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Different Interleukin-1β Converting Enzyme (ICE) Family Protease Requirements For The Apoptotic Death Of T Lymphocytes Triggered By Diverse Stimuli

Apurva Sarin, Ming-Lei Wu, Pierre A. Henkart

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Two cell permeable peptide fluoromethyl ketone inhibitors of Interleukin-1β converting enzyme (ICE) family proteases were tested as inhibitors of apoptotic cell death of T lymphocytes at various stages of differentiation. The CPP-32–like protease activity in apoptotic cell lysates was blocked by both the ICE inhibitor Cbz-Val-Ala-Asp(OMe)-fluoromethyl ketone (ZVADFMK) as well as its truncated analog Boc-Asp(OMe)-fluoromethyl ketone (BD-FMK), which failed to block ICE. In vitro apoptotic death in murine thymocytes triggered by the independent agents dexamethasone, etoposide, radiation, anti-Fas, and anti-CD3 was blocked equally well by BD-FMK and ZVAD-FMK, but not by the control reagent Cbz-Phe-Ala-fluoromethyl ketone. In activated T cell blasts, while anti-CD3/ Fas-induced death was almost completely inhibited by both ZVAD-FMK and BD-FMK, death induced by dexamethasone, etoposide, or irradiation was more sensitive to inhibition by BD-FMK. In the murine T cell line CTLL-2, apoptotic death induced by IL-2 withdrawal, etoposide, or dexamethasone was inhibited by BD-FMK, while ZVAD-FMK was without effect. These data indicate that ICEfamily proteases comprise a common functional step in distinct T cell apoptotic death pathways, but suggest that different family members are likely to be critical in various differentiated T cell types, even when triggered by the same stimulus.