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

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Abstract

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.

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Abbreviations

Jak:

Janus kinase

STAT:

Signal transducer and activator of transcription

MAPK:

Mitogen-activated protein kinase

PBS:

Phosphate-buffered saline

PI3K:

Phosphatidylinositol 3-kinase

PMN:

Polymorphonuclear neutrophils

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Acknowledgements

This work was partially supported by a grant-in-aid from the Research Centre on Aging, Canadian Institute of Health Research (No. 63149) and ImAginE Consortium.

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Authors and Affiliations

  1. Department of Medicine, Research Center on Aging, Laboratory of Biogerontology, Sherbrooke Geriatric University Institute, 1036, rue Belvèdere sud, J1H 4C4, Sherbrooke, QC, Canada

    Carl F. Fortin, Anis Larbi, Gilles Dupuis, Olivier Lesur & Tamàs Fülöp Jr

  2. Signal transduction laboratory, Clinical Research Center Faculty of Medicine, University of Sherbrooke, Sherbrooke, QC, Canada

    Gilles Dupuis

  3. Division of Respiratory Medicine, Clinical Research Center, Faculty of Medicine, University of Sherbrooke, Sherbrooke, QC, Canada

    Olivier Lesur

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  1. Carl F. Fortin
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  2. Anis Larbi
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  5. Tamàs Fülöp Jr
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Correspondence to Tamàs Fülöp Jr.

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Fortin, C.F., Larbi, A., Dupuis, G. et al. GM-CSF activates the Jak/STAT pathway to rescue polymorphonuclear neutrophils from spontaneous apoptosis in young but not elderly individuals. Biogerontology 8, 173–187 (2007). https://doi.org/10.1007/s10522-006-9067-1

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