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A cysteine protease inhibitor prevents activation-induced T-cell apoptosis
and death of peripheral blood cells from human immunodeficiency
virus-infected individuals by inhibiting upregulation of Fas ligand
Y Yang, ZH Liu, CF Ware and JD Ashwell
Laboratory of Immune Cell Biology, National Cancer Institute, Bethesda, MD
20892-1152, USA.
Activation of T-cell hybridomas, preactivated normal T cells, and
peripheral blood lymphocytes (PBL) from human immunodeficiency virus
(HIV)-infected individuals results in apoptosis. In the first two cases,
apoptosis is caused by the upregulation of Fas ligand (FasL) and its
subsequent interaction with Fas; the mechanism for the spontaneous and
activation-induced death of lymph node cells and PBL from HIV+ blood is not
known. A number of protease inhibitors have been shown to prevent T-cell
apoptosis under all of these circumstances, but the mechanism of action has
not been determined. Here we show that the cysteine protease inhibitor E64d
prevent activation-induced T hybridoma cell death by inhibiting the
upregulation of FasL. Quantitative polymerase chain reaction (PCR)
demonstrated that mRNA for FasL is expressed at low levels in fresh PBL
from HIV-infected blood, but increases in cultured PBL from both uninfected
and HIV-infected donors. The ex vivo apoptosis of PBL from HIV+ donors was
prevented by adding the soluble extracellular domain of Fas, demonstrating
a requisite role for Fas/ FasL interactions in this form of cell death.
Furthermore, while having no effect on the death of PBL from HIV-infected
blood stimulated directly via Fas, E64d inhibited FasL upregulation. Thus,
aberrant apoptosis of cultured PBL from HIV-infected individuals is
mediated by FasL and Fas, and E64d blocks this apoptosis by inhibiting the
upregulation of FasL. These results are consistent with the hypothesis that
the abnormal expression of Fas and the inducible expression of FasL,
contributes to the immunodeficiency of patients with acquired immune
deficiency syndrome and suggest that modulation of FasL expression could be
an effective target for therapeutic intervention.
Volume 89,
Issue 2,
pp. 550-557,
01/15/1997
Copyright © 1997 by The American Society of Hematology
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