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 (TNF alpha) 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 TNF alpha 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 TNF alpha secretion using the D10.G4.01 and L929 assays, respectively. Lithium did not stimulate IL-1 secretion but did stimulate TNF alpha secretion (5-10 U/ml of TNF alpha per 2 x 10(5) monocytes). The increased secretion of TNF alpha was associated with a fourfold increase in TNF alpha mRNA. TNF alpha activity in the supernatants was neutralized by a monoclonal antibody against human TNF alpha but not by antibody against human albumin. Other alkali metals such as rubidium and cesium did not stimulate monocytes to secrete TNF alpha. 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.