Endoplasmic Reticulum Stress–Induced IRE1α Activation Mediates Cross-Talk of GSK-3β and XBP-1 To Regulate Inflammatory Cytokine Production
| Autor: | You-Sun Kim, Young-Joon Surh, Hun Taeg Chung, Sun Oh Jeong, Hyo Jeong Kim, Yeonsoo Joe, Stefan W. Ryter, Hyun-Ock Pae, Sena Kim |
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| Rok vydání: | 2015 |
| Předmět: |
Male
Transcriptional Activation X-Box Binding Protein 1 Transcription Genetic RNA Splicing Interleukin-1beta Innate Immunity and Inflammation Immunology Regulatory Factor X Transcription Factors Protein Serine-Threonine Kinases Biology Models Biological Cell Line Proinflammatory cytokine Glycogen Synthase Kinase 3 Mice GSK-3 Endoribonucleases Gene expression Animals Immunology and Allergy GSK3B Regulation of gene expression Glycogen Synthase Kinase 3 beta Tumor Necrosis Factor-alpha Macrophages Endoplasmic reticulum Endoplasmic Reticulum Stress Molecular biology Cell biology DNA-Binding Proteins Enzyme Activation Toll-Like Receptor 4 Gene Expression Regulation Macrophages Peritoneal Unfolded protein response Cytokines Inflammation Mediators Signal transduction Signal Transduction Transcription Factors |
| Zdroj: | The Journal of Immunology. 194:4498-4506 |
| ISSN: | 1550-6606 0022-1767 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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