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Mcl-1-mediated impairment of the intrinsic apoptosis pathway in circulating neutrophils from critically ill patients can be overcome by Fas stimulation.
- Source :
-
Journal of immunology (Baltimore, Md. : 1950) [J Immunol] 2009 Nov 15; Vol. 183 (10), pp. 6198-206. Date of Electronic Publication: 2009 Oct 19. - Publication Year :
- 2009
-
Abstract
- The systemic inflammatory response syndrome and subsequent organ failure are mainly driven by activated neutrophils with prolonged life span, which is believed to be due to apoptosis resistance. However, detailed underlying mechanisms leading to neutrophil apoptosis resistance are largely unknown, and possible therapeutic options to overcome this resistance do not exist. Here we report that activated neutrophils from severely injured patients exhibit cell death resistance due to impaired activation of the intrinsic apoptosis pathway, as evidenced by limited staurosporine-induced mitochondrial membrane depolarization and decreased caspase-9 activity. Moreover, we found that these neutrophils express high levels of antiapoptotic Mcl-1 and low levels of proapoptotic Bax protein. Mcl-1 up-regulation was dependent on elevated concentrations of GM-CSF in patient serum. Accordingly, increased Mcl-1 protein stability and GM-CSF serum concentrations were shown to correlate with staurosporine-induced apoptosis resistance. However, cross-linking of neutrophil Fas by immobilized agonistic anti-Fas IgM resulted in caspase-dependent mitochondrial membrane depolarization and apoptosis induction. In conclusion, the observed impairment of the intrinsic pathway and the resulting apoptosis resistance may be overcome by immobilized agonistic anti-Fas IgM. Targeting of neutrophil Fas by immobilized agonistic effector molecules may represent a new therapeutic tool to limit neutrophil hyperactivation and its sequelae in patients with severe immune disorders.
- Subjects :
- Antibodies pharmacology
Apoptosis drug effects
Caspase 9 metabolism
Critical Illness
Enzyme Inhibitors pharmacology
Fas Ligand Protein immunology
Fas Ligand Protein metabolism
Granulocyte-Macrophage Colony-Stimulating Factor blood
Humans
Mitochondrial Membranes drug effects
Mitochondrial Membranes physiology
Myeloid Cell Leukemia Sequence 1 Protein
Neutrophils drug effects
Neutrophils metabolism
Proto-Oncogene Proteins c-bcl-2 immunology
Staurosporine pharmacology
Up-Regulation drug effects
Up-Regulation immunology
bcl-2-Associated X Protein immunology
fas Receptor immunology
fas Receptor metabolism
Apoptosis immunology
Caspase 9 immunology
Multiple Trauma immunology
Neutrophils immunology
Proto-Oncogene Proteins c-bcl-2 biosynthesis
bcl-2-Associated X Protein metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1550-6606
- Volume :
- 183
- Issue :
- 10
- Database :
- MEDLINE
- Journal :
- Journal of immunology (Baltimore, Md. : 1950)
- Publication Type :
- Academic Journal
- Accession number :
- 19841168
- Full Text :
- https://doi.org/10.4049/jimmunol.0901264