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

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.

HIF-1α Modulates Core Metabolism and Virus Replication in Primary Airway Epithelial Cells Infected with Respiratory Syncytial Virus

“…Several viruses, often associated with chronic infections, such as hepatitis C virus, herpesviruses, human papillomavirus and immunodeficiency virus (HIV), have been shown to induce HIF-1α activation, leading to metabolic cellular reprogramming and promotion of virus replication [ 31 , 34 , 35 ]. Influenza virus infection was also able to induce HIF-1α activation in lung carcinoma and monocytic cell lines; however, a lack of lung epithelial cell expression of HIF-1α in a mouse model of influenza infection was associated with enhanced virus replication [ 36 , 37 ]. HIF-1α expression and stabilization in epithelial and immune cells plays an important role in promoting inflammatory responses, as well as the production of VEGF [ 8 , 33 ], both of which are known to contribute to the pathogenesis of RSV-induced lung disease, supporting further investigation into the use of selective HIF-1a inhibitors to modulate RSV disease, keeping in mind, however, that HIF proteins are also important for repair/healing processes following acute lung injury [ 38 , 39 ].…”

Hypoxia: A key feature of COVID-19 launching activation of HIF-1 and cytokine storm

“…Influenza viruses stabilize HIF-1α through impairing proteasome function and decreasing the expression of factor inhibiting HIF-1α (FIH-1) [ 38 ]. The high production of pro-inflammatory cytokines, cytokine storm, as a key contributor to severe pneumonia in patients with H1N1 infection is mediated by HIF-1α which can induce proinflammatory molecules production in the site of inflammation [ 39 ].…”

Rat astrocytes during anoxia: Secretome profile of cytokines and chemokines

“…A cytokine‐mediated inflammation triggered by HIF‐2α has been revealed in reflux esophagitis (Souza, Bayeh, Spechler, Tambar, & Bruick, ). An in vitro study showed that in vitro infection with influenza H1N1 virus promotes the secretion of proinflammatory cytokines by inducing nuclear translocation of HIF‐1α (Guo et al., ). HIF‐1α appears to control expression of IL‐22 in CD4 T cells (Budda, Girton, Henderson, & Zenewicz, ).…”