Covalent binding of cyclosporine inhibits irreversibly T-lymphocyte activation

Ryffel, B., Woerly, G., Quesniaux, V. F.J., Husi, H. and Foxwell, B. M.J. (1992) Covalent binding of cyclosporine inhibits irreversibly T-lymphocyte activation. Biochemical Pharmacology, 43(5), pp. 953-960. (doi: 10.1016/0006-2952(92)90598-D) (PMID:1554393)

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A diazirine derivative of cyclosporine (PL-CS) was used to photolabel recombinant human cyclophilin (rhCyp), the cytosolic receptor for the immunosuppressant cyclosporine. The affinity of PL-CS for rhCyp and the immunosuppressive activity were 10-fold reduced as compared to cyclosporine A. Whereas cyclosporine immunosuppression was fully reversible, UV cross-linking of PL-CS resulted in permanent inhibition of lymphocyte activation as shown by proliferation of anti-CD3 stimulated human peripheral lymphocyte, interleukin (IL)-2 gene transcription and IL-2 synthesis in the human T-leukemia cell line Jurkat. In vivo photolabeling of viable Jurkat cells revealed that a 21-kDa complex was the major radiolabeled product which was identified as a cyclophilin-cyclosporine complex. In addition, cyclophilin B (25 kDa) and proteins of an unidentified nature at 40, 46 and 60 kDa were observed in Jurkat cells. The cyclosporine-resistant human fibroblast cell line MRC5 displayed a different labeling pattern: cyclophilin B (25 kDa) and a 65-kDa protein were the major labeled products, while the 46- and 60-kDa components were not detectable and cyclophilin was only faintly labeled. In summary, covalent cyclosporine binding caused irreversible lymphocyte inactivation and revealed in addition to cyclophilin other specifically labeled proteins in lymphoid cells. The role and identity of these proteins is presently unknown.

Item Type:Articles
Glasgow Author(s) Enlighten ID:Husi, Dr Holger
Authors: Ryffel, B., Woerly, G., Quesniaux, V. F.J., Husi, H., and Foxwell, B. M.J.
College/School:College of Medical Veterinary and Life Sciences > School of Cardiovascular & Metabolic Health
Journal Name:Biochemical Pharmacology
Publisher:Pergamon Press plc

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