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Published online before print February 24, 2006
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,1
* Laboratory of Immunology, Research Center on Aging, and
Immunology Graduate Program, Clinical Research Center, and
Pneumology and
Geriatrics Divisions, Department of Medicine, Faculty of Medicine, University of Sherbrooke, Quebec, Canada
1Correspondence: Laboratory of Immunology, Research Center on Aging, Immunology Graduate Program, Clinical Research Center, and Department of Medicine, Geriatrics Division, Faculty of Medicine, University of Sherbrooke, 1036 rue Belvédère Sud, Sherbrooke, Québec, J1H 4C4, Canada. E-mail: tamas.fulop{at}usherbrooke.ca
It has been shown that the functions and the rescue from apoptosis by proinflammatory mediators of polymorphonuclear leukocytes (PMN) tend to diminish with aging. Here, we investigated the role of protein tyrosine phosphatases (PTP), especially Src homology domain-containing protein tyrosine phosphatase-1 (SHP-1), in the age-related, altered PMN functions under granulocyte macrophage-colony stimulating factor (GM-CSF) stimulation. The inhibition of PTP suggested a differential effect of GM-CSF on phosphatase activity in modulating PMN functions with aging. The down-regulation of phosphatase activity of immunopurified SHP-1 from lipid rafts of PMN of young donors was found significantly altered at 1 min of stimulation with aging. In young donors, SHP-1 is displaced from lipid rafts at 1 min of stimulation, whereas in the elderly, SHP-1 is constantly present. We assessed in PMN lipid rafts the phosphorylation of tyrosine and serine residues of SHP-1, which regulates its activity. We observed an alteration in the phosphorylation of tyrosine and serine residues of SHP-1 in PMN of elderly subjects, suggesting that GM-CSF was unable to inhibit SHP-1 activity by serine phosphorylation. GM-CSF activates Lyn rapidly, and we found alterations in its activation and translocation to the lipid rafts with aging. We also demonstrate that SHP-1 in the PMN of elderly is constantly recruited to Lyn, which cannot be relieved by GM-CSF. In contrast, in the young, the resting recruitment could be relieved by GM-CSF. Our results suggest an alteration of the SHP-1 modulation by GM-CSF in lipid rafts of PMN with aging. These alterations could contribute to the decreased GM-CSF effects on PMN.
Key Words: phosphatase • aging • Lyn • chemotaxis • ROS • apoptosis
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