Activation of macrophage cytostatic effector mechanisms during acute graft-versus-host disease: release of intracellular iron and nitric oxide-mediated cytostasis

During acute graft-versus-host disease (GVHD) the activation of macrophages (M phi) is mediated by 2 signals, interferon (IFN)-gamma and bacteria-deri ved lipopolysaccharide (LPS). A cascade of inflammatory responses that incl udes the release of mediators of tissue injury follows M phi activation. Am ong the tissues characteristically targeted during acute GVHD are epithelia l tissues of the skin and gastrointestinal tract that normally undergo cont inuous proliferation and are therefore sensitive to cytostatic processes. W e have investigated whether M phi can mediate cytostatic mechanisms capable of interrupting cell proliferation during acute GVHD. GVHD was induced in nonirradiated C57BL/6XAF(1) (B6AF(1)) mice by the injection of 60 x 10(6) ( acute GVHD) or 30 x 10(6) (nonlethal GVHD) C57BL/6 (B6) lymphoid cells. M p hi from animals undergoing acute GVHD could be triggered by normally insign ificant quantities of LPS to mediate a cytostatic effect on target cells, r esulting in the complete shutdown of cellular proliferation. The same amoun ts of LPS had no effect on M phi from normal or syngeneically transplanted animals. M phi mediated the release of significant quantities of intracellu lar iron from target cells undergoing cytostasis. Reversal of cytostasis oc curred following inhibition of nitric oxide (NO) production by NG-monomethy l-l-arginine (NMMA). Production of NO by LPS-triggered M phi reflected the severity of GVHD, NO release increased significantly during acute GVHD but was only transiently increased during nonlethal GVHD. The results provide e vidence that, as a result of activation during acute GVHD, M phi produce NO and induce the release of iron from target cells, resulting in a potent cy tostatic effect that inhibits cellular proliferation. (C) 2000 by The Ameri can Society of Hematology.