Inhibition of cyclosporin A/FK506 resistant, lymphokine-induced T-cell activation by phenothiazine derivatives.
Earlier studies from our laboratory have demonstrated that phenothiazine derivatives are capable of inhibiting mitogen-induced activation of human T-cells and thymocytes. Similar to cyclosporin A, phenothiazine derivatives exert these inhibitory effects by decreasing the accumulation of lymphokine-specific mRNA. However, proliferation of T-cell blasts and of unfractionated human thymocytes can also be induced by interleukin 2. Since activation of T-cells via the interleukin 2 receptor seems to be resistant to the action of cyclosporin A, the present study was designed to investigate whether lymphokine-induced activation could be inhibited by phenothiazine derivatives. The effects of the phenothiazine derivatives chlorpromazine and/or fluphenazine have been studied and compared to the action of cyclosporin A and FK506 in human thymocytes, human T-cell blasts and in the human T-cell line H33-HJ JA1, which is an interleukin 2 producing cell line derived from Jurkat cells. As evidenced by the incorporation of [3H]-thymidine, cyclosporin A (1 microgram/ml) and FK506 (100 ng/ml) have no or only marginal inhibitory capacity on interleukin 2-induced proliferation in all T-cell systems tested. By contrast, phenothiazine derivatives (fluphenazine > chlorpromazine) exert a dose-dependent inhibition of the activation of these cells in pharmacologically relevant micromolar concentrations. Similar results were obtained by measuring the production of interferon-gamma in the supernatants of interleukin 2-induced human thymocytes. Our results suggest that the use of phenothiazines might be helpful in immunosuppressive regimens.
Schleuning
M
M
Medizinische Klinik III, Universitätsklinikum Grosshadern, München, Germany.
Brumme
V
V
Wilmanns
W
W
D002455:Cell Division; D002460:Cell Line; D002478:Cells, Cultured; D002746:Chlorpromazine / Q000494:pharmacology*; D016572:Cyclosporine / Q000494:pharmacology*; D005476:Fluphenazine / Q000494:pharmacology*; D006801:Humans; D007376:Interleukin-2 / Q000096:biosynthesis / Q000378:metabolism; D008213:Lymphocyte Activation / Q000187:drug effects*; D018123:Receptors, Interleukin / Q000378:metabolism; D015375:Receptors, Interleukin-2 / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013601:T-Lymphocytes / Q000187:drug effects* / Q000276:immunology; D016559:Tacrolimus / Q000494:pharmacology*
D007376:Interleukin-2; D018123:Receptors, Interleukin; D015375:Receptors, Interleukin-2; D016572:Cyclosporine; D005476:Fluphenazine; D002746:Chlorpromazine; D016559:Tacrolimus