Selective augmentation by recombinant interferon-γ of the intracellular content of S-adenosylmethionine in murine macrophages

Treatment of mouse peritoneal macrophages with IFN-γ augmented the intracellular content of S-adenosylmethionine, as measured by quantitative high-performance liquid chromatography. Accumulation of S-adenosylhomocysteine, a competitive product of S-adenosylmethionine, was not detectable, either by direct measurement of absorbance or by radioisotopic techniques in IFN-γ-treated macrophages. However, accumulation of S-adenosylhomocysteine was observed after treatment of macrophages with known inhibitors of S-adenosylhomocysteine catabolism. No inhibition of phospholipid methylation was observed upon IFN-γ treatment, indicating that no reduction of the S-adenosylmethionine to S-adenosylhomocysteine ratio is induced by IFN-γ in murine macrophages. The increased content of S-adenosylmethionine was associated with the acquisition of tumoricidal activity by macrophages upon IFN-γ treatment. LPS also augmented the cellular content of S-adenosylmethionine and activated macrophages to become cytotoxic, suggesting a common mechanism of action for IFN-γ and LPS in macrophage activation. Treatment of macrophages with cycloleucine, an agent that induces depletion of cellular S-adenosylmethionine, made the macrophages refractory to induction of cytolytic activity by IFN-γ, suggesting a critical role for S-adenosylmethionine in macrophage activation.