Mechanism of cyclosporin A-induced immunosuppression. Cyclosporin A inhibits receptor-mediated and non-receptor-mediated lymphokine production as well as interleukin-2-induced proliferation in cloned T lymphocytes.
The effects of cyclosporin A (CyA) on the activation processes of cloned murine cytotoxic T lymphocytes (CTL) have been examined. With the use of Day 7 resting cloned CTL it was possible to separate the functions of lymphokine production (macrophage-activating factor, MAF) and interleukin 2 (IL-2)-induced proliferation of these cells. The effect of CyA on each of these activities was analyzed independently. CyA was found to inhibit both receptor-mediated MAF production in response to stimulation with antigen and lectin and MAF production in response to non-receptor-mediated stimulation (by anti-Thy-1 antibodies, ionophore, and phorbol ester). Further, CyA was observed to inhibit the re-entry of these resting CTL into the cell cycle upon stimulation with IL-2. The effect of CyA on MAF production did not appear to be due to inhibition of the signal-transducing mechanism involved in this process (i.e., inositol lipid hydrolysis, calcium mobilization, and protein phosphorylation). The action of CyA on the IL-2-induced proliferation was not due to inhibition of IL-2 receptor expression or the binding of IL-2 to its receptor. Thus, CyA appeared to mediate its suppressive effects on MAF production and IL-2-induced proliferation through an action on some later step(s) in the signal pathways of these activities.
D000818:Animals; D002118:Calcium / Q000378:metabolism; D002455:Cell Division / Q000187:drug effects; D003524:Cyclosporins / Q000494:pharmacology*; D003864:Depression, Chemical; D007376:Interleukin-2 / Q000096:biosynthesis / Q000494:pharmacology*; D008213:Lymphocyte Activation / Q000187:drug effects*; D008222:Lymphokines / Q000096:biosynthesis; D016215:Macrophage-Activating Factors; D051379:Mice; D011971:Receptors, Immunologic / Q000378:metabolism; D015375:Receptors, Interleukin-2; D011975:Receptors, Mitogen / Q000187:drug effects* / Q000378:metabolism; D013602:T-Lymphocytes, Cytotoxic / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism
D003524:Cyclosporins; D007376:Interleukin-2; D008222:Lymphokines; D016215:Macrophage-Activating Factors; D011971:Receptors, Immunologic; D015375:Receptors, Interleukin-2; D011975:Receptors, Mitogen; D002118:Calcium