Age-related impairment of GM-CSF-induced signalling in neutrophils: role of SHP-1 and SOCS proteins

Ageing Res Rev. 2007 Aug;6(2):81-93. doi: 10.1016/j.arr.2006.10.001. Epub 2006 Dec 4.

Abstract

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.

Publication types

  • Review

MeSH terms

  • Aging / physiology*
  • Granulocyte-Macrophage Colony-Stimulating Factor / physiology*
  • Humans
  • Membrane Microdomains / physiology
  • Neutrophils / physiology*
  • Protein Phosphatase 1
  • Protein Tyrosine Phosphatase, Non-Receptor Type 6 / genetics
  • Protein Tyrosine Phosphatase, Non-Receptor Type 6 / physiology
  • Signal Transduction / physiology
  • Suppressor of Cytokine Signaling Proteins / genetics
  • Suppressor of Cytokine Signaling Proteins / physiology
  • Up-Regulation / physiology

Substances

  • Suppressor of Cytokine Signaling Proteins
  • Granulocyte-Macrophage Colony-Stimulating Factor
  • Protein Phosphatase 1
  • PTPN6 protein, human
  • Protein Tyrosine Phosphatase, Non-Receptor Type 6