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Glucocorticoids inhibit type I IFN beta signaling and the upregulation of CD73 in human lung

By Juho Jalkanen, Ville Pettilä, Matti Karvonen, Teppo Huttunen, Jami Mandelin, Markku Jalkanen, Markus Malmberg, Kati Elima, Geoff Bellingan, V. Marco Ranieri, Maija Hollmen, Sirpa Jalkanen

Posted 06 Apr 2020
medRxiv DOI: 10.1101/2020.04.01.20049700

PurposeGlucocorticoids are widely used to treat acute respiratory distress syndrome (ARDS) despite its use is highly controversial based on randomized controlled trials and meta-analyses. As type I interferons (IFNs) are our first line of defense against severe viral respiratory infections, we explored whether glucocorticoids interfere with IFN signaling and whether their use associates to outcome of IFN beta treatment of ARDS. MethodsWe performed a propensity-matched post-hoc-analysis using data from the recent randomized INTEREST-trial comparing IFN beta-1a to placebo in ARDS patients. Based on the results of these analyses we utilized human lung tissue and human pulmonary endothelial cell cultures to investigate the effect of hydrocortisone on IFN nuclear signaling and the protein transcription of CD73, a molecule responsible for vascular integrity. ResultsWe found that hydrocortisone reduces the production, and prevents the nuclear translocation of IRF9, that is required for IFN beta-dependent signaling of multiple IFN-induced genes. In addition, hydrocortisone inhibits IFN beta-dependent upregulation of CD73 in human lung tissue. Additionally, we found that use of glucocorticoids with IFN beta-1a was independently associated with increased mortality (OR 5.4, 95% CI 2.1-13.9, P< 0.001) in the INTEREST-trial. ConclusionsGlucocorticoids inhibit type I IFN beta signaling and the upregulation of CD73 in human lung. This provides the mechanistic basis for the harmful association of glucocorticoids in IFN beta treated patients in the INTEREST-trial. Most importantly, it strongly speaks against the use of glucocorticoids in viral-induced ARDS such as in the currently expanding corona virus outbreak.

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