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

• Published in: Cellular signalling 2001-05, Vol.13 (5), p.335-343
• Main Authors: Klein, Jon B, Buridi, Abdul, Coxon, Patricia Y, Rane, Madhavi J, Manning, Terri, Kettritz, Ralph, McLeish, Kenneth R
• Format: Article
• Language: English
• Subjects: Androstadienes - pharmacology; Apoptosis; Apoptosis - drug effects; Apoptosis - immunology; Chemotaxis, Leukocyte - physiology; Chromones - pharmacology; Enzyme Inhibitors - pharmacology; Flavonoids - pharmacology; Human; Humans; Imidazoles - pharmacology; Inflammatory mediators; Leukotriene B4 - pharmacology; Lipopolysaccharides - pharmacology; MAP Kinase Signaling System - immunology; Mitogen-Activated Protein Kinases - antagonists & inhibitors; Mitogen-Activated Protein Kinases - metabolism; Morpholines - pharmacology; N-Formylmethionine Leucyl-Phenylalanine - analogs & derivatives; N-Formylmethionine Leucyl-Phenylalanine - pharmacology; Neutrophil; Neutrophils - cytology; Neutrophils - enzymology; p38 Mitogen-Activated Protein Kinases; Phosphatidylinositol 3-Kinases - antagonists & inhibitors; Phosphatidylinositol 3-Kinases - metabolism; Protein-Serine-Threonine Kinases; Proto-Oncogene Proteins - metabolism; Proto-Oncogene Proteins c-akt; Pyridines - pharmacology; Signal transduction; Virulence Factors, Bordetella - pharmacology
• ISSN: 0898-6568; 1873-3913
• DOI: 10.1016/S0898-6568(01)00151-6

The present study examined the role of mitogen-activated protein kinases (MAPKs) and phosphatidylinositol-3 kinase-stimulated Akt (PI-3K/Akt) in the regulation of constitutive human neutrophil apoptosis by bacterial lipopolysaccharide (LPS) and two chemoattractants, fMLP and leukotriene B 4 (LTB 4). LPS and LTB 4 inhibited apoptosis, while fMLP had no effect. Inhibition of extracellular signal-regulated kinase (ERK) with PD098059 significantly inhibited the anti-apoptotic effect of both LPS and LTB 4, while inhibition of p38 kinase with SB203580 had no effect. Inhibition of PI-3K with wortmannin and LY294002 significantly attenuated the anti-apoptotic effect of LTB 4, but not LPS. LPS, fMLP, and LTB 4 stimulated similar levels of ERK and Akt activation. LTB 4 and LPS inhibited neutrophil apoptosis when added simultaneously with fMLP, and LTB 4 and LPS demonstrated an additive effect. We conclude that the ERK and/or PI-3K/Akt pathways are necessary, but not sufficient, for LPS and LTB 4 to delay apoptosis, but other anti-apoptotic pathways remain to be identified.