Role of defective ERK phosphorylation in the impaired GM-CSF-induced oxidative response of neutrophils in elderly humans

• Published in: Mechanisms of ageing and development Vol. 125; no. 8; pp. 539 - 546
• Main Authors: Tortorella, Cosimo, Stella, Isabella, Piazzolla, Giuseppina, Simone, Olivia, Cappiello, Valentina, Antonaci, Salvatore
• Format: Journal Article
• Language: English
• Published: Shannon Elsevier Ireland Ltd 01.08.2004; Elsevier Science
• Subjects: Aged; Ageing; Aging - metabolism; Biological and medical sciences; Blotting, Western; Cell Separation; Development. Metamorphosis. Moult. Ageing; Enzyme Inhibitors - pharmacology; ERK1/2; Female; Flavonoids - pharmacology; Fundamental and applied biological sciences. Psychology; GM-CSF; Granulocyte-Macrophage Colony-Stimulating Factor - pharmacology; Humans; Imidazoles - pharmacology; In Vitro Techniques; Indicators and Reagents; Male; Mitogen-Activated Protein Kinases - metabolism; Neutrophils; Neutrophils - drug effects; Neutrophils - metabolism; Oxidation-Reduction; p38 Mitogen-Activated Protein Kinases - metabolism; p38MAPK; Phosphorylation; Pyridines - pharmacology; Respiratory burst; Respiratory Burst - drug effects; Superoxides - metabolism; TNF-α; Tumor Necrosis Factor-alpha - metabolism; Vertebrates: anatomy and physiology, studies on body, several organs or systems; ERK1/2; TNF-α; GM-CSF; Ageing; Neutrophils; Respiratory burst; p38MAPK; Human; Phosphorylation; Senescence; Extracellular signal-regulated protein kinase; Enzyme; Mitogen-activated protein kinase; Neutrophil; Elderly
• ISSN: 0047-6374; 1872-6216
• DOI: 10.1016/j.mad.2004.06.001

GM-CSF-induced oxidative responses are defective in neutrophils of elderly humans. In the present study we evaluated whether this phenomenon might be related to alterations in cytokine-dependent MAPK signalling. Neutrophils obtained from elderly humans and stimulated with GM-CSF showed a significant reduction in phosphorylated ERK1/2 levels and an even higher decrease in ERK1/2 activation with respect to baseline. No changes in GM-CSF-induced p38 MAPK phosphorylation were observed. Cell pretreatment with the MEK inhibitor PD98059 determined a marked suppression of GM-CSF-induced O 2 − release. Interestingly, under the above experimental condition, there was no longer any difference in O 2 − production observed between elderly and young subjects. Furthermore, despite the fact that the p38 MAPK pathway was activated less strongly by GM-CSF, the p38 MAPK inhibitor SB203580 reduced GM-CSF-induced O 2 − production in the neutrophils of the elderly to levels similar to those obtained with PD98059. TNF-α-triggered O 2 − production was not altered by ageing and in fact, a similar ERK1/2 or p38 MAPK activation was found in TNF-α-stimulated neutrophils from elderly and young individuals. In accordance with the different potency of TNF-α in activating ERK1/2 and p38 MAPK, the TNF-α-induced oxidative responses were more sensitive to the inhibitory effects of SB203580 than to those of PD98059 in young as well as elderly subjects. These results suggest that, along the GM-CSF-dependent ERK signalling pathway, a step proximal to MEK1/2 but distal to the connection with the p38 MAPK module likely becomes defective as a feature of age. The consequent decline in ERK1/2 activation could potentially account for the GM-CSF-dependent impairment of the neutrophil respiratory burst that occurs with ageing.