IL-17 attenuates the anti-apoptotic effects of GM-CSF in human neutrophils

Mol Immunol. 2008 Jan;45(1):160-8. doi: 10.1016/j.molimm.2007.04.027. Epub 2007 Jun 6.

Abstract

Interleukin (IL)-17A is a pleiotropic, pro-inflammatory cytokine that is implicated in chronic inflammatory and degenerative disorders. IL-17 has been demonstrated to link activated T-lymphocyte with the recruitment of neutrophils at sites of inflammation, however whether IL-17 can mediate neutrophil survival and subsequently affect inflammatory responses has not fully been elucidated. In our study, we demonstrate that human peripheral blood and HL-60 differentiated neutrophils express mRNA and cell surface IL-17A receptor. IL-17A does not affect the rate of spontaneous neutrophil apoptosis, however significantly decreased granulocyte macrophage-colony stimulating factor (GM-CSF)-mediated survival by antagonizing the signal transduction pathways of p38, Erk1/2 and signal transducer and activator of transcription (STAT) 5B. These events were associated with reduced myeloid cell lymphoma-1 (Mcl-1) protein levels, increased translocation and aggregation of Bax to mitochondria, decreased mitochondrial transmembrane potential and in an increase in caspase-3/7 activity. These events were independent of increased Fas or soluble Fas ligand expression levels. Taken together, our findings suggest that IL-17 may regulate neutrophil homeostasis and favor the resolution of inflamed tissues by attenuating the delay in neutrophil apoptosis induced by inflammatory cytokines.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Apoptosis / drug effects*
  • Caspase Inhibitors
  • Cell Nucleus / drug effects
  • Cell Nucleus / metabolism
  • Cytosol / drug effects
  • Cytosol / metabolism
  • Fas Ligand Protein / metabolism
  • Gene Expression Regulation / drug effects
  • Granulocyte-Macrophage Colony-Stimulating Factor / pharmacology*
  • HL-60 Cells
  • Humans
  • Interleukin-17 / pharmacology*
  • MAP Kinase Signaling System / drug effects
  • Myeloid Cell Leukemia Sequence 1 Protein
  • Neoplasm Proteins / metabolism
  • Neutrophils / cytology*
  • Neutrophils / drug effects*
  • Neutrophils / enzymology
  • Protein Transport / drug effects
  • Proto-Oncogene Proteins c-bcl-2 / metabolism
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • Receptors, Interleukin-17 / genetics
  • Receptors, Interleukin-17 / metabolism
  • Solubility / drug effects
  • bcl-2-Associated X Protein / metabolism

Substances

  • Caspase Inhibitors
  • Fas Ligand Protein
  • Interleukin-17
  • Myeloid Cell Leukemia Sequence 1 Protein
  • Neoplasm Proteins
  • Proto-Oncogene Proteins c-bcl-2
  • RNA, Messenger
  • Receptors, Interleukin-17
  • bcl-2-Associated X Protein
  • Granulocyte-Macrophage Colony-Stimulating Factor