Activation of extracellular signal-regulated kinase 1/2 is involved in production of CXC-chemokine by macrophages during phagocytosis of late apoptotic cells.

Inefficient clearance of apoptotic cells by macrophages may cause an advanced stage of apoptosis, late apoptosis. Coculturing of macrophages with late apoptotic cells leads to high production of CXC-chemokine, IL-8, or MIP-2, a murine homologue of IL-8. However, the signaling mechanism underlying the production remains largely unknown. In this study, we examined the MAP kinase activation on coculturing of macrophages with late apoptotic cells. Extracellular signal-regulated kinase (ERK)1/2, but not p38 or c-Jun N-terminal kinase, was phosphorylated as early as 5 min after interaction of macrophages with late apoptotic cells. We then examined whether or not ERK activation is involved in the production of MIP-2 by employing selective inhibitors for MAP kinase kinase 1/2, PD98059, and U0126. These inhibitors suppressed the production of MIP-2 by macrophages at the protein and mRNA levels, whereas they did not suppress phagocytosis of late apoptotic cells, as judged on confocal microscopy. These results suggest that activation of ERK is involved in the production of MIP-2 on coculturing of macrophages with late apoptotic cells.