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.
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.
Oyaizu
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Department of Pediatrics, North Shore University Hospital-Cornell University Medical College, New York, NY 11030, USA.
McCloskey
T W
TW
Than
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S
Pahwa
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S
D000276:Adjuvants, Immunologic / Q000494:pharmacology*; D000911:Antibodies, Monoclonal / Q000276:immunology; D017209:Apoptosis / Q000187:drug effects*; D015704:CD4 Antigens / Q000276:immunology*; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology / Q000187:drug effects* / Q000276:immunology; D003864:Depression, Chemical; D005786:Gene Expression Regulation / Q000187:drug effects*; D018023:HIV Seronegativity; D006801:Humans; D007152:Immunologic Capping; D008222:Lymphokines / Q000378:metabolism*; D011719:Pyrazines; D011804:Quinolines / Q000494:pharmacology*; D019014:fas Receptor / Q000096:biosynthesis* / Q000235:genetics
D000276:Adjuvants, Immunologic; D000911:Antibodies, Monoclonal; D015704:CD4 Antigens; D008222:Lymphokines; D011719:Pyrazines; D011804:Quinolines; D019014:fas Receptor; C041667:vesnarinone