title: Concentrations of cyclosporin A and FK506 that inhibit IL-2 induction in human T cells do not affect TGF-beta1 biosynthesis, whereas higher doses of cyclosporin A trigger apoptosis and release of preformed TGF-beta1.
abstract: Cyclosporin A (CsA) and FK506 suppress T cell activation by inhibiting calcineurin and the calcineurin-dependent transcription factors nuclear factor of activated T cells (NFATc), which are central regulators of T cell function. It was reported that CsA up-regulated the transcription of transforming growth factor-beta1 (TGF-beta1) in lymphocytes and other cells and activated its promoter in A549 lung carcinoma cells, but the mechanisms involved are poorly understood, and it is unclear whether calcineurin plays any role. We have studied the regulation of TGF-beta1 in normal human lymphocytes and cell lines. In Jurkat T cells, the TGF-beta1 promoter was activated by calcineurin and NFATc and inhibited by CsA and FK506. However, the promoter was insensitive to both drugs in A549 cells. In human T cells preactivated with phytohemagglutinin, biosynthesis of TGF-beta1, induced by the T cell receptor (TCR) or the TGF-beta receptor, was not substantially affected by CsA and FK506 concentrations (< or = 1 microM) that effectively inhibited interleukin-2 production. However, pretreatment of fresh lymphocytes with CsA or FK506 during primary TCR stimulation reduced their production of TGF-beta1 during secondary TCR activation. Finally, high concentrations of CsA (10 microM), in the range attained in vivo in experiments in rodents, caused apoptosis in human T cells and the release of preformed, bioactive TGF-beta1. These effects are unlikely to owe to calcineurin inhibition, as they were not observed with FK506. Our results indicate that CsA and FK506 are not general inducers of TGF-beta1 biosynthesis but can cause different effects on TGF-beta1 depending on the cell type and concentrations used.
authors.affiliation: Department of Experimental and Health Sciences, Universitat Pompeu Fabra, Carrer Dr Aiguader 80, 08003 Barcelona, Spain.
authors.forename: Jordi
authors.initials: J
authors.lastname: Minguillón
authors.forename: Beatriz
authors.initials: B
authors.lastname: Morancho
authors.forename: Seong-Jin
authors.initials: SJ
authors.lastname: Kim
authors.forename: Miguel
authors.initials: M
authors.lastname: López-Botet
authors.forename: José
authors.initials: J
authors.lastname: Aramburu
mesh_terms: D017209:Apoptosis / Q000187:drug effects* / Q000276:immunology; D019703:Calcineurin / Q000494:pharmacology; D002478:Cells, Cultured; D016572:Cyclosporine / Q000008:administration & dosage*; D004268:DNA-Binding Proteins / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D005786:Gene Expression Regulation / Q000187:drug effects / Q000276:immunology; D006801:Humans; D007376:Interleukin-2 / Q000037:antagonists & inhibitors* / Q000276:immunology; D008213:Lymphocyte Activation / Q000187:drug effects / Q000235:genetics; D050778:NFATC Transcription Factors; D009687:Nuclear Proteins / Q000494:pharmacology; D011401:Promoter Regions, Genetic; D011948:Receptors, Antigen, T-Cell / Q000276:immunology; D018125:Receptors, Transforming Growth Factor beta / Q000276:immunology; D013601:T-Lymphocytes / Q000187:drug effects* / Q000276:immunology / Q000473:pathology; D016559:Tacrolimus / Q000008:administration & dosage*; D014157:Transcription Factors / Q000494:pharmacology; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism*; D053773:Transforming Growth Factor beta1
chemical_list: D004268:DNA-Binding Proteins; D007376:Interleukin-2; D050778:NFATC Transcription Factors; D009687:Nuclear Proteins; D011948:Receptors, Antigen, T-Cell; D018125:Receptors, Transforming Growth Factor beta; C508960:TGFB1 protein, human; D014157:Transcription Factors; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; D016572:Cyclosporine; D019703:Calcineurin; D016559:Tacrolimus