A role for PKC- and PI 3-kinase in TNF- -mediated antiapoptotic signaling in the human neutrophil

Kilpatrick, Laurie E., Julia Y. Lee, Kathleen M. Haines, Donald E. Campbell, Kathleen E. Sullivan, and Helen M. Korchak. A role for PKCand PI 3-kinase in TNF-mediated antiapoptotic signaling in the human neutrophil. Am J Physiol Cell Physiol 283: C48–C57, 2002. First published February 6, 2002; 10.1152/ajpcell.00385.2001.— The proinflammatory cytokine tumor necrosis factor (TNF)has been implicated in the attenuation of neutrophil spontaneous apoptosis during sepsis. Antiapoptotic signaling is principally mediated through the p60TNF receptor (p60TNFR). In neutrophils, TNFis an incomplete secretagogue and requires input from a ligated integrin(s) for neutrophil activation. In adherent neutrophils, TNFtriggers association of both protein kinase C (PKC)and phosphatidylinositol (PI) 3-kinase with the p60TNFR. In this study, a role for PKCand PI 3-kinase in TNF-mediated antiapoptotic signaling was examined. TNFinhibited spontaneous apoptosis in fibronectin-adherent neutrophils, and this antiapoptotic signaling was blocked by the PKCinhibitor rottlerin, but not by an inhibitor of Ca2 -dependent PKC isotypes, Go-6976. Inhibition of PI 3-kinase by LY-294002 also inhibited TNF-mediated antiapoptotic signaling. Cycloheximide blocked TNF-mediated antiapoptotic signaling, suggesting protein synthesis is required. Inhibition of either PKCor PI 3-kinase attenuated TNF-mediated activation of the antiapoptotic transcription factor NF B. Thus both PKCand PI 3-kinase have essential roles in TNF-mediated antiapoptotic signaling in adherent neutrophils.