Age-related impairment of GM-CSF-induced signalling in neutrophils: role of SHP-1 and SOCS proteins.
Functional activities of mature human neutrophils are strongly influenced by the pro-inflammatory cytokine granulocyte macrophage-colony stimulating factor (GM-CSF). Accordingly, a defective response to GM-CSF might have dramatic consequences for neutrophil functions and the host defence against infections. Such an event is most likely to occur in senescence. A number of studies have, in fact, reported an impairment of the GM-CSF capacity to prime and/or to activate respiratory burst, as well as to delay apoptotic events, in neutrophils from elderly individuals. In the last 2 decades many efforts have been made to explore at molecular levels the mechanism underlying these defects. Recent studies let us depict a scenario in which an increased activity of inhibitory molecules, such as Src homology domain-containing protein tyrosine phosphatase-1 (SHP-1) and suppressors of cytokine signalling (SOCS), is responsible for the age-related failure of GM-CSF to stimulate neutrophil functions via inhibition of Lyn-, phosphoinositide 3-kinase (PI3-K)/extracellular signal-regulated kinase (ERK)- and signal transducers and activators of transcription (STAT)-dependent pathways. The control of SHP-1 and/or SOCS activity might therefore be an important therapeutic target for the restoration of normal immune responses during senescence.
Tortorella
Cosimo
C
Department of Internal Medicine, Immunology and Infectious Diseases, University of Bari Medical School, Policlinico, 70124 Bari, Italy. c.tortorella@intmed.uniba.it
Simone
Olivia
O
Piazzolla
Giuseppina
G
Stella
Isabella
I
Antonaci
Salvatore
S
D000375:Aging / Q000502:physiology*; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000502:physiology*; D006801:Humans; D021962:Membrane Microdomains / Q000502:physiology; D009504:Neutrophils / Q000502:physiology*; D054645:Protein Phosphatase 1; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6 / Q000235:genetics / Q000502:physiology; D015398:Signal Transduction / Q000502:physiology; D050826:Suppressor of Cytokine Signaling Proteins / Q000235:genetics / Q000502:physiology; D015854:Up-Regulation / Q000502:physiology
D050826:Suppressor of Cytokine Signaling Proteins; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D054645:Protein Phosphatase 1; C509249:PTPN6 protein, human; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6