Pyrithione, a zinc ionophore, inhibits NF-κB activation

Pyrrolidine dithiocarbamate (PDTC) suppresses NF-κB activity and exhibits cytotoxic effects in bovine cerebral endothelial cells (BCECs), and we have previously reported that these PDTC effects were accompanied by an increase in intracellular zinc levels. To further explore the role of zinc in the modulation of NF-κB activation, we studied the effect of pyrithione, a zinc ionophore, on NF-κB activation in BCECs. Pyrithione inhibited NF-κB activity in a time- and dose-dependent manner. Ca-EDTA, but not Zn-EDTA, prevented pyrithione inhibition of NF-κB activity. Pyrithione increased the intracellular zinc level within 15 min. This effect was also abolished by Ca-EDTA, but not by Zn-EDTA. The potency of pyrithione on NF-κB inhibition and zinc influx was approximately one order of magnitude more potent than PDTC. These findings establish the regulatory role of intracellular zinc levels on NF-κB activity in BCECs.