GM-CSF activates the Jak/STAT pathway to rescue polymorphonuclear neutrophils from spontaneous apoptosis in young but not elderly individuals

Polymorphonuclear neutrophils (PMN) are the first cells to be recruited to the site of tissular aggression. They have a short-life span and die by spontaneous apoptosis. However, their life span and functional activities can be extended in vitro by a number of proinflammatory cytokines, including th...

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Published in:	Biogerontology (Dordrecht) Vol. 8; no. 2; pp. 173 - 187
Main Authors:	FORTIN, Carl F, LARBI, Anis, DUPUIS, Gilles, LESUR, Olivier, FÜLÖP, Tamhs
Format:	Journal Article
Language:	English
Published:	Dordrecht Springer 01-04-2007 Springer Nature B.V
Subjects:	Adult Aged Aged, 80 and over Aging - metabolism Apoptosis Apoptosis - drug effects Biological and medical sciences Caspase 3 - metabolism Caspase-3 Cell Survival Cells Cells, Cultured Colony-stimulating factor Cysteine Proteinase Inhibitors - pharmacology Cytokines Development. Metamorphosis. Moult. Ageing Enzymes Fundamental and applied biological sciences. Psychology Granulocyte-macrophage colony-stimulating factor Granulocyte-Macrophage Colony-Stimulating Factor - metabolism Granulocyte-Macrophage Colony-Stimulating Factor - pharmacology Humans Inflammation Janus kinase Janus kinase 2 Janus Kinase 2 - antagonists & inhibitors Janus Kinase 2 - metabolism Leukocytes (granulocytic) Leukocytes (neutrophilic) Leukocytes (polymorphonuclear) Life span Macrophages Neutrophils - drug effects Neutrophils - metabolism Oligopeptides - pharmacology Phosphorylation Protein Kinase Inhibitors - pharmacology Recombinant Proteins Signal Transduction - drug effects STAT Transcription Factors - metabolism Stat3 protein STAT3 Transcription Factor - metabolism Stat5 protein STAT5 Transcription Factor - metabolism Time Factors Tyrphostins - pharmacology Vertebrates: anatomy and physiology, studies on body, several organs or systems Human Senescence Enzyme Polymorphonuclear granulocytes Cysteine endopeptidases Spontaneous Ageing Granulocyte Caspase Jak/STAT Cerebrospinal fluid Peptidases Signal transduction Vertebrata Mammalia Aging Hydrolases Neutrophil Caspases Elderly Apoptosis
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Summary:	Polymorphonuclear neutrophils (PMN) are the first cells to be recruited to the site of tissular aggression. They have a short-life span and die by spontaneous apoptosis. However, their life span and functional activities can be extended in vitro by a number of proinflammatory cytokines, including the granulocyte-macrophage colony stimulating factor (GM-CSF). We have reported that the protective effect of GM-CSF did not occur in PMN of elderly subjects. Data reported here showed that this difference was not due to a change in the expression of the GM-CSF receptor in the PMN of elderly individuals compared to young subjects. Furthermore, we showed here that GM-CSF activated the Janus kinase/signal transducer and activator of transcription (Jak/STAT) pathway and this activation appeared to be maintained for an extended period of time (18 h) playing an important role in the GM-CSF induced delayed PMN apoptosis. In marked contrast, GM-CSF had no effects on Jak2 activation in PMN of elderly individuals. We found that an inhibitor of Jak2 activation (AG490) abolished the protective effect of GM-CSF in PMN from young donors, however had no effect in PMN of elderly subjects. GM-CSF induced a transient activation of STAT3 and STAT5 in PMN of young donors but failed to activate to the same extent these signal transducers in PMN of elderly donors. The levels of proCaspase-3 were reduced in PMN of young donors treated with GM-CSF for 18 h but remained unchanged in PMN of elderly subjects treated under the same conditions compared to the untreated PMN. Our data are consistent with the interpretation that, at least in part (1) the protective effect of GM-CSF against apoptosis results from the activation of the Jak/STAT pathway and (2) decreased rescue from apoptosis in PMN of elderly is related to a failure of GM-CSF to activate this pathway in these cells.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	1389-5729 1573-6768
DOI:	10.1007/s10522-006-9067-1