BETA(2) INTEGRINS (CD11 CD18) PROMOTE APOPTOSIS OF HUMAN NEUTROPHILS/

Apoptosis of human polymorphonuclear neutrophils (PMN) is thought to b e critical for the control of the inflammatory process, but the mechan isms underlying its regulation in physiological settings are still inc ompletely understood, This study was undertaken to test the hypothesis that the beta(2) integrin (CD11/CD18) family of leukocyte adhesion mo lecules contributes to the control of activated PMN by up-regulating a poptosis, Apoptosis of isolated human PMN was investigated by 1) analy sis 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 al pha (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 independen t of Fc receptors, An enhancement of apoptosis was also observed after migration of PMN through an endothelial cell monolayer, TNF-alpha-ind uced apoptosis as well as potentiation' by beta(2) integrins was preve nted by inhibition of tyrosine kinases with herbimycin A or genistein, The present study provides a new model for the regulation of PMN apop tosis by a functional cross-talk between beta(2) integrins and TNF-alp ha with a promoting role for the beta(2) integrins, This mechanism, wh ich allows enhanced elimination of previously emigrated PMN, may be cr itical to abate local inflammatory processes in vivo.