STIMULATING EFFECTS OF MERCURIC AND SILVER IONS ON THE SUPEROXIDE ANION PRODUCTION IN HUMAN POLYMORPHONUCLEAR LEUKOCYTES

In a survey of a number of heavy metal ions for effects on the oxidati ve metabolism (respiratory burst) of human polymorphonuclear leukocyte s (neutrophils) we have found that mercury(II) and silver ions in micr omolar concentration significantly increase the production of superoxi de anions in cells, initiated by formyl-methionyl-leucylphenylalanine (fMLP). The stimulation of radical formation induced by a certain ion concentration varied considerably in cells isolated from different blo od donors, from a moderate increase to a very large (up to 400% of con trol values). When the soluble stimulator phorbol myristate acetate (P MA) or the particulate stimulator Zymosan were used to initiate the ce ll respiratory burst, no additional stimulating effects by the metal i ons on superoxide anion formation were observed. This fact might indic ate that the effect of the metal ions on the fMLP-dependent initiation of cell activity is a mechanism coupled to the interaction between th e chemotactic peptide and its corresponding receptor molecules on the cell surface. By increasing the concentration of silver ions during pr e-incubation of resting neutrophils, a spontaneous activation of the c ells could be recorded at a concentration exceeding 5 muM. However, th e silver ion concentration at which such spontaneous initiation of the respiratory burst occurred varied significantly between blood samples from different donors with a concentration range of 5 to 15 muM. This effect could not be shown for mercuric ions due to the toxicity of th e metal above 5 muM. Blood samples from some donors contained neutroph ils that could be activated by either mercuric- or silver ions at conc entration as low at 1 muM. The spontaneous activation of neutrophils w ith elevated concentrations of silver ions is kinetically similar to t he PMA-induced. The onset of superoxide anion formation is preceeded b y a lag period whose length varies in time with the concentration of a gent applied to the cells. It is a known fact that once the neutrophil s have been activated with fMLP it is not possible to reactivate the c ells by a second supplementation of fMLP. However, after cessation of the fMLP-induced activation, addition of PMA or silver ions gives rise to renewed production of superoxide anions. We propose two different mechanisms of action of silver ions on oxidative metabolism of neutrop hils. At a low concentration the metal ions are thought to interact wi th an activating agent and a corresponding cell surface receptor molec ule, while at elevated ion concentrations, we postulate an action like that of phorbol-esters on neutrophils, (i.e., an interaction between activating agent and the enzyme protein kinase C of the cells).