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.

A Metabolic Inhibitory Cocktail for Grave Cancers: Metformin, Pioglitazone and Lithium Combination in Treatment of Pancreatic Cancer and Glioblastoma Multiforme

“…During iDC differentiation, lithium reduced the activity of GSK3b. In addition, lithium activated PPAR-c during iDC differentiation, a pathway not described before (Liu et al 2011). Elevated CD86 expression by lithium involved the GSK-3b pathway.…”

“…Treatment with lithium during the differentiation of human monocyte-derived immature DCs (iDC) increased CD86 and CD83 expression. On the other hand, the treatment with lithium during LPStriggered maturation of iDC acted oppositely, indicating that lithium may not induce an unspecific inflammatory response rather it induces a specific acquired immunity (Liu et al 2011). During iDC differentiation, lithium reduced the activity of GSK3b.…”

“…Since psychiatric and neurodegenerative diseases often associate with perturbed immune status (Liu et al 2011), it was hypothesized that lithium may act via influencing immune pathways in these patients. Dendritic cells (DCs) play a dominant role in controlling immune responses; hence, the influence of lithium on the development and function of DC was studied.…”

Dendritic cells from the elderly display an intrinsic defect in the production of IL-10 in response to Lithium Chloride

“…LiCl has been reported to downregulate the expression of co-stimulatory molecules in LPS-stimulated DCs. It also suppresses the production of pro-inflammatory cytokines from LPSstimulated monocytes and DCs (Liu et al, 2011;Martin et al, 2005). Suppression was mainly due to increased production of the anti- inflammatory cytokine, IL-10 by LiCl treated DCs.…”

Effects of Lithium on Inflammation

“…Similarly, lithium was shown to enhance IL-1β synthesis in human immature dendritic cells. 69 Despite 94 observed that lithium decreased IL-1β levels in LPS-stimulated monocytes of healthy control subjects. We found that lithium reduced LPSinduced elevation in IL-1β secretion in rat primary glia cells.…”