Molecular mechanisms of immunosuppression by cyclosporins.
Despite the successful clinical application of the immunosuppressive drug cyclosporin A (CsA, Sandimmun), its precise mechanism of action in the process of T cell activation remains elusive. CsA binds to the high-affinity cytosolic receptor cyclophilin whose peptidyl-prolyl cis-trans isomerase activity is inhibited upon binding. The linkage of this effect with the inhibition of the T cell receptor-mediated signal transduction pathway, which leads to a suppression of lymphokine gene transcription, is still unclear. We analyzed the relationship between cyclophilin-binding and immunosuppressive activity (e.g., effect on IL-2 transcription) of cyclosporin derivatives in vitro. The results show that binding to cyclophilin is required, but not sufficient for immunosuppression. Cyclosporin analogues which completely lack immunosuppressive activity but fully retained their cyclophilin-binding capacity antagonize the immunosuppressive activity of CsA. These derivatives inhibit the isomerase activity of cyclophilin, which clearly demonstrates that inhibition of the cyclophilin isomerase activity does not lead to immunosuppression. In analogy to the other immunosuppressants of microbial origin, FK-506 and rapamycin, a specific structure of the "effector" domain of CsA, which is unrelated to the cyclophilin-binding domain, determines the biological activity. In the nucleus, CsA interferes with the DNA-binding of inducible transcription factors to their respective DNA motifs within lymphokine promoters by affecting intracellular translocation of transcription factor subunits.
Zenke
G
G
Preclinical Research, Sandoz Pharma Ltd., Basel, Switzerland.
Baumann
G
G
Wenger
R
R
Hiestand
P
P
Quesniaux
V
V
Andersen
E
E
Schreier
M H
MH
D000591:Amino Acid Isomerases / Q000378:metabolism; D000818:Animals; D002352:Carrier Proteins / Q000378:metabolism; D003524:Cyclosporins / Q000378:metabolism / Q000494:pharmacology*; D006801:Humans; D007108:Immune Tolerance; D008213:Lymphocyte Activation / Q000187:drug effects; D019696:Peptidylprolyl Isomerase; D013601:T-Lymphocytes / Q000187:drug effects* / Q000276:immunology; D016559:Tacrolimus / Q000494:pharmacology
D002352:Carrier Proteins; D003524:Cyclosporins; D000591:Amino Acid Isomerases; D019696:Peptidylprolyl Isomerase; D016559:Tacrolimus