CYCLOSPORIN A ACTIVATES TGF-/SMAD SIGNALING PATHWAY IN RAT LIVER

Cyclosporin A (CsA) is one of the most important immunosuppressive agents and therefore is widely used in organ transplantation. However, the clinical use of CsA is strongly limited by several side effects including hepatotoxicity which remains a major clinical problem. Transforming growth factor-b (TGF-b) and downstream Smad signaling pathways have been found to play an important role in liver fibrosis via induction of profibrotic genes such as tissue inhibitors of matrix metallproteinases-1 (TIMP-1), and connective tissue growth factor (CTGF). The present work demonstrates that treatment of animals with CsA causes a rapid activation of TGF-b/Smad signalingcascade in rat liver as demonstrated by an increase in plasma TGFb level and Smad-2 phosphorylation. Activation of TGF-b/Smad signalingcascade was accompanied by activation of Smad-dependent expression of TIMP-1and CTGF. However, concomitant administration of neutralizing anti-TGF-b antibody markedly reduced Smad-2 phosphorylation as well as CTGF and TIMP-1 expression induced by CsA. Furthermore, it was found that administration of the antioxidant N-acetyl cysteine (NAC) along with CsA significantly reduced plasma TGF-b level, Smad-2 phosphorylation as well as CTGF and TIMP-1 expression. These data demonstrates for the first time that administration of CsA causes a rapid activation of TGF-b/Smad signaling pathway and subsequent CTGF and TIMP-1 expression in rat liver.