SOME NEW ASPECTS OF MOLECULAR MECHANISMS OF CYCLOSPORINE-A EFFECT ON IMMUNE-RESPONSE

A few protein targets were found to display a specific high-affinity i nteraction with the immunosuppressant cyclosporin A (CsA): cytosolic c yclophilins (CyP)A, B, C, D, E containing from 122 to 174 amino acid r esidues in a polypeptide chain, and secreted forms of CyP; CyP-40, 40- kDa CsA-binding polypeptide complexed with steroid receptor (SR); CyP- related 150-kDa receptor of natural killer (NK) cells; interleukin 8 ( IL-8); actin; a family of molecular chaperones hsp70 and P-glycoprotei n (P-GP). All CyPs possess peptidyl-prolyl cis-trans isomerase activit y (PPIase) and may serve as ATP-independent molecular chaperone protei ns. The CsA-CyP complexes are specific inhibitors of Ca2+ - and calmod ulin-dependent protein phosphatase calcineurin (CaN). The inhibition o f CaN blocks the activation of genes of IL-2, IL-2R, IL-4, etc. in T c ells. In addition, immunosuppressive and/or antiinflammatory activity of CsA can be executed via CyP-40 and hsp70 complexed with SR, and fol lowing the interaction with CyP-related receptor of NK and with IL-8. CsA binding to CyPC, P-GP and actin may throw light on the biochemical events leading to nephrotoxicity and graft vessel disease, two major side effects produced by CsA. The discovery of the interaction of huma n immunodeficiency virus type 1 (HIV-1) Gag protein with CyP and effec tive disruption of this interaction by CsA may be important for our un derstanding of the pathology caused by this immunosuppressive virus an d will inspire therapeutic strategies to nip HIV in the bud. Bacterial immunophilins (ImPs) contribute to the virulence of pathogenic microo rganisms. Elucidation of molecular mechanisms of microbial ImPs' actio n in the pathogenesis of bacterial infections may lead to new strategi es for designing antibacterial drugs.