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Nuclear translocation of HIF-1? 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-1?) is associated with the production of proinflammatory molecules, but whether HIF-1? participates in the acute inflammatory responses against H1N1 infection is still unclear. To investigate the role of HIF-1? in H1N1 infection, the expression and nuclear translocation of HIF-1? 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-1?, H1N1 infection only induced nuclear translocation of HIF-1? under normal oxygen concentrations. The use of 2-methoxyestradiol (2ME2), a HIF-1? inhibitor that blocks HIF-1? nuclear accumulation, in H1N1-infected cells decreased the mRNA and protein expression of tumor necrosis factor-alpha (TNF-?) and interleukin (IL)-6 and increased the levels of IL-10. In contrast, H1N1-infected cells under hypoxic conditions had increased HIF-1? nuclear accumulation, increased expression of TNF-? and IL-6 and decreased levels of IL-10. In conclusion, our data implied that in vitro H1N1 infection induced nuclear translocation of HIF-1? without altering the expression of HIF-1?, which may promote the secretion of proinflammatory cytokines during H1N1 infection.

SUBMITTER: Guo X

PROVIDER: S-EPMC5520484 | biostudies-literature | 2017 May

REPOSITORIES: biostudies-literature

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

Guo Xinkun X Zhu Zhaoqin Z Zhang Wanju W Meng Xiaoxiao X Zhu Yong Y Han Peng P Zhou Xiaohui X Hu Yunwen Y Wang Ruilan R

Emerging microbes & infections 20170524 5

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 ...[more]

PMID: 28536432

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Project description:BackgroundHypoxia-inducible factor (HIF)-1 is involved in the regulation of hypoxic preconditioning in cardiomyocytes. Under hypoxic conditions, HIF-1α accumulates and is translocated to the nucleus, where it forms an active complex with HIF-1β and activates transcription of approximately 60 kinds of hypoxia-adaptive genes. Microtubules are hollow tubular structures in the cell that maintain cellular morphology and that transport substances. This study attempted to clarify the role of microtubule structure in the endonuclear aggregation of HIF-1α following hypoxic preconditioning of cardiomyocytes.MethodsPrimary rat cardiomyocytes were isolated and cultured. The cardiomyocyte culture system was used to establish a hypoxia model and a hypoxic preconditioning model. Interventions were performed on primary cardiomyocytes using a microtubule-depolymerizing agent and different concentrations of a microtubule stabilizer. The microtubule structure and the degree of HIF-1α nuclear aggregation were observed by confocal laser scanning microscopy. The expression of HIF-1α in the cytoplasm and nucleus was detected using Western blotting. Cardiomyocyte energy content, reflected by adenosine triphosphate/adenosine diphosphate (ATP/ADP), and key glycolytic enzymes were monitored by colorimetry and high-performance liquid chromatography (HPLC). Reactive oxygen species (ROS) production was also used to comprehensively assess whether microtubule stabilization can enhance the myocardial protective effect of hypoxic preconditioning.ResultsDuring prolonged hypoxia, it was found that the destruction of the microtubule network structure of cardiomyocytes was gradually aggravated. After this preconditioning, an abundance of HIF-1α was clustered in the nucleus. When the microtubules were depolymerized and hypoxia pretreatment was performed, HIF-1α clustering occurred around the nucleus, and HIF-1α nuclear expression was low. The levels of key glycolytic enzymes were significantly higher in the microtubule stabilizer group than in the hypoxia group. Additionally, the levels of lactate dehydrogenase and ROS were significantly lower in the microtubule stabilizer group than in the hypoxia group.ConclusionThe microtubules of cardiomyocytes may be involved in the process of HIF-1α endonuclear aggregation, helping to enhance the anti-hypoxic ability of cardiomyocytes.

Project description:PURPOSE:Proinflammatory cytokines interferon gamma (IFN-?), tumor necrosis factor alpha (TNF-?), and interleukin-1 beta (IL-1?) secreted by infiltrating lymphocytes or macrophages may play a role in triggering RPE dysfunction associated with age-related macular degeneration (AMD). Binding of these proinflammatory cytokines to their specific receptors residing on the RPE cell surface can activate signaling pathways that, in turn, may dysregulate cellular gene expression. The purpose of the present study was to investigate whether IFN-?, TNF-?, and IL-1? have an adverse effect on the expression of genes essential for RPE function, employing the RPE cell line ARPE-19 as a model system. METHODS:ARPE-19 cells were cultured for 3-4 months until they exhibited epithelial morphology and expressed mRNAs for visual cycle genes. The differentiated cells were treated with IFN-?, TNF-?, and/or IL-1?, and gene expression was analyzed with real-time PCR analysis. Western immunoblotting was employed for the detection of proteins. RESULTS:Proinflammatory cytokines (IFN-? + TNF-? + IL-1?) greatly increased the expression of chemokines and cytokines in cultured ARPE-19 cells that exhibited RPE characteristics. However, this response was accompanied by markedly decreased expression of genes important for RPE function, such as CDH1, RPE65, RDH5, RDH10, TYR, and MERTK. This was associated with decreased expression of the genes MITF, TRPM1, and TRPM3, as well as microRNAs miR-204 and miR-211, which are known to regulate RPE-specific gene expression. The decreased expression of the epithelial marker gene CDH1 was associated with increased expression of mesenchymal marker genes (CDH2, VIM, and CCND1) and epithelial-mesenchymal transition (EMT) promoting transcription factor genes (ZEB1 and SNAI1). CONCLUSIONS:RPE cells exposed to proinflammatory cytokines IFN-?, TNF-?, and IL-1? showed decreased expression of key genes involved in the visual cycle, epithelial morphology, and phagocytosis. This adverse effect of proinflammatory cytokines, which could be secreted by infiltrating lymphocytes or macrophages, on the expression of genes indispensable for RPE function may contribute to the RPE dysfunction implicated in AMD pathology.

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

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

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