2,3,7,8-Tetrachlorodibenzo-p-dioxin stimulates proliferation of HAPI microglia by affecting the Akt/GSK-3β/cyclin D1 signaling pathway.
2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) is an environmental toxin that induces apoptosis of neurons and a pro-inflammatory response in microglial cells. First, we found that TCDD induced proliferation of HAPI microglial cells in a dose- and time-dependent manner. Flow cytometry analysis showed that this proliferation by TCDD was due to mainly enhancing the G1 to S phase transition. Next, it was found that TCDD treatment led to up-regulation of cyclin D1, which induces cell cycle progression from G1 to S phase, in a time-dependent manner. As for molecular mechanism, we revealed that TCDD was capable of inducing Akt phosphorylation and activation, resulting in phosphorylation and inactivation of glycogen synthase kinase-3β (GSK-3β). Inactivated GSK-3β attenuated proteasomal degradation of cyclin D1 by reducing Thr(286)-phosphorylated cyclin D1 levels. Moreover, inactivated GSK-3β increased cyclin D1 gene transcription by increasing its transcription factor β-catenin in the nucleus. Further, blockage of phosphoinositide 3-kinase/Akt kinase with their specific inhibitors, LY294002 and Akt 1/2 kinase inhibitor, significantly reduced TCDD-enhanced proliferation of HAPI microglial cells. In conclusion, TCDD stimulates proliferation of HAPI microglial cells by affecting the Akt/GSK-3β/cyclin D1 signaling pathway.
Department of Nutrition and Food Hygiene, School of Public Health, Nantong University, Nantong 226001, Jiangsu, People's Republic of China; Department of Medical Pharmacology, Institute of Health Biosciences, The University of Tokushima Graduate School, Tokushima 770-8504, Japan. Electronic address: xugf@ntu.edu.cn.
Guangfei
G
Xu
Department of Nutrition and Food Hygiene, School of Public Health, Nantong University, Nantong 226001, Jiangsu, People's Republic of China; Department of Occupational Medicine and Environmental Toxicology, School of Public Health, Nantong University, Nantong 226001, Jiangsu, People's Republic of China.
Yuanye
Y
Li
Department of Medical Pharmacology, Institute of Health Biosciences, The University of Tokushima Graduate School, Tokushima 770-8504, Japan.
Katsuhiko
K
Yoshimoto
Department of Nutrition and Food Hygiene, School of Public Health, Nantong University, Nantong 226001, Jiangsu, People's Republic of China.
Qiyun
Q
Wu
Department of Occupational Medicine and Environmental Toxicology, School of Public Health, Nantong University, Nantong 226001, Jiangsu, People's Republic of China.
Gang
G
Chen
Department of Medical Pharmacology, Institute of Health Biosciences, The University of Tokushima Graduate School, Tokushima 770-8504, Japan.
Takeo
T
Iwata
Department of Medical Pharmacology, Institute of Health Biosciences, The University of Tokushima Graduate School, Tokushima 770-8504, Japan.
Noriko
N
Mizusawa
Department of Nutrition and Food Hygiene, School of Public Health, Nantong University, Nantong 226001, Jiangsu, People's Republic of China.
Chunhua
C
Wan
Department of Nutrition and Food Hygiene, School of Public Health, Nantong University, Nantong 226001, Jiangsu, People's Republic of China.
Xiaoke
X
Nie
D002448:Cell Adhesion / Q000187:drug effects; D002452:Cell Count; D002453:Cell Cycle / Q000187:drug effects; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects*; D019938:Cyclin D1 / Q000235:genetics / Q000502:physiology*; D003857:Deoxyuridine / Q000031:analogs & derivatives; D004785:Environmental Pollutants / Q000633:toxicity*; D004797:Enzyme-Linked Immunosorbent Assay; D038362:Glycogen Synthase Kinase 3 / Q000235:genetics / Q000502:physiology*; D006801:Humans; D017628:Microglia / Q000187:drug effects*; D051058:Oncogene Protein v-akt / Q000235:genetics / Q000502:physiology*; D010766:Phosphorylation / Q000187:drug effects / Q000502:physiology; D000072317:Polychlorinated Dibenzodioxins / Q000633:toxicity*; D012313:RNA / Q000096:biosynthesis / Q000235:genetics; D034741:RNA, Small Interfering / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects*; D051176:beta Catenin / Q000378:metabolism
D004785:Environmental Pollutants; D000072317:Polychlorinated Dibenzodioxins; D034741:RNA, Small Interfering; D051176:beta Catenin; D019938:Cyclin D1; D012313:RNA; D051058:Oncogene Protein v-akt; D038362:Glycogen Synthase Kinase 3; C031086:5-ethynyl-2'-deoxyuridine; D003857:Deoxyuridine
2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD); 2,3,7,8-tetrachlorodibenzo-p-dioxin; 5-ethynyl-2′-deoxyuridine; AhR; Akt; CNS; Cyclin D1; ELISA; ERK; EdU; GAPDH; GSK-3β; Glycogen synthase kinase-3β (GSK-3β); IL-1β; Microglia; PBS; PI; PI3K; Proliferation; RNS; ROS; RT-PCR; TCDD; TNF-α; aryl hydrocarbon receptor; central nervous system; enzyme-linked immunosorbent assay; extracellular signal-regulated kinase; glyceraldehyde-3-phosphate dehydrogenase; glycogen synthase kinase-3β; interleukin-1 beta; phosphate-buffered saline; phosphoinositide 3-kinase; propidium iodide; reactive nitrogen species; reactive oxide species; reverse transcription-polymerase chain reaction; tumor necrosis factor-alpha.