ADAM17 activity during human neutrophil activation and apoptosis.
Substrates of the metalloprotease ADAM17 (also known as TNF-alpha converting enzyme or TACE) undergo ectodomain shedding and include various inflammatory modulators. Though polymorphonuclear leukocytes contribute significantly to inflammation, direct analyses of ADAM17 on human neutrophils are very limited. In addition, the current understanding of the processes regulating ADAM17 activity primarily relate to its rapid activation. Therefore, to extend insights into the mechanisms of ADAM17 activity, we examined its surface expression and the shedding of its substrates during extended periods of neutrophil activation and apoptosis. Contrary to studies with immortalized hematopoietic cell lines, we report that surface expression of ADAM17 is maintained by human neutrophils activated with formyl peptides or by FcR/complement receptor-mediated phagocytosis. Interestingly, bacterial phagocytosis resulted in a significant increase in ADAM17 expression several hours after pathogen engulfment. We provide novel evidence that ADAM17 surface expression is also maintained during spontaneous and anti-Fas-induced neutrophil apoptosis. The well-validated ADAM17 substrates L-selectin and proTNF-alpha were shed efficiently by neutrophils under each of the conditions tested. Our data thus indicate prolonged ADAM17 expression during neutrophil effector functions. The implications of this may be a role by ADAM17 in both the induction and down-regulation of neutrophil activity.
Department of Veterinary and Biomedical Sciences, University of Minnesota, St. Paul, MN 55108, USA. walch003@umn.edu
Bruce
B
Walcheck
Amy H
AH
Herrera
Catherine
C
St Hill
Polly E
PE
Mattila
Adeline R
AR
Whitney
Frank R
FR
Deleo
D051722:ADAM Proteins / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism; D000072198:ADAM17 Protein; D017209:Apoptosis / Q000187:drug effects / Q000276:immunology*; D004591:Electrophoresis, Polyacrylamide Gel; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D006801:Humans; D015151:Immunoblotting; D009240:N-Formylmethionine Leucyl-Phenylalanine / Q000031:analogs & derivatives / Q000494:pharmacology; D018375:Neutrophil Activation / Q000187:drug effects / Q000276:immunology*; D009504:Neutrophils / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D010587:Phagocytosis / Q000187:drug effects / Q000276:immunology; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology / Q000378:metabolism
D014409:Tumor Necrosis Factor-alpha; D009240:N-Formylmethionine Leucyl-Phenylalanine; C068657:N-formylmethionyl-leucyl-phenylalanyl tert-butyl ester; D051722:ADAM Proteins; D000072198:ADAM17 Protein; C000606462:ADAM17 protein, human