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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.

The mechanisms underlying pathophysiological states such as metabolic syndrome and obesity include endoplasmic reticulum (ER) stress and aberrant inflammatory responses. ER stress results from the accumulation of misfolded proteins during stress conditions. However, the precise mechanisms by which ER stress modulates inflammation remain incompletely understood. In this study, we hypothesized that ER stress alone could represent a sufficient signal for the modulation of inflammasome-dependent cytokine responses. We found that several ER stress-inducing chemicals and the free fatty acid palmitate can trigger IL-1β secretion in various cell types, including monocytic leukemia cells, primary macrophages and differentiated adipocytes. We show that ER stress primes cells for the expression of pro-IL-1β via NF-κB activation and promotes IL-1β secretion. Enhanced IL-1β secretion depended on the activation of the NLRP3 inflammasome through a mechanism involving reactive oxygen species formation and activation of thioredoxin-interacting protein. Chemical chaperone treatment and the pharmacological application of carbon monoxide inhibited IL-1β secretion in response to ER stress. Our results provide a mechanistic link between ER stress and the regulation of inflammation, and suggest that modulation of ER stress may provide a therapeutic opportunity to block progression of low grade chronic inflammation to metabolic syndrome.

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