title: Evaluation of hypoxia inducible factor expression in inflammatory and neurodegenerative brain models.
abstract: 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-1α (HIF-1α), the key transcription factor regulating the expression of hypoxia-inducible genes, during glial activation is less known. Thus, we examined the significance of HIF-1α in three experimental models: first in an acute model of inflammation induced by pro-inflammatory cytokines TNF-α, IL-1β and IFN-γ; 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-α, IL-1β and IFN-γ, mRNA expression levels of HIF-1α 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-1α regulation. In addition, we observed that HIF-1α 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-1α mRNA in APP/PS1 mice during the course of the study (3-12 months of age). Thus, we demonstrated that HIF-1α 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-1α is not involved in neuronal apoptosis after PI3K/AKT inhibition.
authors.affiliation: Unitat de Farmacologia I Farmacognòsia, Facultat de Farmàcia, Institut de Biomedicina, IBUB, Centros de Investigación Biomédica en Red de Enfermedades Neurodegenerativas, Universitat de Barcelona, Spain.
authors.forename: Maria Luisa
authors.initials: ML
authors.lastname: de Lemos
authors.forename: Aurelio Vazquez
authors.initials: AV
authors.lastname: de la Torre
authors.forename: Dimitry
authors.initials: D
authors.lastname: Petrov
authors.forename: Susana
authors.initials: S
authors.lastname: Brox
authors.forename: Jaume
authors.initials: J
authors.lastname: Folch
authors.forename: Mercè
authors.initials: M
authors.lastname: Pallàs
authors.forename: Alberto
authors.initials: A
authors.lastname: Lazarowski
authors.forename: Carlos
authors.initials: C
authors.lastname: Beas-Zarate
authors.forename: Carme
authors.initials: C
authors.lastname: Auladell
authors.forename: Antoni
authors.initials: A
authors.lastname: Camins
mesh_terms: D000544:Alzheimer Disease / Q000378:metabolism*; D000818:Animals; D017209:Apoptosis; D001921:Brain / Q000378:metabolism / Q000473:pathology; D002478:Cells, Cultured; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000494:pharmacology; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D007249:Inflammation / Q000378:metabolism*; D007371:Interferon-gamma / Q000378:metabolism; D053583:Interleukin-1beta / Q000378:metabolism; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors; D009457:Neuroglia; D000081082:Phosphoinositide-3 Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D012333:RNA, Messenger / Q000096:biosynthesis; D051381:Rats; D017207:Rats, Sprague-Dawley; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D015854:Up-Regulation
chemical_list: D004791:Enzyme Inhibitors; C497443:Hif1a protein, mouse; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D053583:Interleukin-1beta; D000081082:Phosphoinositide-3 Kinase Inhibitors; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; D007371:Interferon-gamma; D051057:Proto-Oncogene Proteins c-akt; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases