Lithium chloride stimulates human monocytes to secrete tumor necrosis factor/cachectin

The purpose of this study was to examine the effect of lithium chloride (LiCl) on human monocytes. Patients undergoing lithium therapy have elevated white blood cell counts. Since both tumor necrosis factor alpha (TNFα) and interleukin 1 (IL-1), which are secreted by monocytes, can stimulate endothelial cells to produce granulocyte-macrophage colony-stimulating factor (GM-CSF), we determined whether lithium-stimulated monocytes produced TNFα and/or IL-1. Normal human monocytes were incubated for 24 h with medium (negative control), lipopolysaccharide (positive control), or LiCl (0.05-50 mM). The supernatants were removed and assayed for IL-1 and TNFα secretion using the D10.G4.01 and L929 assays, respectively. Lithium did not stimulate IL-1 secretion but did stimulate TNFα secretion (5-10 U/ml of TNFα per 2 x 10⁵ monocytes). The increased secretion of TNFα was associated with a fourfold increase in TNFα mRNA. TNFα activity in the supernatants was neutralized by a monoclonal antibody against human TNFα but not by antibody against human albumin. Other alkali metals such as rubidium and cesium did not stimulate monocytes to secrete TNFα. These data indicate that one mechanism by which Li may cause granulocytosis is through a transcriptional enhancement of TNF production and subsequent secretion by monocytes.