Ito cells are the primary matrix-producing cells in the liver. In hepatic fibrosis in uiuo or culture on plastic, these cells undergo activation, a process characterized by cell proliferation, fibrogenesis, and smooth muscle a- actin expression. The cytosolic-binding proteins of cyclosporin A (CsA) and FK506 accelerate folding of various proteins including collagen and become inactivated by binding to those agents. C s A is shown to inhibit collagen synthesis in cultured fibroblasts. These findings prompted us to examine the effect of cyclosporin A and FK506 on Ito cell activation. CsA and FK506 reduced DNA synthesis in a dose-related manner, to 26% and 45% of controls at 5 pmollL, respectively, without affecting total protein synthesis. CsA reduced collagen synthesis in a dose-related manner, to 700/0 of controls at 5 pmoV L without affecting noncollagenous protein synthesis, whereas FK506 changed neither collagen synthesis nor noncollagenous protein synthesis. Moreover, smooth muscle a-actin expression was reduced by 0.5 pmollL CsA, but not by FK506. CsA merits consideration for the therapy of hepatic fibrosis. FK506 may also be a candidate for such therapy through inhibitory action on It0 cell proliferation. (HEPATOLOGY 1995;21:1161-1166.) Cyclosporin A (CsA) is a cyclic undecapeptide of fungal origin with potent immunosuppressive properties, and widely used to prevent graft rejection and to treat autoimmune disorders.' FK506 is a recently discovered immunosuppressive macloride produced by Streptomyces tsukubaensis and also used in organ transplantat i ~n . " ~
The cytosolic-binding proteins of both agents have been shown to be peptidyl-prolyl cis-truns-isome r a ~e . ~-~ This enzyme is known to accelerate rate-determining isomerization steps in the folding of oligopeptides and proteins such as immunoglobulin light chain, pancreatic RNase, and Its activity is proven to be completely inhibited when it binds to those agents in uitro. 5,6~10 In cultured human fibroblasts, CsA Abbreviations: CsA, cyclosporin A mRNA, messenger RNA.