title: Valproic Acid and Lithium Meditate Anti-Inflammatory Effects by Differentially Modulating Dendritic Cell Differentiation and Function.
abstract: Valproic acid (VPA), with inhibition activity mainly toward histone deacetylase (HDAC) and Glycogen Synthase Kinase (GSK)-3, and lithium, with inhibition activity mainly toward GSK-3, are both prescribed in clinical as mood-stabilizers and anticonvulsants for the control of bipolar disorder. This study aims to compare the immuno-modulation activities of VPA and lithium, especially on the differentiation and functions of dendritic cells (DC). Our data show that treatment with VPA or lithium effectively alleviated the severity of collagen-induced arthritis triggered by LPS in mice. Both agents reduced the serum level of IL-6 and IL-10 after LPS challenge in mice. VPA and lithium both induce significant down-regulation of group I CD1 expression and secretion of IL-6 during differentiation of human monocyte-derived immature DC, while they differ in the induction of CD83 and CD86 expression, secretion of IL-8, IL-10, and TNF-α. Upon stimulation of immature DC with LPS, VPA, and lithium both reduced the secretion of IL-6 and TNF-α. However, only lithium significantly increased the production of IL-10, while VPA increased the production of IL-8 but substantially reduce the secretion of IL-10 and IL-23. Treatment with VPA resulted in a reduced capacity of LPS-stimulated DC to promote the differentiation of T helper 17 cells that are critical in the promotion of inflammatory responses. Taken together, our results suggest that VPA and lithium may differentially modulate inflammation through regulating the capacity of DC to mediate distinct T cell responses, and they may provide a complementary immunomodulatory effects for the treatment of inflammation-related diseases. J. Cell. Physiol. 232: 1176-1186, 2017. © 2016 Wiley Periodicals, Inc.
authors.affiliation: Department of Microbiology and Immunology, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan.|Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, Taipei, Taiwan.|Center for Reproductive Medicine and Sciences, Taipei Medical University, Taipei, Taiwan.
authors.forename: Sy-Jye
authors.initials: SJ
authors.lastname: Leu
authors.affiliation: School of Medical Laboratory Science and Biotechnology, Taipei Medical University, Taipei, Taiwan.|Department of Laboratory Medicine, Taipei Municipal Wan Fang Hospital, Taipei, Taiwan.
authors.forename: Yi-Yuan
authors.initials: YY
authors.lastname: Yang
authors.affiliation: Department of Psychiatry, Taipei City Psychiatric Center, Taipei City Hospital, Taipei, Taiwan.|Department of Psychiatry, School of Medicine, Taipei Medical University, Taipei, Taiwan.
authors.forename: Hsing-Cheng
authors.initials: HC
authors.lastname: Liu
authors.affiliation: Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, Taipei, Taiwan.
authors.forename: Chieh-Yu
authors.initials: CY
authors.lastname: Cheng
authors.affiliation: National Institute of Cancer Research, National Health Research Institutes, Tainan, Taiwan.
authors.forename: Yu-Chen
authors.initials: YC
authors.lastname: Wu
authors.affiliation: Department of Psychiatry, Taipei City Psychiatric Center, Taipei City Hospital, Taipei, Taiwan.|Department of Psychiatry, School of Medicine, Taipei Medical University, Taipei, Taiwan.
authors.forename: Ming-Chyi
authors.initials: MC
authors.lastname: Huang
authors.affiliation: Department of Microbiology and Immunology, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan.|Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, Taipei, Taiwan.
authors.forename: Yuen-Lun
authors.initials: YL
authors.lastname: Lee
authors.affiliation: Department of Pathology and Laboratory Medicine, Landseed Hospital, Taoyuan, Taiwan.
authors.forename: Chi-Ching
authors.initials: CC
authors.lastname: Chen
authors.affiliation: Department of Psychiatry, School of Medicine and Taipei Medical University-Wan Fang Hospital, Taipei, Taiwan.
authors.forename: Winston W
authors.initials: WW
authors.lastname: Shen
authors.affiliation: School of Medical Laboratory Science and Biotechnology, Taipei Medical University, Taipei, Taiwan.|National Institute of Cancer Research, National Health Research Institutes, Tainan, Taiwan.|Institute of Clinical Pharmacy and Pharmaceutical Sciences, National Cheng Kung University, Tainan, Taiwan.
authors.forename: Ko-Jiunn
authors.initials: KJ
authors.lastname: Liu
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D015703:Antigens, CD / Q000378:metabolism; D001169:Arthritis, Experimental / Q000188:drug therapy; D002417:Cattle; D002454:Cell Differentiation / Q000187:drug effects*; D016764:Cell Polarity / Q000187:drug effects; D016207:Cytokines / Q000378:metabolism; D003713:Dendritic Cells / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D007249:Inflammation / Q000473:pathology; D016753:Interleukin-10 / Q000378:metabolism; D015850:Interleukin-6 / Q000378:metabolism; D016209:Interleukin-8 / Q000378:metabolism; D050356:Lipid Metabolism / Q000187:drug effects; D008070:Lipopolysaccharides; D018021:Lithium Chloride / Q000494:pharmacology* / Q000627:therapeutic use; D051379:Mice; D009000:Monocytes / Q000166:cytology; D058504:Th17 Cells / Q000166:cytology / Q000187:drug effects; D051193:Toll-Like Receptors / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D014635:Valproic Acid / Q000494:pharmacology* / Q000627:therapeutic use
chemical_list: D000893:Anti-Inflammatory Agents; D015703:Antigens, CD; D016207:Cytokines; D015850:Interleukin-6; D016209:Interleukin-8; D008070:Lipopolysaccharides; D051193:Toll-Like Receptors; D014409:Tumor Necrosis Factor-alpha; D016753:Interleukin-10; D014635:Valproic Acid; D018021:Lithium Chloride