Modulation of Dendritics Cells Differentiation and Maturation by Valproic Acid

Bipolar disorder (BD) is a severe and chronic mood disorder with a complex pathophysiology. Several studies have reported on an activated immune system in BD patients. Valproic acid (VPA) is a mood-stabilizer, anticonvulsant and histone deacetylase (HDAC) inhibitor which was clinical prescribed for the control of BD. Many studies, encompassing in vitro, in vivo, and clinical analyses, have concluded that VPA, in addition to a mood stabilizer, is neuroprotective. Accumulated evidences for the action of VPA in the brain suggest that VPA can affect protein kinase C (PKC) saignalling, gene expression and improving neurodegeneration. Dendritic cells (DC) are the most efficient and crucial antigen presenting cells and the only cells capable of stimulating naïve T cells and initiating an effect immune response toward foreign antigens. Previous research show an aberrant T-cell activation and increased autoantibodies in BD patients. Therefore, we hypothesized that BD patients may have abnormal immune function, and that the clinical use of VPA may affect immune system. Therefore, we attempt to elucidate in more depth the possible molecular action of mechanisms underlying VPA-induced DC’s immuno-modulation. Our preliminary data show that treatment with VPA, enhanced cell aggregation of human monocyte-derived immature DC by increasing CD86 and down-regulation of CD1 molecule expression. In addition, IL-6 cytokines secretion was increased with VPA treatment. All these preliminary data suggest that VPA can modulate DC functions. Therefore, this 3-year research proposal is intended to study the action of mechanisms of VPA in modulating DC differentiation and maturation, CD1 isoform molecules, adhesion molecules expression, possible signaling pathways, and the possible mechanisms underlied. (I). To investigate the effect of VPA, on human monocyte-derived DC functions, including surface markers expression, phagocytosis ability, cytokines production, and T cell proliferation/polarization. (II). To study the effect of VPA on CD1 isoforms expression and lipid antigen presentation. (III). To investigate the effect of VPA, on adhesion molecules expression, and possible signal transduction pathway. We will study the adhesive interaction between DC/endothelial and DC/T cells.