Affiliation:
1. Takasaki University of Health and Welfare
Abstract
Abstract
Proinflammatory cytokine interleukin (IL)-6 was associated with disease severity in patients with COVID-19. The mechanism underlying the excessive production of IL-6 by SARS-Cov-2 infection remains unclear. Respiratory viruses initially infect alveolar epithelial cells that produce various immunomodulatory inflammatory mediators. Here, we show that pretreatment of human bronchial epithelial cells (NCl-H292) with interferon (IFN)-γ markedly increased IL-6 production induced by the toll-like receptor (TLR) 3 agonist poly(I:C). A similar priming effect of IFN-γ on poly(I:C)-induced IL-6 production was observed in human primary bronchial and A549 epithelial cells. TLR3 knockdown using siRNA in NCl-H292 cells diminished the priming effects of IFN-γ on poly(I:C)-induced IL-6 production. Furthermore, the Janus kinase (JAK) inhibitor tofacitinib inhibited IFN-γ priming-induced upregulation of TLR3 and suppressed poly(I:C)-induced IL-6 production. Quantitative chromatin immunoprecipitation revealed that IFN-γ stimulated histone modifications associated with the IL-6 gene locus. Finally, IFN-γ priming significantly increased lung IL-6 mRNA and protein levels in the alveolar lavage fluid of mice with poly(I:C)-induced bronchial inflammation. Thus, priming bronchial epithelial cells with IFN-γ markedly increases poly(I:C)-induced IL-6 production via JAK-dependent upregulation of TLR3 and IL-6 gene locus chromatin remodeling. These mechanisms may be involved in severe respiratory inflammation with excess production of IL-6 following infection with RNA viruses.
Publisher
Research Square Platform LLC
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