Zinc at pharmacologic concentrations affects cytokine expression and induces apoptosis of human peripheral blood mononuclear cells

Objective: The present study examined the effect of zinc at concentrations of the apoptotic signaling pathway and immune function of peripheral blood mononuclear cells (PBMCs). Methods: PBMCs from healthy subjects were treated in vitro with various zinc concentrations to imitate different serum statuses of physiologic (2 to 15 mu M) and pharmacologic (15 to 100 mu M) concentrations to higher than 100 mu M and analyzed their expressions of cytokines and apoptotically related factors. Results: Although a normal physiologic concentration of zinc had no effect on immunologic function or apoptosis of PBMCs, a pharmacologic concentration (100 mu M) or higher affected both functions. Zinc decreased cell proliferation at concentrations higher than 100 mu M and stimulated cytokine expression at concentrations of at least 100 mu M. Further, at concentrations of at least 100 mu M, apoptosis was induced, and expressions of caspase-3 and proapoptotic genes, including Fas (FasL) and c-fos, which trigger apoptosis through receptor-mediated extrinsic and mitochondrion-mediated apoptotic pathways, respectively, were increased. At concentrations at least 300 mu M, expressions of antiapoptotic factors nuclear factor-kappa B, Bcl-2, and Bcl-X-L were markedly decreased. Conclusions: Zinc stimulates cytokine expression and induces apoptosis of PBMCs from healthy subjects only at concentrations equal to or greater than the serum pharmacologic range. Receptor-mediated extrinsic and mitochondrial-mediated intrinsic pathways are involved in this zinc-induced apoptosis. (C) 2006 Elsevier Inc. All rights reserved.