Aminopeptidase N (CD13) Regulates Tumor Necrosis Factor-α-induced Apoptosis in Human Neutrophils
Neutrophil apoptosis plays a central role in the resolution of granulocytic inflammation. We have shown previously that tumor necrosis factor-α (TNFα) enhances the rate of neutrophil apoptosis at early time points via a mechanism involving both TNF receptor (TNFR) I and TNFRII. Here we reveal a ma...
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Published in | The Journal of biological chemistry Vol. 281; no. 18; p. 12458 |
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Main Authors | , , , , , , , |
Format | Journal Article |
Language | English |
Published |
American Society for Biochemistry and Molecular Biology
05.05.2006
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Online Access | Get full text |
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Summary: | Neutrophil apoptosis plays a central role in the resolution of granulocytic inflammation. We have shown previously that tumor
necrosis factor-α (TNFα) enhances the rate of neutrophil apoptosis at early time points via a mechanism involving both TNF
receptor (TNFR) I and TNFRII. Here we reveal a marked but consistent variation in the magnitude of the pro-apoptotic effect
of TNFα in neutrophils isolated from healthy donors, and we show that inhibition of cell surface aminopeptidase N (APN) using
actinonin, bestatin, or inhibitory peptides significantly enhanced the efficacy of TNFα-induced killing. Notably, an inverse
correlation is shown to exist between neutrophil APN activity and the sensitivity of donor cells to TNFα-induced apoptosis.
Inhibition of cell surface APN appears to interfere with the shedding of TNFRI, and as a consequence results in augmented
TNFα-induced apoptosis, cell polarization, and TNFα-primed, formyl-methionyl-leucyl-phenylalanine-stimulated respiratory burst.
Of note, actinonin and bestatin had no effect on TNFRII expression under resting or TNFα-stimulated conditions and did not
alter CXCRI or CXCRII expression. These data suggest significant variation in the activity of APN/CD13 on the cell surface
of neutrophils in normal individuals and reveal a novel mechanism whereby APN/CD13 regulates TNFα-induced apoptosis via inhibition
of TNFRI shedding. This has therapeutic relevance for driving neutrophil apoptosis in vivo . |
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ISSN: | 0021-9258 1083-351X |
DOI: | 10.1074/jbc.M511277200 |