Role of extracellular signal-regulated kinase and phosphatidylinositol-3 kinase in chemoattractant and LPS delay of constitutive neutrophil apoptosis

The present study examined the role of mitogen-activated protein kinases (M APKs) and phosphatidylinositol-3 kinase-stimulated Akt (PI-3K/Akt) in the r egulation of constitutive human neutrophil apoptosis by bacterial lipopolys accharide (LPS) and two chemoattractants, fMLP and leukotriene B-4 (LTB4). LPS and LTB4 inhibited apoptosis, while fMLP had no effect. Inhibition of e xtracellular signal-regulated kinase (ERK) with PD098059 significantly inhi bited the anti-apoptotic effect of both LPS and LTB4, while inhibition of p 38 kinase with SR203580 had no effect. Inhibition of PI-3K with wortmannin and LY294002 significantly attenuated the anti-apoptotic effect of LTB4, bu t not LPS. LPS, fMLP, and LTB4 stimulated similar levels of ERK and Akt act ivation, LTB4 and LPS inhibited neutrophil apoptosis when added simultaneou sly with fMLP, and LTB4 and LPS demonstrated an additive effect. We conclud e that the ERK and/or PI-3K/Akt pathways are necessary, but not sufficient, for LPS and LTB4 to delay apoptosis, but other anti-apoptotic pathways rem ain to be identified. (C) 2001 Elsevier Science Inc. All rights reserved.