IMMUNOMODULATORY ACTIVITIES OF EXTRACELLULAR METALLOTHIONEIN .2. EFFECTS ON MACROPHAGE FUNCTIONS

Metallothionein (MT) is a thiol-rich protein that is rapidly induced b y exposure to heavy metal cations. We have previously demonstrated tha t exogenous MT stimulates murine splenocytes to proliferate, but inhib its humoral responses to antigen. These observations suggest that meta llothionein released from cells has a complex role in heavy metal-medi ated immune dysfunction. Here we examine one possible mechanism by whi ch MT mediates suppression of humoral immunity. Exposure of macrophage s to 20 mu M MT did nor affect their ability to engulf opsonized sheep erythrocytes, but in the presence of 20 mu M MT, peritoneal macrophag es were stimulated to produce increased levels of oxygen radicals. The se results correlated with observations that while macrophage phagocyt osis of opsonized Candida albicans was unaltered by the presence of ex ogenous MT, killing of the engulfed yeast cells was dramatically enhan ced by 20 mu M MT. Amounts of free cadmium and zinc equimolar to that added as Zn,Cd-MT had no effect on candidacidal activity. MT was also found to significantly decrease lymphocyte proliferation mediated by m acrophage activity. Biotinylated MT (MT-b) bound specifically to the p lasma membranes of these macrophages, suggesting that membrane-associa ted molecules of the macrophage may transduce a signal mediated by MT binding. These results demonstrate that macrophages are a sensitive ta rget for MT-mediated immunomodulation and that some of the consequence s of the MT interaction with macrophages may be alterations in the cap acity to produce an effective immune response and increased extracellu lar exposure to damaging free radicals.