title: Folic Acid Represses Hypoxia-Induced Inflammation in THP-1 Cells through Inhibition of the PI3K/Akt/HIF-1α Pathway.
abstract: Though hypoxia has been implicated as a cause of inflammation, the underlying mechanism is not well understood. Folic acid has been shown to provide protection against oxidative stress and inflammation in patients with cardiovascular disease and various models approximating insult to tissue via inflammation. It has been reported that hypoxia-induced inflammation is associated with oxidative stress, upregulation of hypoxia-inducible factor 1-alpha (HIF-1α), and production of pro-inflammatory molecules. Whether folic acid protects human monocytic cells (THP-1 cells) against hypoxia-induced damage, however, remains unknown. We used THP-1 cells to establish a hypoxia-induced cellular injury model. Pretreating THP-1 cells with folic acid attenuated hypoxia-induced inflammatory responses, including a decrease in protein and mRNA levels of interleukin (IL)-1β and tumor necrosis factor-alpha (TNF-α), coupled with increased levels of IL-10. Folic acid also reduced hypoxia-induced Akt phosphorylation and decreased nuclear accumulation of HIF-1α protein. Both LY294002 (a selective inhibitor of phosphatidyl inositol-3 kinase, PI3K) and KC7F2 (a HIF-1α inhibitor) reduced levels of hypoxia-induced inflammatory cytokines. We also found that insulin (an Akt activator) and dimethyloxallyl glycine (DMOG, a HIF-1α activator) induced over-expression of inflammatory cytokines, which could be blocked by folic acid. Taken together, these findings demonstrate how folic acid attenuates the hypoxia-induced inflammatory responses of THP-1 cells through inhibition of the PI3K/Akt/HIF-1α pathway.
authors.affiliation: Department of Nutrition, School of Public Health, Sun Yat-Sen University, Guangzhou, P. R. China.
authors.forename: Xiaoyan
authors.initials: X
authors.lastname: Huang
authors.affiliation: Department of Nutrition, School of Public Health, Sun Yat-Sen University, Guangzhou, P. R. China.
authors.forename: Zhiying
authors.initials: Z
authors.lastname: He
authors.affiliation: Department of Nutrition, School of Public Health, Sun Yat-Sen University, Guangzhou, P. R. China.
authors.forename: Xinwei
authors.initials: X
authors.lastname: Jiang
authors.affiliation: Experimental and Teaching Center for public health, School of Public Health, Sun Yat-Sen University, Guangzhou, P. R. China.
authors.forename: Mengjun
authors.initials: M
authors.lastname: Hou
authors.affiliation: Experimental and Teaching Center for public health, School of Public Health, Sun Yat-Sen University, Guangzhou, P. R. China.
authors.forename: Zhihong
authors.initials: Z
authors.lastname: Tang
authors.affiliation: Department of Nutrition, School of Public Health, Sun Yat-Sen University, Guangzhou, P. R. China.
authors.forename: Xiaozhou
authors.initials: X
authors.lastname: Zhen
authors.affiliation: Department of Nutrition, School of Public Health, Sun Yat-Sen University, Guangzhou, P. R. China.
authors.forename: Yuming
authors.initials: Y
authors.lastname: Liang
authors.affiliation: Department of Nutrition, School of Public Health, Sun Yat-Sen University, Guangzhou, P. R. China.
authors.forename: Jing
authors.initials: J
authors.lastname: Ma
mesh_terms: D015687:Cell Hypoxia / Q000187:drug effects; D002460:Cell Line; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D019610:Cytoprotection / Q000187:drug effects; D005492:Folic Acid / Q000494:pharmacology* / Q000633:toxicity; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism*; D007249:Inflammation / Q000378:metabolism / Q000473:pathology*; D018836:Inflammation Mediators / Q000378:metabolism; D008954:Models, Biological; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D060888:Real-Time Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects*; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000378:metabolism
chemical_list: D016207:Cytokines; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D018836:Inflammation Mediators; D012333:RNA, Messenger; D042461:Vascular Endothelial Growth Factor A; D005492:Folic Acid; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt