Caspase10
In the present study, we investigated the molecular mechanisms of spontaneous
and tumor necrosis factor alpha (TNF-alpha)-mediated apoptosis of human
polymorphonuclear neutrophils (PMN). Whereas TNF-alpha-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-alpha, suggesting that
caspase-10 was not involved in TNF-alpha-induced apoptosis. Taken together, our
study demonstrates that spontaneous and TNF-alpha-mediated apoptosis of PMN
have different molecular requirements. Whereas TNF-alpha-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.
PMID: 14761933 [PubMed - as supplied by publisher]