Nickel modifies the cytotoxicity of hexavalent chromium in human dermal fibroblasts

We investigated combined effects of hexavalent chromium and nickel on viability, intracellular signaling and cell death of primary human skin fibroblasts during 24 h of exposure. We show that nickel at non-toxic concentrations prevents hexavalent chromium-induced cell damage and apoptosis, mainly by overexpression of heat shock proteins (HSPs), in particular HSP27 and activation of nuclear factor kappa B (NFkappaB) as demonstrated by specific knockdown of HSPs or NFkappaB. Conversely, cytotoxic nickel concentrations which induce apoptosis in dermal fibroblasts by themselves act to enhance hexavalent chromium effects in the same cells by stimulating oxidative stress and depleting ATP leading to rapid necrosis as demonstrated by markedly increased LDH release in exposed cells. Using specific pharmacological inhibitors it was further demonstrated that oxidative stress and PARP-1 activity are responsible for rapid necrosis. In conclusion, exposure of dermal fibroblasts to high nickel concentrations in combination with hexavalent chromium may result in rapid cell damage leading to necrosis while low nickel concentrations may prevent hexavalent chromium-induced cell death with potential accumulation of damaged but otherwise viable cells.