u-0126 and halofuginone

Halofuginone, an alkaloid isolated from the plant Dichroa febrifuga, has been shown to be a potent inhibitor of tissue fibrosis. We herein demonstrate that, at concentrations below 10(-7) M, halofuginone does not affect the cell cycle but efficiently induces extracellular signal-regulated kinases(1,2) (ERK(1,2)), p38 and Jun NH2-terminal kinases(1,2) (JNK(1,2)) phosphorylation. In addition, at these non cytotoxic concentrations, halofuginone diminishes the capacity of fibroblasts to contract mechanically unloaded collagen lattices, an effect that is specifically blocked by the ERK inhibitors PD98059 and U0126, not by inhibitors of the JNK or p38 pathways. These data thus indicate that the inhibitory effect of halofuginone on fibroblast contractile activity, a key function for wound healing implicated in the development of tissue fibrosis, is an ERK-mediated mechanism.

Topics: Blotting, Western; Butadienes; Cell Line; Cell Proliferation; Cell Survival; Collagen Type I; Dose-Response Relationship, Drug; Extracellular Matrix; Extracellular Signal-Regulated MAP Kinases; Fibroblasts; Flavonoids; Humans; Imidazoles; MAP Kinase Signaling System; Nitriles; p38 Mitogen-Activated Protein Kinases; Phosphorylation; Piperidines; Protein Synthesis Inhibitors; Pyridines; Quinazolinones; Time Factors