Impairment of SHP-1 down-regulation in the lipid rafts of human neutrophils under GM-CSF stimulation contributes to their age-related, altered functions.
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.
Fortin
Carl F
CF
Laboratory for Immunology, Research Center on Aging, Clinical Research Center, and Department of Medicine, Faculty of Medicine, University of Sherbrooke, Sherbrooke, Québec, Canada.
Larbi
Anis
A
Lesur
Olivier
O
Douziech
Nadine
N
Fulop
Tamas
T
D000328:Adult; D000367:Age Factors; D000368:Aged; D000375:Aging / Q000276:immunology*; D017209:Apoptosis / Q000187:drug effects / Q000276:immunology; D002634:Chemotaxis, Leukocyte / Q000187:drug effects / Q000276:immunology; D015536:Down-Regulation / Q000187:drug effects / Q000276:immunology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000276:immunology* / Q000494:pharmacology; D006801:Humans; D007111:Immunity, Cellular / Q000187:drug effects / Q000276:immunology*; D047908:Intracellular Signaling Peptides and Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism*; D021962:Membrane Microdomains / Q000187:drug effects / Q000378:metabolism*; D009504:Neutrophils / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D054645:Protein Phosphatase 1; D021381:Protein Transport / Q000187:drug effects / Q000276:immunology; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6; D017027:Protein Tyrosine Phosphatases / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism*; D017382:Reactive Oxygen Species / Q000378:metabolism; D012694:Serine / Q000378:metabolism; D014443:Tyrosine / Q000378:metabolism; D019061:src-Family Kinases / Q000187:drug effects / Q000276:immunology
D004791:Enzyme Inhibitors; D047908:Intracellular Signaling Peptides and Proteins; D017382:Reactive Oxygen Species; D014443:Tyrosine; D012694:Serine; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; C060902:lyn protein-tyrosine kinase; D019061:src-Family Kinases; D054645:Protein Phosphatase 1; C509249:PTPN6 protein, human; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6; D017027:Protein Tyrosine Phosphatases