beta(2) 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 beta(2) 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 beta(2) integrins potentiated the tumor necrosis factor alpha (TNF-alpha) -induced apoptosis within 4 and 8 h after stimulation, The effect required aggregation of the beta(2) 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 beta(2) 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 beta(2) integrins and TNF-alpha with a promoting role for the beta(2) integrins, This mechanism, which allows enhanced elimination of previously emigrated PMN, may be critical to abate local inflammatory processes in vivo.