RAW 264.7 macrophages induce apoptosis selectively in transformed fibroblasts: intercellular signaling based on reactive oxygen and nitrogen species.

The rationale for this study was to determine whether macrophages induce apoptosis selectively in transformed compared with nontransformed fibroblasts and to elucidate the underlying intercellular signaling chemistry. Murine fibroblasts transformed by oncogene expression (ras, src) or methylcholanthrene treatment were sensitive for apoptosis induction by RAW 264.7 macrophages, whereas parental cells and revertants were insensitive. Moreover, RAW 264.7 macrophages induced apoptosis in normal rat kidney (NRK) fibroblasts transiently transformed by epidermal growth factor/transforming growth factor-beta. Sensitivity for intercellular apoptosis induction was based on target cell-derived superoxide anions and effector cell-derived peroxidase and nitric oxide (NO). Superoxide anions dismutate to hydrogen peroxide, which is converted to HOCl by the peroxidase. The interaction of HOCl with superoxide anions then generates hydroxyl radicals. In parallel, NO interacts with superoxide anions and generates apoptosis-inducing peroxynitrite. Signaling by reactive oxygen and nitrogen species seems to represent a hitherto unrecognized signaling principle for the selective elimination of potential tumor cells by macrophages.