The mechanisms of action of cyclosporine.
CS most probably manifests its immunosuppressive effects by inhibiting the synthesis of IL-2 and other lymphokine mRNAs during the process of T-cell activation. The detailed molecular events involved in CS's inhibition of mRNA synthesis are not known, but it is likely that the drug prevents transduction of the mitogenic signal from the cell surface to the nucleus at a point subsequent to the rise in intracellular calcium generated by the mitogenic signal. CS immunosuppression also appears to be related to the binding of an intracellular receptor protein, cyclophilin, which is a major cytosolic constituent of all cells and has peptidyl-prolyl isomerase activity. The involvement of this protein in T-cell activation, if any, is not yet known. Studies on the biochemical basis of CS-induced nephrotoxicity are still in their infancy and the relation of toxicity to immunosuppression is not understood. It is evident that the mode of action of CS provides an intriguing puzzle and a challenge in both its immunosuppressive and nephrotoxic aspects. The elucidation of the biochemistry of CS will surely not only improve the use of this important drug but will also increase our understanding of T-lymphocyte activation and the mechanism underlying the control of gene expression.
Foxwell
B M
BM
Charing Cross Sunley Research Centre, London, England.
Ruffel
B
B
D002352:Carrier Proteins / Q000378:metabolism; D002454:Cell Differentiation; D003524:Cyclosporins / Q000009:adverse effects / Q000276:immunology* / Q000494:pharmacology; D006801:Humans; D007166:Immunosuppressive Agents / Q000627:therapeutic use; D007668:Kidney / Q000187:drug effects; D008222:Lymphokines / Q000096:biosynthesis; D019696:Peptidylprolyl Isomerase; D013601:T-Lymphocytes / Q000276:immunology / Q000502:physiology; D006377:T-Lymphocytes, Helper-Inducer / Q000276:immunology / Q000378:metabolism
D002352:Carrier Proteins; D003524:Cyclosporins; D007166:Immunosuppressive Agents; D008222:Lymphokines; D019696:Peptidylprolyl Isomerase