-1. Surprisingly, IL-1β gene expression was modulated by IRE1α-mediated GSK-3β activation, but not by XBP-1. However, IRE1α-mediated XBP-1 splicing regulated TNF-α gene expression. SB216763, a GSK-3 inhibitor, selectively inhibited IL-1β gene expression, whereas the IRE1α RNase inhibitor STF083010 suppressed only TNF-α production. Additionally, inhibition of GSK-3β greatly increased IRE1α-dependent XBP-1 splicing. Our results identify an unsuspected differential role of downstream mediators GSK-3β and XBP-1 in ER stress-induced IRE1α 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.
MeSH

DOI
10.4049/jimmunol.1401399
PMID
25821218
Appears in Collections:
Journal Papers > School of Medicine / Graduate School of Medicine > Biochemistry & Molecular Biology
Ajou Authors
김, 유선
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