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The accumulation of improperly folded proteins within the endoplasmic reticulum (ER) generates perturbations known as ER stress that engage the unfolded protein response. ER stress is involved in many inflammatory pathologies that are also associated with the production of the proinflammatory cytokine IL-1β. In this study, we demonstrate that macrophages undergoing ER stress are able to drive the production and processing of pro-IL-1β in response to LPS stimulation in vitro. Interestingly, the classical NLRP3 inflammasome is dispensable, because maturation of pro-IL-1β occurs normally in the absence of the adaptor protein ASC. In contrast, processing of pro-IL-1β is fully dependent on caspase-8. Intriguingly, we found that neither the unfolded protein response transcription factors XBP1 and CHOP nor the TLR4 adaptor molecule MyD88 is necessary for caspase-8 activation. Instead, both caspase activation and IL-1β production require the alternative TLR4 adaptor TRIF. This pathway may contribute to IL-1-driven tissue pathology in certain disease settings.

Original publication

DOI

10.4049/jimmunol.1302549

Type

Journal article

Journal

J Immunol

Publication Date

01/03/2014

Volume

192

Pages

2029 - 2033

Keywords

Adaptor Proteins, Vesicular Transport, Animals, Caspase 8, DNA-Binding Proteins, Endoplasmic Reticulum Stress, Enzyme Activation, Inflammation, Interleukin-1beta, Macrophages, Mice, Mice, Knockout, Myeloid Differentiation Factor 88, Regulatory Factor X Transcription Factors, Toll-Like Receptor 4, Transcription Factor CHOP, Transcription Factors, Unfolded Protein Response, X-Box Binding Protein 1