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Published online before print February 3, 2004

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© by The Society for Leukocyte Biology
Journal of Leukocyte Biology, doi:10.1189/jlb.0703317

Received for publication July 9, 2003.
Revised December 17, 2003.
Accepted for publication December 24, 2003.

Article

Identification of caspase-10 in human neutrophils and its role in spontaneous apoptosis

Friederike Goepel ^*, Pamela Weinmann ^*, Jürgen Schymeinsky , and Barbara Walzog ^@

*Department of Physiology, Freie Universität, Berlin, Germany; and Department of Physiology, Ludwig-Maximilians-Universität, München, Germany

^@ To whom correspondence should be addressed. E-mail: walzog{at}lrz.uni-muenchen.de.

	Abstract

In the present study, we investigated the molecular mechanisms of spontaneous and tumor necrosis factor (TNF-)-mediated apoptosis of human polymorphonuclear neutrophils (PMN). Whereas TNF--mediated apoptosis was almost absent in the presence of the caspase-8 inhibitor Z-Ac-Ala-Glu-Val-Asp-7-fluoromethyl ketone (Z-AEVD-FMK), the inhibitor had no effect on spontaneous apoptosis, suggesting that spontaneous apoptosis was independent of caspase-8. Subsequently, we identified different isoforms of caspase-10 in human PMN and found high expression of caspase-10/b and/or -10/d and low expression of caspase-10/a and -10/c at the mRNA level. At the protein level, freshly isolated PMN showed high expression of caspase-10/b and -10/d as well as moderate expression of caspase-10/a and -10/c. Upon spontaneous apoptosis, caspase-10/b was down-regulated, which was accompanied by the appearance of a specific 47-kDa caspase-10/b cleavage product and an increased caspase-10 activity. In contrast, no down-regulation of caspase-10/a, -10/c, or -10/d was observed, suggesting that spontaneous apoptosis was associated with a differential activation of caspase-10/b. This was confirmed by the finding that spontaneous apoptosis was inhibited in the presence of Z-Ile-Glu-Thr-Asp (Z-IETD)-FMK, which blocks caspase-10. However, no down-regulation of caspase-10 isoforms was observed in the presence of TNF-, suggesting that caspase-10 was not involved in TNF--induced apoptosis. Taken together, our study demonstrates that spontaneous and TNF--mediated apoptosis of PMN have different molecular requirements. Whereas TNF--mediated apoptosis depends on the activation of caspase-8, spontaneous apoptosis requires the activation of caspase-10/b. This finding may reveal that PMN apoptosis in different (patho-) physiological settings results from distinct molecular mechanisms.

Key Words: polymorphonuclear meutrophil • tumor necrosis factor • Z-AEVD-FMK • Z-IETD-FMK

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