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IRE1α Is a Therapeutic Target for Cystic Fibrosis Airway Inflammation by Emily A. Hull-Ryde; John T. Minges; Mary E. B. Martino; Takafumi Kato; Jacqueline L. Norris-Drouin; Carla M. P. Ribeiro is a Biochemistry, Genetics and Molecular Biology article available to read on EtoBox.

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New anti-inflammatory treatments are needed for CF airway disease. Studies have implicated the endoplasmic reticulum stress transducer inositol requiring enzyme 1α (IRE1α) in CF airway inflammation. The activation of IRE1α promotes activation of its cytoplasmic kinase and RNase, resulting in mRNA splicing of X-box binding protein-1 (XBP-1s), a transcription factor required for cytokine production. We tested whether IRE1α kinase and RNase inhibition decreases cytokine production induced by the exposure of primary cultures of homozygous F508del CF human bronchial epithelia (HBE) to supernatant of mucopurulent material (SMM) from CF airways. We evaluated whether IRE1α expression is increased in freshly isolated and native CF HBE, and couples with increased XBP-1s levels. A FRET assay confirmed binding of the IRE1α kinase and RNase inhibitor, KIRA6, to the IRE1α kinase. F508del HBE cultures were exposed to SMM with or without KIRA6, and we evaluated the mRNA levels of XBP-1s, IL-6, and IL-8, and the secretion of IL-6 and IL-8. IRE1α mRNA levels were up-regulated in freshly isolated CF vs. normal HBE and coupled to increased XBP-1s mRNA levels. SMM increased XBP-1s, IL-6, and IL-8 mRNA

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Author

Emily A. Hull-Ryde; John T. Minges; Mary E. B. Martino; Takafumi Kato; Jacqueline L. Norris-Drouin; Carla M. P. Ribeiro

Publisher

MDPI AG

Published

2021

Language

EN

Field

Biochemistry, Genetics and Molecular Biology (Life Sciences)