HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

J. Biol. Chem., Vol. 281, Issue 18, 12458-12467, May 5, 2006

This Article Full Text Full Text (PDF) All Versions of this Article: 281/18/12458    most recent M511277200v1 Submit a Letter to Editor Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Cowburn, A. S. Articles by Chilvers, E. R. Search for Related Content PubMed PubMed Citation Articles by Cowburn, A. S. Articles by Chilvers, E. R. Social Bookmarking                      What's this?

Aminopeptidase N (CD13) Regulates Tumor Necrosis Factor--induced Apoptosis in Human Neutrophils^*

Andrew S. Cowburn¹, Anastasia Sobolewski, Ben J. Reed, John Deighton, Joanna Murray, Karen A. Cadwallader, John R. Bradley, and Edwin R. Chilvers²

From the Respiratory Medicine Division, Department of Medicine, University of Cambridge School of Clinical Medicine, Addenbrooke's and Papworth Hospitals, Cambridge CB2 2QQ, United Kingdom and Respiratory Medicine Unit, Medical Research Council Centre for Inflammation, University of Edinburgh Medical School, Teviot Place, Edinburgh EH16 4TJ, Scotland, United Kingdom

Neutrophil apoptosis plays a central role in the resolution of granulocytic inflammation. We have shown previously that tumor necrosis factor- (TNF) 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 TNF 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 TNF-induced killing. Notably, an inverse correlation is shown to exist between neutrophil APN activity and the sensitivity of donor cells to TNF-induced apoptosis. Inhibition of cell surface APN appears to interfere with the shedding of TNFRI, and as a consequence results in augmented TNF-induced apoptosis, cell polarization, and TNF-primed, formyl-methionyl-leucyl-phenylalanine-stimulated respiratory burst. Of note, actinonin and bestatin had no effect on TNFRII expression under resting or TNF-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 TNF-induced apoptosis via inhibition of TNFRI shedding. This has therapeutic relevance for driving neutrophil apoptosis in vivo.

Received for publication, October 17, 2005 , and in revised form, February 13, 2006.

^* This work was supported in part by The Wellcome Trust, British Lung Foundation, Isaac Newton Trust, and Papworth Hospital NHS Foundation Trust Hospital. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

² Recipient of noncommercial grants from AstraZeneca, UK, and Boehringer Ingelheim, UK.

¹ To whom correspondence should be addressed: Respiratory Medicine Division, Dept. of Medicine, University of Cambridge School of Clinical Medicine, Box 157, Addenbrooke's Hospital, Hills Rd., Cambridge, CB2 2QQ, UK. Tel./Fax: 44-1223-762007; E-mail: asc32{at}cam.ac.uk.

CiteULike    Complore    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

This article has been cited by other articles:

				L. Blanco, G. Larrinaga, I. Perez, J. I. Lopez, J. Gil, E. Agirregoitia, and A. Varona Acid, basic, and neutral peptidases present different profiles in chromophobe renal cell carcinoma and in oncocytoma Am J Physiol Renal Physiol, April 1, 2008; 294(4): F850 - F858. [Abstract] [Full Text] [PDF]

				Y. Bai, U. Ahmad, Y. Wang, J. H. Li, J. C. Choy, R. W. Kim, N. Kirkiles-Smith, S. E. Maher, J. G. Karras, C. F. Bennett, et al. Interferon-{gamma} Induces X-linked Inhibitor of Apoptosis-associated Factor-1 and Noxa Expression and Potentiates Human Vascular Smooth Muscle Cell Apoptosis by STAT3 Activation J. Biol. Chem., March 14, 2008; 283(11): 6832 - 6842. [Abstract] [Full Text] [PDF]