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Published online before print February 16, 2005

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(Journal of Leukocyte Biology. 2005;77:748-758.)
© 2005 by Society for Leukocyte Biology

Concentrations of cyclosporin A and FK506 that inhibit IL-2 induction in human T cells do not affect TGF-ß1 biosynthesis, whereas higher doses of cyclosporin A trigger apoptosis and release of preformed TGF-ß1

Jordi Minguillón^*, Beatriz Morancho^*, Seong-Jin Kim, Miguel López-Botet^* and José Aramburu^*,1

^* Department of Experimental and Health Sciences, Universitat Pompeu Fabra, Barcelona, Spain; and
Laboratory of Cell Regulation and Carcinogenesis, National Cancer Institute, National Institutes of Health, Bethesda, Maryland

¹ Correspondence: Departament de Ciències Experimentals i de la Salut, Universitat Pompeu Fabra, Carrer Dr Aiguader 80, 08003 Barcelona, Spain. E-mail: jaramburu{at}imim.es

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-ß1 (TGF-ß1) 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-ß1 in normal human lymphocytes and cell lines. In Jurkat T cells, the TGF-ß1 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-ß1, induced by the T cell receptor (TCR) or the TGF-ß receptor, was not substantially affected by CsA and FK506 concentrations (1 µM) that effectively inhibited interleukin-2 production. However, pretreatment of fresh lymphocytes with CsA or FK506 during primary TCR stimulation reduced their production of TGF-ß1 during secondary TCR activation. Finally, high concentrations of CsA (10 µM), in the range attained in vivo in experiments in rodents, caused apoptosis in human T cells and the release of preformed, bioactive TGF-ß1. 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-ß1 biosynthesis but can cause different effects on TGF-ß1 depending on the cell type and concentrations used.

Key Words: calcineurin • lymphocytes • immunosuppressants

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