Nitric oxide causes apoptotic cell death in RAW 264.7 macrophages. The cellular response to the NO donor S-nitrosoglutathione (GSNO) comprises an apoptotic morphology and DNA fragmentation, which largely depends on the accumulation of the tumor suppressor gene product p53. Pre-treatment of macrophages with LPS, IFN-gamma in the presence of NG-monomethyl-L-arginine (NMMA) imparts resistance to apoptotic cell death, normally elicited by exogenously-supplied GSNO. Similarly, pre-treatment with low-dose GSNO (25-200 microM) conferred resistance from a second exposure to a higher dose of GSNO (1 mM). Protection is comprehended at the level of blocked p53 accumulation. Upregulation of protective mechanisms in response to non-lethal NO concentrations or by LPS, cytokine pre-stimulation may redirect the ability of nitric oxide to upregulate p53 and to initiate macrophage apoptosis, thereby modulating cellular susceptibility towards NO-intoxication.