Cytokine-Induced iNOS in A549 Alveolar Epithelial Cells: A Potential Role in COVID-19 Lung Pathology
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Published:2023-10-03
Issue:10
Volume:11
Page:2699
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ISSN:2227-9059
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Container-title:Biomedicines
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language:en
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Short-container-title:Biomedicines
Author:
Barilli Amelia1ORCID, Recchia Luciani Giulia1, Visigalli Rossana1, Sala Roberto1ORCID, Soli Maurizio2, Dall’Asta Valeria1ORCID, Rotoli Bianca Maria1
Affiliation:
1. Laboratory of General Pathology, Department of Medicine and Surgery, University of Parma, 43125 Parma, Italy 2. Immunohematology and Transfusion Medicine, University Hospital of Parma, 43125 Parma, Italy
Abstract
Background. In COVID-19, an uncontrolled inflammatory response might worsen lung damage, leading to acute respiratory distress syndrome (ARDS). Recent evidence points to the induction of inducible nitric oxide synthase (NOS2/iNOS) as a component of inflammatory response since NOS2 is upregulated in critical COVID-19 patients. Here, we explore the mechanisms underlying the modulation of iNOS expression in human alveolar cells. Methods. A549 WT and IRF1 KO cells were exposed to a conditioned medium of macrophages treated with SARS-CoV-2 spike S1. Additionally, the effect of IFNγ, IL-1β, IL-6, and TNFα, either alone or combined, was addressed. iNOS expression was assessed with RT-qPCR and Western blot. The effect of baricitinib and CAPE, inhibitors of JAK/STAT and NF-kB, respectively, was also investigated. Results. Treatment with a conditioned medium caused a marked induction of iNOS in A549 WT and a weak stimulation in IRF1 KO. IFNγ induced NOS2 and synergistically cooperated with IL-1β and TNFα. The inhibitory pattern of baricitinb and CAPE indicates that cytokines activate both IRF1 and NF-κB through the JAK/STAT1 pathway. Conclusions. Cytokines secreted by S1-activated macrophages markedly induce iNOS, whose expression is suppressed by baricitinib. Our findings sustain the therapeutic efficacy of this drug in COVID-19 since, besides limiting the cytokine storm, it also prevents NOS2 induction.
Subject
General Biochemistry, Genetics and Molecular Biology,Medicine (miscellaneous)
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