CYTOKINE AND LOW-LEVEL NITRIC-OXIDE PRESTIMULATION BLOCK P53 ACCUMULATION AND APOPTOSIS OF RAW-264.7 MACROPHAGES

Nitric oxide causes apoptotic cell death in RAW 264.7 macrophages. The cellular response to the NO donor S-nitrosoglutathione (GSNO) compris es an apoptotic morphology and DNA fragmentation, which largely depend s on the accumulation of the tumor suppressor gene product p53. Pre-tr eatment of macrophages with LPS, IFN-gamma in the presence of N-G-mono methyl-L-arginine (NMMA) imparts resistance to apoptotic cell death, n ormally elicited by exogenously-supplied GSNO. Similarly, pre-treatmen t with low-dose GSNO (25-200 mu M) conferred resistance from a second exposure to a higher dose of GSNO (1 mM). Protection is comprehended a l the level of blocked p53 accumulation. Upregulation of protective me chanisms in response to non-lethal NO concentrations or by LPS, cytoki ne pre-stimulation may redirect the ability of nitric oxide to upregul ate p53 and to initiate macrophage apoptosis, thereby modulating cellu lar susceptibility towards NO-intoxication. (C) 1996 Academic Press, I nc.