Evaluation of hypoxia inducible factor expression in inflammatory and neurodegenerative brain models

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• 作者：Maria Luisa de Lemos^a ; Aurelio Vazquez de la Torre^a ; Dimitry Petrov^a ; ^c ; Susana Brox^c ; Jaume Folch^b ; Mercè ; Pallà ; s^a ; Alberto Lazarowski^d ; Carlos Beas-Zarate^e ; Carme Auladell^c ; Antoni Camins^a ; ^{camins@ub.edu}
• 关键词：APP/PS1 ; c-Jun ; HIF-1¦Á ; Alzheimer's ; Apoptosis
• 刊名：The International Journal of Biochemistry and Cell Biology
• 出版年：2013
• 出版时间：July, 2013
• 年：2013
• 卷：45
• 期：7
• 页码：1377-1388
• 全文大小：2809 K

文摘

The neuroinflammatory process is thought to contribute to the progression of neurological disorders and brain pathologies. The release of pro-inflammatory cytokines and chemokines by activated glial cells, astrocytes and microglia plays an important role in this process. However, the role of hypoxia-inducible factor-1¦Á (HIF-1¦Á), the key transcription factor regulating the expression of hypoxia-inducible genes, during glial activation is less known. Thus, we examined the significance of HIF-1¦Á in three experimental models: first in an acute model of inflammation induced by pro-inflammatory cytokines TNF-¦Á, IL-1¦Â and IFN-¦Ã; secondly, in a chronic model of inflammation using an APPswe/PS1dE9 (APP/PS1) transgenic mouse model of Alzheimer's disease and thirdly via the inhibition of the PI3K/AKT pathway in a model of neuronal apoptosis. During acute glial inflammation induced by in vitro administration of TNF-¦Á, IL-1¦Â and IFN-¦Ã, mRNA expression levels of HIF-1¦Á were significantly upregulated; however, this effect was blocked by SP600126, a pharmacological inhibitor of mitogen-activated protein kinases (MAPKs). These data suggest that MAPKs could be involved in HIF-1¦Á regulation. In addition, we observed that HIF-1¦Á is not involved in the neuronal apoptotic process mediated by PI3-kinase inhibition, which is regulated by c-Jun. Finally, we did not detect significant differences in the expression of HIF-1¦Á mRNA in APP/PS1 mice during the course of the study (3-12 months of age). Thus, we demonstrated that HIF-1¦Á has a prominent role in acute but not in chronic inflammatory processes, such as the one which occurs in the APP/PS1 experimental model of AD. Moreover, HIF-1¦Á is not involved in neuronal apoptosis after PI3K/AKT inhibition.