Original Article

Differential Roles for _Mß₂ Integrin Clustering or Activation in the Control of Apoptosis Via Regulation of Akt and ERK Survival Mechanisms

Correspondence to: Ben B. Whitlock, D505, National Jewish Medical and Research Center, 1400 Jackson St., Denver, CO 80206. Tel:303-398-1282 Fax:303-398-1381 E-mail:whitlockb{at}njc.org.

The role of integrins in leukocyte apoptosis is unclear, some studies suggest enhancement, others inhibition. We have found that ß₂-integrin engagement on neutrophils can either inhibit or enhance apoptosis depending on the activation state of the integrin and the presence of proapoptotic stimuli. Both clustering and activation of _Mß₂ delays spontaneous, or unstimulated, apoptosis, maintains mitochondrial membrane potential, and prevents cytochrome c release. In contrast, in the presence of proapoptotic stimuli, such as Fas ligation, TNF, or UV irradiation, ligation of active _Mß₂ resulted in enhanced mitochondrial changes and apoptosis. Clustering of inactive integrins did not show this proapoptotic effect and continued to inhibit apoptosis. This discrepancy was attributed to differential signaling in response to integrin clustering versus activation. Clustered, inactive _Mß₂ was capable of stimulating the kinases ERK and Akt. Activated _Mß₂ stimulated Akt, but not ERK. When proapoptotic stimuli were combined with either _Mß₂ clustering or activation, Akt activity was blocked, allowing integrin activation to enhance apoptosis. Clustered, inactive _Mß₂ continued to inhibit stimulated apoptosis due to maintained ERK activity. Therefore, ß₂-integrin engagement can both delay and enhance apoptosis in the same cell, suggesting that integrins can play a dual role in the apoptotic progression of leukocytes.

Key Words: apoptosis, beta2 integrin, mitochondria, cytochrome c, neutrophil

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