IL-17 attenuates the anti-apoptotic effects of GM-CSF in human neutrophils.
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.
Dragon
Stéphane
S
Department of Immunology and the CIHR National Training Program in Allergy and Asthma, University of Manitoba, Winnipeg, Manitoba, Canada.
Saffar
Arash Shoja
AS
Shan
Lianyu
L
Gounni
Abdelilah Soussi
AS
D017209:Apoptosis / Q000187:drug effects*; D061945:Caspase Inhibitors; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism; D003600:Cytosol / Q000187:drug effects / Q000378:metabolism; D053222:Fas Ligand Protein / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000494:pharmacology*; D018922:HL-60 Cells; D006801:Humans; D020381:Interleukin-17 / Q000494:pharmacology*; D020935:MAP Kinase Signaling System / Q000187:drug effects; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D009363:Neoplasm Proteins / Q000378:metabolism; D009504:Neutrophils / Q000166:cytology* / Q000187:drug effects* / Q000201:enzymology; D021381:Protein Transport / Q000187:drug effects; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D053722:Receptors, Interleukin-17 / Q000235:genetics / Q000378:metabolism; D012995:Solubility / Q000187:drug effects; D051028:bcl-2-Associated X Protein / Q000378:metabolism
D061945:Caspase Inhibitors; D053222:Fas Ligand Protein; D020381:Interleukin-17; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D009363:Neoplasm Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D012333:RNA, Messenger; D053722:Receptors, Interleukin-17; D051028:bcl-2-Associated X Protein; D016178:Granulocyte-Macrophage Colony-Stimulating Factor