In vivo hyperexpression of transforming growth factor-beta1 in mice: stimulation by cyclosporine.

BACKGROUND

We have demonstrated that cyclosporine (CsA) stimulates transforming growth factor (TGF) beta1 expression in vitro and that growth of mammalian cells can be arrested by CsA via a TGF-beta1-dependent mechanism. Herein, we have explored whether CsA stimulates TGF-beta1 hyperexpression in vivo.

METHODS

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.

RESULTS

CsA pretreatment augmented TGF-beta1 protein expression and increased intrarenal display of TGF-beta1 mRNA. This heightened TGF-beta1 expression was associated with an impaired T cell proliferative response.

CONCLUSIONS

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-beta1, a potent immunosuppressive cytokine. Moreover, prevention of TGF-beta1 hyperexpression might prevent CsA-associated renal fibrosis, as TGF-beta1 is a fibrogenic cytokine.