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Inhibition of CD4 cross-linking-induced lymphocytes apoptosis by
vesnarinone as a novel immunomodulating agent: vesnarinone inhibits Fas
expression and apoptosis by blocking cytokine secretion
N Oyaizu, TW McCloskey, S Than and S Pahwa
Department of Pediatrics, North Shore University Hospital-Cornell
University Medical College, New York, NY 11030, USA.
Evidence is accumulating that T cells from human immunodeficiency virus
type 1 (HIV-1)-infected individuals show accelerated cell death through
apoptosis. We have recently demonstrated that the cross-linking of CD4
molecules (CD4XL) results in death of normal peripheral T cells through
apoptosis and imbalanced cytokine secretion (ie, induction of tumor
necrosis factor-alpha [TNF-alpha] and interferon-gamma [IFN-gamma] in the
absence of interleukin-2 [IL-2] or IL-4 secretion). These upregulated
cytokines (TNF-alpha/IFN-gamma) largely contributed to upregulation of the
apoptosis-inducing cell surface molecule, Fas (APO- 1/CD95) and apoptosis
induction. The present study investigated the effect of vesnarinone as a
novel immunomodulating agent on CD4XL- induced T-cell apoptosis. The
addition of vesnarinone to peripheral blood mononuclear cells (PBMC)
significantly inhibited CD4XL-induced lymphocyte apoptosis. This
apoptosis-inhibitory effect of vesnarinone was associated with the blocking
of CD4XL-induced TNF-alpha IFN-gamma secretion and of Fas antigen
upregulation. However, vesnarinone did not block effects of exogenously
supplemented TNF-alpha/IFN-gamma on Fas induction. These data suggest that
vesnarinone inhibits CD4XL-induced TNF-alpha/IFN-gamma secretion, thereby
blocking subsequent Fas upregulation and apoptosis induction. Given the
potent pathogenic role of imbalanced cytokine secretion observed in
HIV-infection, an agent such as vesnarinone may be of therapeutic value in
slowing disease progression.
Volume 87,
Issue 6,
pp. 2361-2368,
03/15/1996
Copyright © 1996 by The American Society of Hematology
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