Production of reactive nitrogen intermediates by bone marrow-derived macrophages on treatment with cisplatin in vitro

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Abstract
SUMMARY: L929 culture medium (a source of macrophage colony stimulating factor (M-CSF) or recombinant granulocyte-macrophage colony stimulating factor (rGM-CSF)-derived bone marrow macrophages treated with cisplatin or lipopolysaccharide (LPS) (10 μ/ml) were effective in the production of L-arginine-dependent reactive nitrogen intermediates (RNI) and generation of tumouricidal activity. The abilities of RNI secretion and related tumouricidal activity against P 815 mastocytoma cells were compared. These parameters were found to be closely correlated in various experiments, RNI secretion and generation of bone marrow macrophage-mediated tumouricidal activity were significantly inhibited by l-n-monomethyl arginine (l-NMMA), a specific inhibitor of the L-arginine pathway, but l-NMMA did not inhibit macrophage-mediated killing of tumour necrosis factor (TNF)-sensitive Wehi cells, suggesting that activated macrophages exhibit at least two cytolytic mechanisms, one by L-arginine-dependent nitric oxide pathway and another by TNF-mediated killing. The present findings suggest that the mechanism of tumour cell killing by activated macrophages may differ, depending on the tumour cell type, and reactive nitrogen intermediates play a major role in cisplatin-mediated activation of bone marrow-derived macrophages.