Involvement of the Akt/NF-κB Pathways in the HTNV-Mediated Increase of IL-6, CCL5, ICAM-1, and VCAM-1 in HUVECs

Abstract

BackgroundHantaan virus (HTNV) infection causes a severe form of HFRS(hemorrhagic fever with renal syndrome)in Asia. Although HTNV has been isolated for nearly forty years, the pathogenesis of HFRS is still unknown, and little is known regarding the signaling pathway that is activated by the virus.Methodology/Principal FindingsCardamonin was selected as a NF-κB inhibitor, and indirect immunofluorescence assays were used to detect the effect of cardamonin on HTNV-infected HUVECs. The effect of cardamonin on the HTNV-induced phosphorylation of Akt and DNA-binding activity of NF-κB were determined using Western blot analysis and electrophoretic mobility shift assays (EMSAs), respectively. Then, flow cytometric and quantitative real-time PCR analyses were performed to quantify the expression levels of the adhesion molecules ICAM-1 and VCAM-1, and the concentrations of IL-6, IL-8, and CCL5 in HUVEC supernatants were examined using ELISA. The results showed that cardamonin did not effect the proliferation of HUVECs or the replication of HTNV in HUVECs. Instead, cardamonin inhibited the phosphorylation of Akt and nuclear transduction of NF-κB and further reduced the expression of the adhesion molecules ICAM-1 and VCAM-1 in HTNV-infected HUVECs. Cardamonin also inhibited the secretion of IL-6 and CCL5, but not IL-8.Conclusion/SignificanceHTNV replication may not be dependent upon the ability of the virus to activate NF-κB in HUVECs. The Akt/NF-κB pathways may be involved in the pathogenesis of HFRS; therefore, cardamonin may serve as a potential beneficial agent for HFRS therapy.

Suppression of Sirtuin-1 Increases IL-6 Expression by Activation of the Akt Pathway During Allergic Asthma

“…It was reported that the PI3K/Akt pathway might play important roles in modulating IL-6 release in various cells [16, 17]. Thus, we examined whether Akt activation increased IL-6 expression in human lung epithelial cells.…”

IL-33/ST2 Correlates with Severity of Haemorrhagic Fever with Renal Syndrome and Regulates the Inflammatory Response in Hantaan Virus-Infected Endothelial Cells

“…IL-33 is a selective activator and preferentially targets nonquiescent HUVECs [ 11 ]. Previous reports have demonstrated that HTNV infection could induce increased levels of VCAM-1 and ICAM-1 in HUVECs [ 39 ], which could drive HUVECs into the nonquiescent state. Therefore, we hypothesised that HTNV infection activated HUVECs, causing them to become nonquiescent cells, which then became the target cells for IL-33.…”

“…Thus, IL-33 could augment its pro-inflammatory function. Furthermore, HTNV infection could activate the NF-κB pathway in HUVECs [ 7 , 39 ]. Acting as cross-talk between HTNV and IL-33, the NF-κB pathway was highly activated when the HUVECs were treated with both HTNV and IL-33 ( Fig.…”

Interferon-Induced Transmembrane Protein 3 Inhibits Hantaan Virus Infection, and Its Single Nucleotide Polymorphism rs12252 Influences the Severity of Hemorrhagic Fever with Renal Syndrome

“…Cells were used within passage 10 after primary culture. HTNV strain 76-118 was cultured in Vero E6 cells (ATCC Cat# CRL-1586, RRID:CVCL_0574) in our laboratory and titrated using an immunofluorescence staining assay for HTNV nucleocapsid protein (NP) as previously described (22). The TCID50 was 10 5 /ml, which was calculated using the Reed-Muench method.…”