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

Abstract

Running head: Glucocorticoids abolish beneficial effects of IFNAbbreviations: Acute Physiology and Chronic Health Evaluation (APACHE) II, interferon (IFN(, Sequential Organ Failure Assessment (SOFA) Take home message: Glucocorticoids inhibit type I interferon beta signaling and the upregulation of CD73 that is a key molecule preventing vascular leakage and harmful leukocyte infiltration into the lungs. This work provides the mechanistic basis for the need to avoid glucocorticoids in viralinduced ARDS, in which endogenous interferon is needed to combat the infection and its consequences. AbstractPurpose: Glucocorticoids 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. Methods:We 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. Results:We 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. Conclusions:Glucocorticoids 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 current corona virus pandemia.

Intravenous Interferon β-1a for Severe ARDS—Reply

“…Patients in the IFN-β-1a group with baseline glucocorticoid use had an increased risk of dying (hazard ratio, 1.676 [95% CI, 0.951-2.950] for IFN-β-1a vs placebo) (Figure). Glucocorticoid use after intervention (study day 7 onward) was explored but did not show interaction with the study treatment …”