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

Abstract

Chronic, low grade inflammation is a characteristic of old age. Innate immune system cells such as dendritic cells (DCs) from the elderly display a pro-inflammatory phenotype associated with increased reactivity to self. Lithium is a well-established anti-inflammatory agent used in the treatment of bipolar disorders. It has also been reported to reduce inflammation in DCs. Here, we investigated whether Lithium is effective in reducing the inflammatory responses in DCs from the elderly. The effect of Lithium Chloride (LiCl) was compared on the response of TLR4 agonist, LPS and TLR2 agonist, PAM3CSK4 stimulated aged and young DCs. LiCl enhanced the production of IL-10 in LPS stimulated young DCs. However, it did not affect TNF-α and IL-6 production. In contrast, in aged DCs, LiCl reduced the secretion of TNF-α and IL-6 in LPS stimulated DCs but did not increase IL-10. LiCl had no significant effect on PAM3CSK4 responses in aged and young DCs. LiCl treated DCs also displayed differences at the level of CD4 T cell priming and polarization. LPS-stimulated young DCs reduced IFN-γ secretion and biased the Th cell response towards Th2/Treg while LiCl treated aged DCs only reduced IFN-γ secretion but did not bias the response towards Th2/Treg. In summary, our data suggests that LiCl reduces inflammation in aged and young DCs via different mechanisms. Furthermore, the effect of LiCl is different on LPS and PAM3CSK4 responses.

Effects of Lithium on Inflammation

“…Furthermore, in some studies lithium was found to lack a significant influence on IL-6 production. 67,85,86 Taken together, these data suggest that the effect of lithium on IL-6 varies under different experimental conditions.…”

“…65,66,104 However, most of the reviewed studies found opposite results, demonstrating that lithium inhibits INF-γ synthesis. 82,86,87,[104][105][106]115,116 For example, lithium was found to decrease INF-γ levels in whole blood cultures from normal control subjects. 104 Tay et al 82 showed that lithium reduced INF-γ production in serum and multiple organs of bacteria-treated mice.…”

“…IL-10 is an anti-inflammatory cytokine. Most of the studies that investigated the effect of lithium on IL-10 found that it increases IL-10 production, 66,67,69,73,74,80,82,83,86,88,103,104,113 attesting for a strong antiinflammatory action of the drug. For example, Maes et al 66 observed that treatment with lithium enhanced IL-10 secretion in whole blood cultures taken from normal volunteers.…”

The effect of mood-stabilizing drugs on cytokine levels in bipolar disorder: A systematic review

“…Indeed, some in vitro studies suggest a biphasic proinflammatory effect of lithium after short-time use (Kleinerman et al, 1989;Petersein et al, 2015) and an attenuating antiinflammatory effect after longer-term use (Boufidou et al, 2004;Knijff et al, 2007;Maes et al, 1999;Rapaport and Manji, 2001). While some of these in vitro findings have been countered, the immunoregulatory properties of lithium are still mainly accepted (Agrawal et al, 2013;Himmerich et al, 2013Himmerich et al, , 2014. Lithium has been proposed to exert its immunomodulatory role at the gene expression level.…”

Therapeutic Role for TSP-2 Antibody in a Murine Asthma Model

“…As such, TLR2 could serve as a target for therapeutic treatment of allergic asthma [13][14][15]. Moreover, the TLR2 agonist Pam 3 CSK 4 exhibits unique immunomodulatory properties, characterized by the capacity to induce robust cytokine production by naive CD4+ T lymphocytes (both IL-10 and IFN-γ) [16][17][18][19]. In a murine asthma model, Pam 3 CSK 4 treatment improved allergic hyper-responsiveness within the airways (AHR).…”