IN VIVO HYPEREXPRESSION OF TRANSFORMING GROWTH FACTOR-??1 IN MICE: STIMULATION BY CYCLOSPORINE1

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Abstract
We have demonstrated that cyclosporine (CsA) stimulates transforming growth factor (TGF) β1 expression in vitro and that growth of mammalian cells can be arrested by CsA via a TGF-β1-dependent mechanism. Herein, we have explored whether CsA stimulates TGF-β1 hyperexpression in vivo. Four groups of B6AF1 mice were studied: group 1, control; group 2, CsA pretreatment; group 3, anti-CD3 monoclonal antibody pretreatment; and group 4, CsA plus anti-CD3 pretreatment. CsA pretreatment augmented TGF-β1 protein expression and increased intrarenal display of TGF-β1 mRNA. This heightened TGF-β1 expression was associated with an impaired T cell proliferative response. Our observations, together, advance the hypothesis that CsA might function in vivo as an immunosuppressant not only by inhibiting the expression of proinflammatory cytokines (e.g., interleukin 2), but also by stimulating the expression of TGF-β1, a potent immunosuppressive cytokine. Moreover, prevention of TGF-β1 hyperexpression might prevent CsA-associated renal fibrosis, as TGF-β1 is a fibrogenic cytokine.