ABSTRACT
Transforming growth factor-beta (TGF-beta), a multifunctional cytokine which is involved in extracellular matrix modulation, has a major role in the pathogenesis and progression of fibrotic diseases. We now report the effects of ursolic acid on TGF-beta1 receptor binding and TGF-beta1-induced cellular functions in vitro. Ursolic acid inhibited [(125)I]-TGF-beta1 receptor binding to Balb/c 3T3 mouse fibroblasts with an IC(50) value of 6.9+/-0.8 microM. Ursolic acid dose-dependently recovered reduced proliferation of Minc Mv1Lu cells in the presence of 5 nM of TGF-beta1 and attenuated TGF-beta1-induced collagen synthesis and production in human fibroblasts. Molecular dynamics simulations suggest that ursolic acid may interact with the hydrophobic region of the dimeric interface and thereby inhibit the binding of TGF-beta1 to its receptor. All these findings taken together show that ursolic acid functions as an antagonist for TGF-beta1. This is the first report to show that a small molecule can inhibit TGF-beta1 receptor binding and influence functions of TGF-beta1.
Subject(s)
Transforming Growth Factor beta/antagonists & inhibitors , Triterpenes/pharmacology , Animals , BALB 3T3 Cells , Cell Division/drug effects , Cells, Cultured , Collagen Type I/biosynthesis , Dose-Response Relationship, Drug , Epithelial Cells/cytology , Epithelial Cells/metabolism , Fibroblasts/metabolism , Humans , Lung/cytology , Mice , Mink , Models, Molecular , Proline/metabolism , Radioligand Assay , Recombinant Proteins/antagonists & inhibitors , Recombinant Proteins/genetics , Recombinant Proteins/metabolism , Thymidine/metabolism , Transforming Growth Factor beta/genetics , Transforming Growth Factor beta/metabolism , Transforming Growth Factor beta/pharmacology , Transforming Growth Factor beta1 , Ursolic AcidABSTRACT
The mechanism of action of the aerial parts of Clerodendranthus spicatus (Thunb.) C.Y. Wu, [syn. Orthosiphon aristatus (Blume) Miq,] a medicinal plant used in China to treat human renal disease, was investigated. The aqueous and methanol crude extracts exhibited dose-dependent inhibitory activity on 125I-TGF-beta1 binding to its receptor in Balb/c 3T3 cells. Subsequent bioassay-guided fractionation led to identification of two known triterpenoidal constituents, ursolic and oleanolic acids. Ursolic and oleanolic acids inhibited the binding of 125I-TGF-beta1 to its receptor with IC 50 values of 6.9 +/- 0.8 and 21.0 +/- 2.3 microM, respectively. The results suggest that TGF-beta1 antagonistic activity is responsible, at least in part, for the therapeutic efficacy of this plant to treat humans with renal disease.