Metallothionein and Innate Activation of Primary Human and Mouse Monocytes

Abstract

Group IIB metal ions exert a wide range of toxicities in human tissues and organs. They also induce a variety of genes (including those encoding metallothionein [MT]), through signal transduction mechanisms that do not require overt toxicity for effect. Monocyte/macrophages undergo activation in response to extracellular signals that are received, transduced to the nucleus, and processed to trigger transcription and/or repression of genes. We hypothesized that zinc (Zn) ions can affect the capacity of primary monocytes to respond to activation signals, and that they do so at concentrations that have no discernible toxic effect. Zn is required for normal leukocyte development and function. Zinc-deficient animals and humans have reduced levels of markers of macrophage activation (Wirth et al., 1989; Vruwink et al., 1991; Briggs et al., 1982). On the other hand, zinc supplementation has been reported to have inhibitory effects: macrophage and monocyte activation, measured by a variety of parameters, has been reported to be suppressed by in vitro zinc treatment (Nakamura et al., 1987; Chvapil et al., 1977; Kiremidjian-Schumacher et al., 1981; Kazimierczak et al., 1974; Marone et al., 1981). Immunomodulation, and not only cytotoxicity, may be a consequence of exposure to metal salts. We tested the hypothesis that treatment of primary mouse and human monocytes with low, non-toxic doses of affects the ability of the cells to be activated, as assessed oxygen free radical production and induction. We have reported that metallothionein (which is induced by metal pretreatment in primary and immortalized monocytes) is required for activation of immortalized human