REGULATION OF NEW DNA SYNTHESIS IN MAMMALIAN CELLS BY CYCLOSPORINE: DEMONSTRATION OF A TRANSFORMING GROWTH FACTOR β-DEPENDENT MECHANISM OF INHIBITION OF CELL GROWTH

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Abstract

Immunosuppressants such as cyclosporine are considered to constrain cell growth by preventing the production of growth stimulatory cytokines (e.g., interleukin-2). The possibility exists, however, that CsAand other immunosuppressants might restrain cell growth by promoting the production of growth-inhibitory cytokines. We have explored herein the hypothesis that CsA stimulates the production of transforming growth factor-β (TGF-β), and restrains new DNA synthesis in mammalian cells via a TGF-β-dependent mechanism. To investigate this new postulate independently of an IL-2-dependent mechanism, we utilized, as probes, two mammalian cell lines, distinguished by their sensitivity to growth inhibition by TGF-β and resistance to IL-2: CCL-64 mink lung epithelial cells (CCL-64 cells) and A-549 human adenocarcinoma cells (A-549 cells).

Our experimental approach revealed the following: (A) CsA and not cyclosporine H, an inactive analogue of CsA, mediates growth inhibition of TGF-β-sensitive cells, CCL-64 cells, and A-549 cells; (B) CsA stimulates these mammalian cells to secrete TGF-β; and (C) TGF-β induced by CsA is biologically active in inducing cell growth inhibition (demonstrated by the reversal of CsA-associated inhibition with anti-TGF-β monoclonal antibodies).

Our observations suggest that CsA can regulate cell growth via a TGF-β-dependent mechanism. Since the multifunctional cytokine TGF-β can enhance extracellular matrix accumulation as well as augment endothelin production, our findings also advance a mechanism that links, via TGF-β, the beneficial (immunosup-pression) and the harmful (fibrosis, hypertension) consequences of CsA usage.

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