title: Modulation of the development of human monocyte-derived dendritic cells by lithium chloride.
abstract: Lithium has been used or explored to treat psychiatric and neurodegenerative diseases that are frequently associated with an abnormal immune status. It is likely that lithium may work through modulation of immune responses in these patients. Because dendritic cells (DC) play a central role in regulating immune responses, this study investigated the influence of lithium chloride (LiCl) on the development and function of DC. Exposure to LiCl during the differentiation of human monocyte-derived immature DCs (iDC) enhances CD86 and CD83 expression and increases the production of IL-1β, IL-6, IL-8, IL-10, and TNF-α. However, the presence of LiCl during LPS-induced maturation of iDC has the opposite effect. During iDC differentiation, LiCl suppresses the activity of glycogen synthase kinase (GSK)-3β, and activates PI3K and MEK. In addition, LiCl activates peroxisome proliferator-activated receptor γ (PPARγ) during iDC differentiation, a pathway not described before. Each of these signaling pathways appears to have distinct impact on the differentiating iDC. The enhanced CD86 expression by LiCl involves the PI3K/AKT and GSK-3β pathway. LiCl modulates the expression of CD83 in iDC mainly through MEK/ERK, PI3K/AKT, and PPARγ pathways, while the increased production of IL-1β and TNF-α mainly involves the MEK/ERK pathway. The effect of LiCl on IL-6/IL-8/IL-10 secretion in iDC is mediated through inhibition of GSK-3β. We have also demonstrated that PPARγ is downstream of GSK-3β and is responsible for the LiCl-mediated modulation of CD86/83 and CD1 expression, but not IL-6/8/10 secretion. The combined influence of these molecular signaling pathways may account for certain clinical effect of lithium.
authors.affiliation: National Institute of Cancer Research, National Health Research Institutes, Tainan, Taiwan.
authors.forename: Ko-Jiunn
authors.initials: KJ
authors.lastname: Liu
authors.forename: Yueh-Lun
authors.initials: YL
authors.lastname: Lee
authors.forename: Yi-Yuan
authors.initials: YY
authors.lastname: Yang
authors.forename: Neng-Yao
authors.initials: NY
authors.lastname: Shih
authors.forename: Chia-Chen
authors.initials: CC
authors.lastname: Ho
authors.forename: Yu-Chen
authors.initials: YC
authors.lastname: Wu
authors.forename: Tze-Sing
authors.initials: TS
authors.lastname: Huang
authors.forename: Ming-Chyi
authors.initials: MC
authors.lastname: Huang
authors.forename: Hsing-Cheng
authors.initials: HC
authors.lastname: Liu
authors.forename: Winston W
authors.initials: WW
authors.lastname: Shen
authors.forename: Sy-Jye
authors.initials: SJ
authors.lastname: Leu
mesh_terms: D000276:Adjuvants, Immunologic / Q000494:pharmacology; D000818:Animals; D015703:Antigens, CD / Q000276:immunology; D051940:B7-2 Antigen / Q000276:immunology; D002454:Cell Differentiation / Q000187:drug effects / Q000276:immunology; D002478:Cells, Cultured; D003713:Dendritic Cells / Q000166:cytology / Q000187:drug effects* / Q000502:physiology*; D004791:Enzyme Inhibitors / Q000378:metabolism; D038362:Glycogen Synthase Kinase 3 / Q000276:immunology; D000071679:Glycogen Synthase Kinase 3 beta; D006801:Humans; D007136:Immunoglobulins / Q000276:immunology; D007378:Interleukins / Q000276:immunology; D018021:Lithium Chloride / Q000494:pharmacology*; D008562:Membrane Glycoproteins / Q000276:immunology; D020929:Mitogen-Activated Protein Kinase Kinases / Q000276:immunology; D009000:Monocytes / Q000166:cytology / Q000187:drug effects* / Q000502:physiology*; D047495:PPAR gamma / Q000276:immunology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D015398:Signal Transduction; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology; D000097802:CD83 Antigen
chemical_list: D000276:Adjuvants, Immunologic; D015703:Antigens, CD; D051940:B7-2 Antigen; D004791:Enzyme Inhibitors; D038362:Glycogen Synthase Kinase 3; D000071679:Glycogen Synthase Kinase 3 beta; D007136:Immunoglobulins; D007378:Interleukins; D018021:Lithium Chloride; D008562:Membrane Glycoproteins; D020929:Mitogen-Activated Protein Kinase Kinases; D047495:PPAR gamma; D019869:Phosphatidylinositol 3-Kinases; D014409:Tumor Necrosis Factor-alpha; D000097802:CD83 Antigen; C000605506:GSK3B protein, human