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 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.
Fortin
Carl F
CF
Department of Medicine, Research Center on Aging, Laboratory of Biogerontology, Sherbrooke Geriatric University Institute, 1036, rue Belvèdere sud, J1H 4C4 Sherbrooke, QC, Canada.
Larbi
Anis
A
Dupuis
Gilles
G
Lesur
Olivier
O
Fülöp
Tamàs
T
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000375:Aging / Q000378:metabolism*; D017209:Apoptosis / Q000187:drug effects; D053148:Caspase 3 / Q000378:metabolism; D002470:Cell Survival; D002478:Cells, Cultured; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000378:metabolism* / Q000494:pharmacology; D006801:Humans; D053614:Janus Kinase 2 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D009504:Neutrophils / Q000187:drug effects / Q000378:metabolism*; D009842:Oligopeptides / Q000494:pharmacology; D010766:Phosphorylation; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011994:Recombinant Proteins; D050791:STAT Transcription Factors / Q000378:metabolism*; D050796:STAT3 Transcription Factor / Q000378:metabolism; D050799:STAT5 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013997:Time Factors; D020032:Tyrphostins / Q000494:pharmacology
D015853:Cysteine Proteinase Inhibitors; D009842:Oligopeptides; D047428:Protein Kinase Inhibitors; D011994:Recombinant Proteins; D050791:STAT Transcription Factors; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D050799:STAT5 Transcription Factor; D020032:Tyrphostins; C095512:alpha-cyano-(3,4-dihydroxy)-N-benzylcinnamide; C110772:benzoylcarbonyl-aspartyl-glutamyl-valyl-aspartyl-fluoromethyl ketone; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; C507924:JAK2 protein, human; D053614:Janus Kinase 2; D053148:Caspase 3