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Abstract
We previously reported that IL-27, which belongs to the IL-12 family of cytokines, is elevated in the serum of patients infected with influenza A virus (IAV). Here, we show that the expression of IL-27 was significantly up-regulated in A549 human lung epithelial cells and human peripheral blood mononuclear cells infected with IAV. Additionally, IAV triggered IL-27 expression through protein kinase A and cAMP-response element-binding protein signaling, which was mediated by cyclooxygenase-2-derived prostaglandin E(2). IL-27 inhibited IAV replication by STAT1/2/3 phosphorylation and activated antiviral factor protein kinase R phosphorylation. Clinical analysis showed that IL-27 levels were significantly elevated in a cohort of patients infected with IAV compared with healthy individuals and that circulating IL-27 levels were tightly and positively correlated with prostaglandin E(2) levels. These results indicate that IL-27 expression is one host immune factor produced in response to IAV infection and that elevated IL-27 levels inhibit viral replication.
Highlights
Interleukin (IL)-27 is significantly elevated in influenza patients
In our previously published study, we conducted protein-antibody arrays and reported that IL-27 is one of the proteins up-regulated in serum of influenza patients and freshly isolated PBMCs infected with influenza A virus (IAV), and down-regulated when IAV-infected PBMCs were treated with the COX-2 inhibitor NS-398 [20]
Because it has been previously reported that IL-27/P28 is up-regulated after IAV infection and that Epstein-Barr virus-induced 3 (EBI3) is responsible for secretion of the IL-27 complex [25, 37, 38], we tested whether IAV triggers IL-27 expression by activation of the IL-27/EBI3 promoter
Summary
Results: IL-27 inhibits influenza A virus (IAV) replication and its expression is mediated by cyclooxygenase-2, protein kinase A (PKA), and the cAMP-response element-binding protein pathway. Clinical analysis showed that IL-27 levels were significantly elevated in a cohort of patients infected with IAV compared with healthy individuals and that circulating IL-27 levels were tightly and positively correlated with prostaglandin E2 levels These results indicate that IL-27 expression is one host immune factor produced in response to IAV infection and that elevated IL-27 levels inhibit viral replication. We demonstrate that IL-27 is significantly upregulated in IAV-infected A549 lung epithelial cells and freshly isolated PBMCs. We show that IAV triggers IL-27/EBI3 promoter activity and IL-27 expression through a protein kinase A (PKA)-CREB signaling pathway and that this response is mediated by COX-2-derived prostaglandin E2 (PGE2). We further demonstrate IL-27 is significantly elevated in serum of patients infected with 2009 pandemic H1N1 and seasonal H3N2 compared with that from healthy individuals, and that circulating IL-27 levels are closely associated with PGE2 levels
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