Beta2 integrins (CD11/CD18) promote apoptosis of human neutrophils.
Apoptosis of human polymorphonuclear neutrophils (PMN) is thought to be critical for the control of the inflammatory process, but the mechanisms underlying its regulation in physiological settings are still incompletely understood. This study was undertaken to test the hypothesis that the beta2 integrin (CD11/CD18) family of leukocyte adhesion molecules contributes to the control of activated PMN by up-regulating apoptosis. Apoptosis of isolated human PMN was investigated by 1) analysis of DNA content, 2) detection of DNA degradation, 3) morphological studies, and 4) measurement of CD16 expression on the cell surface. We found that beta2 integrins potentiated the tumor necrosis factor alpha (TNF-alpha) -induced apoptosis within 4 and 8 h after stimulation. The effect required aggregation of the beta2 integrin Mac-1 (CD11b/CD18), which was induced by antibody cross-linking, and was independent of Fc receptors. An enhancement of apoptosis was also observed after migration of PMN through an endothelial cell monolayer. TNF-alpha-induced apoptosis as well as potentiation by beta2 integrins was prevented by inhibition of tyrosine kinases with herbimycin A or genistein. The present study provides a new model for the regulation of PMN apoptosis by a functional cross-talk between beta2 integrins and TNF-alpha with a promoting role for the beta2 integrins. This mechanism, which allows enhanced elimination of previously emigrated PMN, may be critical to abate local inflammatory processes in vivo.
Walzog
B
B
Department of Physiology, Freie Universität, Berlin, Germany.
Jeblonski
F
F
Zakrzewicz
A
A
Gaehtgens
P
P
D000911:Antibodies, Monoclonal / Q000494:pharmacology; D015703:Antigens, CD / Q000096:biosynthesis / Q000502:physiology; D017209:Apoptosis; D018821:CD18 Antigens / Q000276:immunology / Q000502:physiology*; D002460:Cell Line; D002634:Chemotaxis, Leukocyte / Q000187:drug effects / Q000502:physiology; D003432:Cross-Linking Reagents; D004247:DNA / Q000097:blood; D053938:DNA Fragmentation; D004730:Endothelium, Vascular / Q000502:physiology; D006801:Humans; D066298:In Vitro Techniques; D018799:Intercellular Adhesion Molecule-1 / Q000096:biosynthesis; D007700:Kinetics; D016177:Macrophage-1 Antigen / Q000276:immunology / Q000502:physiology*; D009240:N-Formylmethionine Leucyl-Phenylalanine / Q000494:pharmacology; D009504:Neutrophils / Q000166:cytology / Q000187:drug effects / Q000502:physiology*; D017452:Receptors, IgG / Q000096:biosynthesis; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
D000911:Antibodies, Monoclonal; D015703:Antigens, CD; D018821:CD18 Antigens; D003432:Cross-Linking Reagents; D016177:Macrophage-1 Antigen; D017452:Receptors, IgG; D014409:Tumor Necrosis Factor-alpha; D018799:Intercellular Adhesion Molecule-1; D009240:N-Formylmethionine Leucyl-Phenylalanine; D004247:DNA