Nuclear translocation of HIF-1α induced by influenza A (H1N1) infection is critical to the production of proinflammatory cytokines

Xinkun Guo,Zhaoqin Zhu,Wanju Zhang,Xiaoxiao Meng,Yong Zhu,Peng Han,Xiaohui Zhou,Yunwen Hu,Ruilan Wang

doi:10.1038/emi.2017.21

Abstract

Infection with the influenza A (H1N1) virus is a major challenge for public health because it can cause severe morbidity and even mortality in humans. The over-secretion of inflammatory cytokines (cytokine storm) is considered to be a key contributor to the severe pneumonia caused by H1N1 infection. It has been reported that hypoxia-inducible factor 1-alpha (HIF-1α) is associated with the production of proinflammatory molecules, but whether HIF-1α participates in the acute inflammatory responses against H1N1 infection is still unclear. To investigate the role of HIF-1α in H1N1 infection, the expression and nuclear translocation of HIF-1α in A549 and THP-1 cell lines infected with H1N1 virus were observed. The results showed that without altering the intracellular mRNA or protein expression of HIF-1α, H1N1 infection only induced nuclear translocation of HIF-1α under normal oxygen concentrations. The use of 2-methoxyestradiol (2ME2), a HIF-1α inhibitor that blocks HIF-1α nuclear accumulation, in H1N1-infected cells decreased the mRNA and protein expression of tumor necrosis factor-alpha (TNF-α) and interleukin (IL)-6 and increased the levels of IL-10. In contrast, H1N1-infected cells under hypoxic conditions had increased HIF-1α nuclear accumulation, increased expression of TNF-α and IL-6 and decreased levels of IL-10. In conclusion, our data implied that in vitro H1N1 infection induced nuclear translocation of HIF-1α without altering the expression of HIF-1α, which may promote the secretion of proinflammatory cytokines during H1N1 infection.Emerging Microbes & Infections (2017) 6, e39; doi:10.1038/emi.2017.21; published online 24 May 2017

Highlights

IntroductionSince it first emerged in Mexico in the early 2009,1 H1N1 viral infections have been recorded in most areas of the world[2,3,4] and are an important cause of severe acute pneumonia, which often results in acute respiratory distress syndrome (ARDS), a syndrome with a high risk of mortality.[5,6,7] H1N1 infection represents a severe challenge and a significant threat to public health.Many factors may complicate the severe respiratory syndrome caused by influenza virus infection, of which, the cytokine storm is a key contributor in modulating the immune response.[8,9] High levels of proinflammatory cytokines were characterized in the sera of patients infected with the H1N1, H5N1 and H7N9 influenza viruses.[9,10,11] Proinflammatory cytokines, such as tumor necrosis factor-alpha (TNF-α) and interleukin (IL)-6, promote inflammation and directly damage the alveolar–capillary membrane, leading to edema and surfactant inactivation.[12,13] Diffused inflammation and damage of alveolar and capillary lung structures can cause progressive hypoxemia, eventually leading to ARDS.[14]
H1N1 infection of A549 and THP-1 cells induced nuclear translocation of Hypoxia-inducible factor (HIF)-1α but did not alter HIF-1α mRNA and total protein levels To investigate the influence of H1N1 infection on the expression of HIF-1α, A549 and THP-1 cells were infected with H1N1 at different
The results showed that HIF-1α mRNA expression was not upregulated in either A549 or THP-1 cells infected with H1N1 compared with the non-infected controls (Figures 1A and 1B), the virus RNA levels increased with the infection dosage (Figures 1C and 1D)

Summary

Introduction

Since it first emerged in Mexico in the early 2009,1 H1N1 viral infections have been recorded in most areas of the world[2,3,4] and are an important cause of severe acute pneumonia, which often results in acute respiratory distress syndrome (ARDS), a syndrome with a high risk of mortality.[5,6,7] H1N1 infection represents a severe challenge and a significant threat to public health.Many factors may complicate the severe respiratory syndrome caused by influenza virus infection, of which, the cytokine storm is a key contributor in modulating the immune response.[8,9] High levels of proinflammatory cytokines were characterized in the sera of patients infected with the H1N1, H5N1 and H7N9 influenza viruses.[9,10,11] Proinflammatory cytokines, such as tumor necrosis factor-alpha (TNF-α) and interleukin (IL)-6, promote inflammation and directly damage the alveolar–capillary membrane, leading to edema and surfactant inactivation.[12,13] Diffused inflammation and damage of alveolar and capillary lung structures can cause progressive hypoxemia, eventually leading to ARDS.[14].

Methods

Results

Conclusion