* Department of Internal Medicine, University of Genova Medical School, Italy; and
Immunogenetic Department, National Institute of Cancer Research, Genova, Italy
Correspondence: Luciano Ottonello, M.D., Department of Internal Medicine and Medical Specialties, Viale Benedetto XV n.6, I-16132 Genova, Italy. E-mail: otto{at}unige.it
Neutrophil apoptosis represents a crucial step in the mechanisms governing the resolution of neutrophilic inflammation. Several soluble mediators of inflammation modulate neutrophil survival, retarding their apoptosis, whereas neutrophil activation by immune complexes (IC) results in the acceleration of apoptosis. To investigate neutrophil fate at the site of inflammation, we studied the effects of interleukin (IL)-2, IL-6, IL-8, IL-15, GM-CSF, and fMLP on spontaneous and IC-induced neutrophil apoptosis and the mechanisms regulating the survival of these cells. Spontaneous apoptosis was inhibited by GM-CSF, IL-6, and IL-15, but only GM-CSF overturned IC-induced apoptosis. No role of oxidants on the modulation of IC-dependent apoptosis was found. Indeed, fMLP or GM-CSF augmented the IC-dependent oxidative response, whereas the other compounds were ineffective. CGD neutrophils showed low levels of spontaneous apoptosis, but when exposed to IC, underwent a sharp increment of the apoptotic rate in a GM-CSF-inhibitable manner. Conversely, the expression of the proapoptotic protein Bax in 18-h aged neutrophils was down-regulated by GM-CSF, IL-6, and IL-15. Furthermore, IC induced a nearly threefold Bax up-regulation, which was completely reversed only by GM-CSF. Accordingly, the spontaneous activity of caspase-3 was inhibited by GM-CSF, IL-6, and IL-15. Furthermore, IC induced a sharp increment of enzymatic activity, and only GM-CSF inhibited the IC-dependent acceleration. Our results show that apoptosis of resting and IC-activated neutrophils is regulated differently, GM-CSF being the most potent neutrophil antiapoptotic factor. The results also unveil the existence of an oxidant-independent, Bax- and caspase-3-dependent, intracellular pathway regulating neutrophil apoptosis.
Key Words: GM-CSF • interleukin • fMLP • CGD • inflammation
This article has been cited by other articles:
 |
|
 |
|
  H. P. Carroll, V. Paunovic, and M. Gadina Signalling, inflammation and arthritis: Crossed signals: the role of interleukin-15 and -18 in autoimmunity Rheumatology, September 1, 2008; 47(9): 1269 - 1277. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 L. Raffaghello, G. Bianchi, M. Bertolotto, F. Montecucco, A. Busca, F. Dallegri, L. Ottonello, and V. Pistoia Human Mesenchymal Stem Cells Inhibit Neutrophil Apoptosis: A Model for Neutrophil Preservation in the Bone Marrow Niche Stem Cells, January 1, 2008; 26(1): 151 - 162. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. D. Gregory, L. A. Hogue, T. W. Ferkol, and D. C. Link Regulation of systemic and local neutrophil responses by G-CSF during pulmonary Pseudomonas aeruginosa infection Blood, April 15, 2007; 109(8): 3235 - 3243. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Linden, M. Laan, and G. P. Anderson Neutrophils, interleukin-17A and lung disease Eur. Respir. J., January 1, 2005; 25(1): 159 - 172. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 V. Asensi, E. Valle, A. Meana, J. Fierer, A. Celada, V. Alvarez, J. Paz, E. Coto, J. A. Carton, J. A. Maradona, et al. In Vivo Interleukin-6 Protects Neutrophils from Apoptosis in Osteomyelitis Infect. Immun., July 1, 2004; 72(7): 3823 - 3828. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Bouchard, C. Ratthe, and D. Girard Interleukin-15 delays human neutrophil apoptosis by intracellular events and not via extracellular factors: role of Mcl-1 and decreased activity of caspase-3 and caspase-8 J. Leukoc. Biol., May 1, 2004; 75(5): 893 - 900. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. Ottonello, A. L. Epstein, M. Mancini, P. Dapino, and F. Dallegri Monoclonal LYM-1 antibody-dependent cytolysis by human neutrophils exposed to GM-CSF: auto-regulation of target cell attack by cathepsin G J. Leukoc. Biol., January 1, 2004; 75(1): 99 - 105. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 e. Moisan, e. Kouassi, and D. Girard Mechanisms involved in methylmercuric chloride (MeHgCl)-induced suppression of human neutrophil apoptosis Human and Experimental Toxicology, December 1, 2003; 22(12): 629 - 637. [Abstract] [PDF]
|
|
