APOPTOSIS A Legacy from Dead Cells?

Unlike cells that undergo necrotic death, apoptotic cells inhibit inflammatory responses in the professional phagocytes that clear them. The macrophage inflammatory response is inhibited in response to binding the apoptotic cell and involves inhibition of cytokine transcription. Noting that apoptotic cells are found in all tissues, Cvetanovic et al. investigated the possibility that other cells--even nonphagocytic cells--might also recognize and respond to them. Using transcriptional activation of a nuclear factor B (NF-B)-dependent gene reporter as an assay, the authors found that exposure to apoptotic cells inhibited not only the response to lipopolysaccharide of RAW264.7 macrophages but also the response of HeLa cells to the inflammatory cytokine tumor necrosis factor α. Marked reductions in activation of the NF-B-dependent reporter in response to various proinflammatory stimuli also occurred in mouse 3T3 fibroblasts, human 293T renal epithelial cells, human umbilical vein endothelial cells, Chinese hamster ovary cells, and human T cell and B cell lines. Exposure to apoptotic cells inhibited secretion of interleukin-6 (IL-6) by 3T3 fibroblasts stimulated with IL-1β and secretion of IL-8 by 293T cells stimulated with PMA (phorbol myristate acetate). Moreover, apoptotic cells elicited signaling responses in 3T3 cells reminiscent of those previously seen in macrophages (inhibition of extracellular signal-regulated kinase 1 and 2 phosphorylation and activation of Akt). The ability of apoptotic cells to inhibit inflammatory responses was independent of their species and tissue of origin relative to that of the responding cell, did not depend on phosphatidylserine exposure, and was retained in membrane vesicles derived from apoptotic cells. The authors argue that the ability of numerous cell types to recognize and respond characteristically to apoptotic cells represents a ubiquitous and unconventional form of innate immunity that may act systemically to regulate the inflammatory response.

M. Cvetanovic, J. E. Mitchell, V. Patel, B. S. Avner, Y. Su, P. T. van der Saag, P. L. Witte, S. Fiore, J. S. Levine, D. S. Ucker, Specific recognition of apoptotic cells reveals a ubiquitous and unconventional innate immunity. J. Biol. Chem. 281, 20055-20067 (2006). [Abstract] [Full Text]