title: Therapeutic concentration of lithium stimulates complement C3 production in dendritic cells and microglia via GSK-3 inhibition.
abstract: Evidence indicates that widely prescribed mood stabilizer, lithium (Li), mediates cellular functions of differentiated monocytic cells, including microglial migration, monocyte-derived dendritic cell (MoDC) differentiation, and amelioration of monocytic malfunctions observed in neuropsychiatric diseases. Here, we surveyed molecules which take major roles in regulating these monocytic cellular functions. MoDCs treated with 1 and 5 mM Li, and microglia separated from Li-treated mice were subjected to microarray-based comprehensive gene expression analyses. Findings were validated using multiple experiments, including quantitative PCR, ELISA and immunostaining studies. Differing effects of Li on the two cell types were observed. Inflammation- and chemotaxis-relevant genes were significantly over-represented among Li-induced genes in MoDCs, whereas no specific category of genes was over-represented in microglia. The third component of complement (C3) was the only gene which was significantly induced by a therapeutic concentration of Li in both MoDCs and microglia. C3 production was increased by Li via GSK-3 inhibition. Li-induced C3 production was seen only in differentiated monocytic cells, but not in circulating monocytes. Our findings highlight a link between Li treatment and C3 production in differentiated monocytic cells, and reveal a regulatory role of GSK-3 in C3 production. Induction of microglial C3 production might be a novel neuroprotective mechanism of Li via regulating interactions between microglia and neurons. GLIA 2015;63:257-270.
authors.affiliation: Department of Disaster Psychiatry, International Research Institute for Disaster Science, Tohoku University, Sendai, Japan; Department of Biological Psychiatry, Graduate School of Medicine, Tohoku University, Sendai, Japan; Tohoku Medical Megabank Organization, Tohoku University, Sendai, Japan.
authors.forename: Zhiqian
authors.initials: Z
authors.lastname: Yu
authors.forename: Chiaki
authors.initials: C
authors.lastname: Ono
authors.forename: Setsuya
authors.initials: S
authors.lastname: Aiba
authors.forename: Yoshie
authors.initials: Y
authors.lastname: Kikuchi
authors.forename: Ichiro
authors.initials: I
authors.lastname: Sora
authors.forename: Hiroo
authors.initials: H
authors.lastname: Matsuoka
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Tomita
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D002454:Cell Differentiation / Q000187:drug effects; D002478:Cells, Cultured; D003176:Complement C3 / Q000378:metabolism*; D003713:Dendritic Cells / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004797:Enzyme-Linked Immunosorbent Assay; D005786:Gene Expression Regulation / Q000187:drug effects; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism*; D006801:Humans; D008094:Lithium / Q000494:pharmacology*; D051379:Mice; D008810:Mice, Inbred C57BL; D046228:Microarray Analysis; D017628:Microglia / Q000187:drug effects*; D009000:Monocytes / Q000187:drug effects; D010587:Phagocytosis / Q000187:drug effects
chemical_list: D003176:Complement C3; D004791:Enzyme Inhibitors; D008094:Lithium; D038362:Glycogen Synthase Kinase 3
keywords: complement component 3; glia cell; monocytic cells; mood stabilizer; psoriasis