Regulation of new DNA synthesis in mammalian cells by cyclosporine. Demonstration of a transforming growth factor beta-dependent mechanism of inhibition of cell growth.
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 CsA and 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-beta (TGF-beta), and restrains new DNA synthesis in mammalian cells via a TGF-beta-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-beta 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-beta-sensitive cells, CCL-64 cells, and A-549 cells; (B) CsA stimulates these mammalian cells to secrete TGF-beta; and (C) TGF-beta induced by CsA is biologically active in inducing cell growth inhibition (demonstrated by the reversal of CsA-associated inhibition with anti-TGF-beta monoclonal antibodies). Our observations suggest that CsA can regulate cell growth via a TGF-beta-dependent mechanism. Since the multifunctional cytokine TGF-beta can enhance extracellular matrix accumulation as well as augment endothelin production, our findings also advance a mechanism that links, via TGF-beta, the beneficial (immunosuppression) and the harmful (fibrosis, hypertension) consequences of CsA usage.
Khanna
A
A
Iris and B. Gerald Cantor Laboratory for Immunological Research in Diabetes and Immunogenetics, Cornell University Medical College, New York, New York 10021.
Li
B
B
Stenzel
K H
KH
Suthanthiran
M
M
D000818:Animals; D002455:Cell Division / Q000187:drug effects; D002460:Cell Line; D016572:Cyclosporine / Q000494:pharmacology*; D004261:DNA Replication / Q000187:drug effects*; D006131:Growth Inhibitors; D006801:Humans; D066298:In Vitro Techniques; D008907:Mink; D016212:Transforming Growth Factor beta / Q000502:physiology*
D006131:Growth Inhibitors; D016212:Transforming Growth Factor beta; D016572:Cyclosporine