Pivotal Advance: A suppressive role of nitric oxide in MIP-2 production by macrophages upon coculturing with apoptotic cells

Macrophages phagocytose apoptotic cells without causing neutrophil infiltration in vivo under physiological conditions. Our recent study, however, showed that macrophages produce IL-8 or MIP-2, a murine IL-8 homologue, upon coculturing with apoptotic cells, indicating that there must be unknown mechanisms for preventing IL-8 or MIP-2 production. As activated macrophages produce NO to regulate inflammation, we examined the NO production by macrophages upon coculturing with apoptotic or necrotic cells and explored the role of NO in MIP-2 production. NO was produced on coculturing with early apoptotic cells much more significantly than with late apoptotic or necrotic cells. On the contrary, MIP-2 was produced on coculturing with late apoptotic or necrotic cells much more significantly than with early apoptotic cells. N-G -Nitro-L-arginine methyl ester, an inhibitor of NO synthase, or 2-(4-carboxyphenyl)-4,4,5,5-tetramethylimidazoline-1- oxyl-3-oxide, a scavenger of NO, augmented MIP-2 production on coculturing with early apoptotic cells. The addition of N-ethylethanamine: 1,1-diethyl-2-hydroxy-2-nitrosohydrazine [1:1], a donor of NO, conversely, caused suppression of MIP-2 production on coculturing with late apoptotic cells. These results suggest an important role of NO for preventing MIP-2 production by macrophages upon coculturing with early apoptotic cells. J. Leukoc. Biol. 80: 744-752; 2006.