Differential effects of the immunosuppressive macrolides FK-506 and rapamycin on activation-induced T-cell apoptosis.
Activation of certain T-cell lines induces, besides lymphokine production, a suicide process (apoptosis) mediated by fragmentation of the cell's genome. This also occurs intrathymically during negative selection of the T-cell receptor (TcR) repertoire. Cyclosporin A (CsA) has been shown to block activation-driven T-cell apoptosis, an effect which may account for the perturbations of TcR repertoire selection caused by this agent in vivo. Recently, the macrolide FK-506 was demonstrated to suppress T-cell activation by inhibiting lymphokine production in a manner apparently similar to CsA. Thus, it seemed important to determine whether FK-506 would also prevent T-cell apoptosis. For the purpose of comparison, we also investigated rapamycin (RAP), a macrolide structurally related to FK-506, but that does not block lymphokine production and antagonizes the immunosuppressive action of FK-506. The DO-11.10 T-cell hybridoma stimulated with ionomycin plus PMA was used as a model system. FK-506 (1.2 nM) totally prevented DNA fragmentation detectable by agarose gel electrophoresis at 16 h of culture. FK-506 still inhibited this phenomenon when added 2 h after the initiation of the cultures but not later. In contrast, concentrations of RAP as high as 1 microM failed to block apoptosis. However, RAP (110 nM) reversed the apoptosis-inhibitory effect of FK-506, even if added 1-2 h after the latter to the cultures. Consistent with this antagonism, RAP also reversed the binding of a radiolabeled derivative of FK-506 in DO-11.10 cells. Therefore, FK-506 interferes with an early event of T-cell activation that leads to apoptosis whereas RAP does not.(ABSTRACT TRUNCATED AT 250 WORDS)
Staruch
M J
MJ
Department of Immunology Research, Merck, Sharp and Dohme Research Laboratories, Rahway, NJ 07065.
Sigal
N H
NH
Dumont
F J
FJ
D000818:Animals; D016923:Cell Death / Q000187:drug effects; D016572:Cyclosporine / Q000494:pharmacology; D006825:Hybridomas / Q000187:drug effects / Q000276:immunology; D007166:Immunosuppressive Agents / Q000494:pharmacology; D008213:Lymphocyte Activation; D011090:Polyenes / Q000494:pharmacology*; D020123:Sirolimus; D013601:T-Lymphocytes / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D016559:Tacrolimus / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000494:pharmacology*
D007166:Immunosuppressive Agents; D011090:Polyenes; D016572:Cyclosporine; D020123:Sirolimus; D016559:Tacrolimus