Increased T cell cytotoxicity by Betathine-induced upregulation of TNFalpha.
Betathine (BT) is a low molecular weight disulfide that has previously been shown to exhibit in vivo antitumor activity in murine myeloma and melanoma models. We have shown that BT treatment of both human T cells and monocytes is associated with an increase in surface tumor necrosis alpha (TNFalpha) expression. Further, in T cells and monocytes that have been stimulated with PMA and ionomycin, the addition of BT results in a dose and time dependent increase in the percentage of high TNFalpha-expressing cells. Unlike TNFalpha upregulation produced by the commonly used thiol antioxidant N-acetyl-L-cysteine (NAC), the BT-induced increase in TNFalpha is observed consistently in different donors. This increase in surface TNFalpha is associated with elevated levels of TNFalpha mRNA. In addition, expression of TNFalpha receptor I is also significantly enhanced by BT treatment. The upregulation of surface TNFalpha by BT has functional consequences, in that, BT-treated T cells exhibit enhanced cytotoxic activity. Thus, increased TNFalpha expression may be one mechanism responsible for the antineoplastic activity of BT.
Dunn
T M
TM
Department of Cell Biology and Molecular Genetics, University of Maryland, College Park, MD 20742, USA.
Wormsley
S
S
Taub
F E
FE
Pontzer
C H
CH
D000276:Adjuvants, Immunologic / Q000494:pharmacology*; D015703:Antigens, CD / Q000096:biosynthesis / Q000187:drug effects; D000970:Antineoplastic Agents / Q000494:pharmacology*; D003543:Cysteamine / Q000031:analogs & derivatives* / Q000494:pharmacology; D003602:Cytotoxicity, Immunologic / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D006801:Humans; D015759:Ionomycin / Q000494:pharmacology; D009000:Monocytes / Q000187:drug effects / Q000276:immunology; D012333:RNA, Messenger / Q000032:analysis; D018124:Receptors, Tumor Necrosis Factor / Q000096:biosynthesis / Q000187:drug effects; D047888:Receptors, Tumor Necrosis Factor, Type I; D013601:T-Lymphocytes / Q000187:drug effects* / Q000276:immunology; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D013997:Time Factors; D016212:Transforming Growth Factor beta / Q000096:biosynthesis; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis* / Q000235:genetics
D000276:Adjuvants, Immunologic; D015703:Antigens, CD; D000970:Antineoplastic Agents; D012333:RNA, Messenger; D018124:Receptors, Tumor Necrosis Factor; D047888:Receptors, Tumor Necrosis Factor, Type I; D016212:Transforming Growth Factor beta; D014409:Tumor Necrosis Factor-alpha; D015759:Ionomycin; D003543:Cysteamine; C090058:alethine; D013755:Tetradecanoylphorbol Acetate