Zinc-induced NF-kappaB inhibition can be modulated by changes in the intracellular metallothionein level.

Metallothionein (MT), a small metal-binding protein, is involved in the regulation of cellular metal homeostasis. Sequestration and the release of metals to and from MT plays an important role in the attenuation or amplification of signal transduction. Zinc has been suggested to be an important regulator of nuclear factor kappaB (NF-kappaB). In this study, the effect of MT expression on the zinc-induced inhibition of NF-kappaB activity was examined. In HeLa cells, pyrrolidine dithiocarbamate (PDTC), a zinc ionophore, and zinc itself inhibited NF-kappaB activity. When the cells were pretreated with MT-inducers, cadmium, or dexamethasone, PDTC did not inhibit NF-kappaB activity. We transfected HeLa cells with a DNA construct in which expression of MT-IIA is controlled by tet operator protein. Treatment of HeLa cells with doxycycline, a tetracycline analogue, induced the expression of MT-IIA, which attenuated the effect of PDTC on NF-kappaB activity. These results implicate MT in the zinc regulation of NF-kappaB and identify MT as one of the potential intracellular modulators of NF-kappaB activation.