Cell-specific immune-modulation of cadmium on murine macrophages and mast cell lines in vitro: Short title: Immunomodulation of cadmium in murine macrophages and mast cells

Toxic trace metals are widespread contaminants that are potentially immunotoxic even at environmentally low exposure levels. They can modulate the immunity to infections, e.g., in wildlife species living in contaminated areas. The diverse immune cell types can be differentially affected by the exposure leading to the modulation of specific protective mechanisms. Macrophages and mast cells, part of the innate immune system, trigger immune responses and perform particular effector functions. The present study compared toxicological and functional effects of cadmium in two models of murine macrophages (RAW264.7 and NR8383 cell lines) and two models of murine mast cells (MC/9 and RBL-2H3 cell lines). Cadmium was selected as a model compound because its known potential to induce reactive oxygen species and its relevance as an environmental contaminant. Mechanisms of toxicity, such as redox imbalance and apoptosis induction were measured in stationary cells, while functional outcome effects were measured in activated cells. Cadmium-depleted glutathione antioxidant in all four cell lines tested although reactive oxygen species was not significantly increased. Mast cells had full dose-response depletion of glutathione below cytotoxic levels while in macrophages the depletion was not complete. Functional endpoints tumour necrosis factor-alpha and nitrite production in lipopolysaccharide-activated macrophages were increased by cadmium exposure. In contrast, mast cell lipopolysaccharide-induced tumour necrosis factor-alpha and IgE-mediated histamine release were reduced by cadmium. These data indicate potentially differential effects of cadmium among murine innate immune cell types, where mast cells would be more susceptible to oxidative stress and their function might be at a higher risk to be modulated compared to macrophages.