REGULATION OF MACROPHAGE PHAGOCYTOSIS OF APOPTOTIC CELLS BY CAMP

Regulation of macrophage capacity to remove apoptotic cells may contro l the balance of apoptotic and necrotic leukocytes at inflamed foci an d the extent of leukocyte-mediated tissue damage, Although the molecul es involved in the phagocytic process are beginning to be defined, lit tle is known about the underlying regulatory and signaling mechanisms controlling this process, In this paper, we have investigated the effe cts of treatment of human monocyte-derived macrophages with PGs and ot her agents that elevate intracellular cAMP on phagocytosis. PGE(2) and PGD(2) specifically reduced the proportion of macrophages that phagoc ytosed apoptotic cells, Similar results were obtained with the membran e-permeable cAMP analogues dibutyryl-cAMP and 8-bromo-cAMP but not wit h the cGMP analogue dibutyryl-GMP, Consistent with the observation tha t phagocytosis was inhibited by cAMP elevation, treatment of monocyte- derived macrophages with PGE(2) resulted in rapid, transient increase in levels of intracellular cAMP, These effects were not due to nonspec ific inhibition of monocyte-derived macrophage phagocytosis given that ingestion of Ig-opsonized erythrocytes was unaffected, Elevation of c AMP induced morphologic alterations indicative of changes in the adhes ive status of the macrophage, including cell rounding and disassembly of structures that represent points of contact with substrate containi ng actin and talin. These results strongly suggest that rapid activati on of cAMP signaling pathways by inflammatory mediators regulates proc esses that limit tissue injury and that modulation of cAMP levels repr esents an additional therapeutic target in the control of resolution o f inflammation.