Arsenite suppresses IL-2‒ and IL-12‒induced cytokine production in natural killer cells

Natural killer (NK) cells play an important role in suppressing the progression of cancer by activating themselves through the production of cytokines or by killing cancer cells. Previously we found that the addition of IL-2 to NK-92 cells induced the production of IFN-γ, IL-10, IL-6, and LT-α, and that arsenite (As(III)) suppressed the production of these cytokines. Here we examined the effects of As(III) on the production of IFN-γ, IL-10, IL-6, and LT-α following stimulation with IL-12, which activates NK cells similarly to IL-2, or with the combined addition of IL-2 and IL-12 in NK-92 cells. The results showed that IFN-γ and IL-10 were produced in response to IL-12 alone, whereas IL-6 and LT-α were detected only when IL-12 was co-treated with IL-2. The production of all four cytokines induced by IL-2, IL-12, or IL-2 + IL-12 was suppressed by concurrent exposure to As(III) in NK-92 cells. Exposure of primary NK cells isolated from mouse spleens to As(III) also inhibited the IL-2 + IL-12‒induced increase in IFN-γ production. Furthermore, when IL-2 + IL-12 was added to primary NK cells collected from the spleens of mice that had consumed drinking water containing 50 ppm or 100 ppm As(III) for 7 months, IFN-γ production was significantly reduced. This report is the first to demonstrate that As(III) inhibits cytokine production induced by IL-2 and/or IL-12 not only in cultured NK cells but also in primary NK cells derived from mouse spleen.