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

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.