Mechanism of immunosuppressive effect of alprazolam: alprazolam suppresses T-cell proliferation by selectively inhibiting the production of IL2 but not acquisition of IL2 receptor.
The purpose of this study was to elucidate the mechanism of action of alprazolam on concanavalin A (Con A)-induced murine T-cell proliferation. Splenic cells of BALB/c mice were first cultured with an optimum dose of Con A in the presence or absence of varying doses of alprazolam to assess effects of alprazolam on T-cell proliferation, interleukin 2 (IL2) production and IL2 receptor (IL2R) expression. Then, Con A-induced T-blast cells from BALB/c mice were cultured with an excess dose of human recombinant IL2 (rIL2) or crude rat IL2 supernate in the presence or absence of alprazolam to assess the effects of alprazolam on the interaction of IL2 and IL2R. The results of these studies clearly demonstrated that alprazolam can inhibit the T-cell proliferation in response to Con A but not to IL2. Alprazolam also reduced the production of IL2 by splenic T-cells, but did not alter the expression of IL2R on Con A-induced T-blast cells. Furthermore, the results also showed that (a) alprazolam did not inhibit the proliferative response of splenic T-cells to a combination of phorbol 12-myristate-13-acetate (PMA) and ionomycin, and (b) the addition of exogenous IL2 reversed the inhibitory effect of alprazolam on T-cell proliferation. Finally, the addition of alprazolam produced a time-dependent inhibiting effect on T-cell proliferation. However, this inhibitory effect of alprazolam was abolished when the drug was added to the cultures of competent cells that fully expressed IL2R. Taken together, these results suggest that alprazolam inhibits murine T-cell proliferation by affecting the mitogenic receptor-mediated events (initiation) rather than the IL2R-mediated events (progression) of ligand-activated T-cells through the cell cycle.
Chang
M P
MP
Geriatric Research, Education and Clinical Center (GRECC), VA Medical Center West Los Angeles, CA 90073.
Castle
S C
SC
Norman
D C
DC
D000525:Alprazolam / Q000494:pharmacology*; D000818:Animals; D003208:Concanavalin A; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D007376:Interleukin-2 / Q000096:biosynthesis* / Q000494:pharmacology; D015759:Ionomycin / Q000494:pharmacology; D008213:Lymphocyte Activation / Q000187:drug effects*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D015375:Receptors, Interleukin-2 / Q000032:analysis / Q000187:drug effects*; D013601:T-Lymphocytes / Q000187:drug effects*; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000032:analysis
D007166:Immunosuppressive Agents; D007376:Interleukin-2; D015375:Receptors, Interleukin-2; D014409:Tumor Necrosis Factor-alpha; D003208:Concanavalin A; D015759:Ionomycin; D013755:Tetradecanoylphorbol Acetate; D000525:Alprazolam