TGF-β1 Induces Fibroblast Proliferation Partly Through Actibation of RaF/MEK/ERK Signaling Pathway by Inhibition of RAF-KINASE Inhibitor Protein Expression

The Raf-kinase inhibitor protein （RKIP） physically binds to Raf and MEK, and inhibits the Raf/MEK/ERK signaling pathway. Transforming growth factor （TGF）-β1 is a multifunctional cytokine that has a proliferative effect on fibroblasts. A considerable effort has been applied to studies of cell growth inhibition by TGF-β1, whereas far less attention has been given to the elucidation of the mechanism of TGF-β1-induced growth stimulation. In this study, we revealed that TGF-β1 significantly enhanced the proliferation of normal human dermal fibroblasts（ NHDFs）. In addition, we showed that TGF-β1 inhibited the expression of RKIP mRNA and protein. Moreover, a transfection experiment demonstrated that overexpression of RKIP significantly inhibited NHDF cell growth. These data point to a relationship between enhanced NHDF cell growth and reduction of RKIP expression by TGF-β1, suggesting that TGF-β1 may induce fibroblast proliferation partly through the inhibition of RKIP. Furthermore, we revealed that EGF and PDGF-BB, known activators of the Raf/MEK/ERK signal transduction pathway, failed to modulate RKIP expression. Finally, TGF-β1 induced a transient phosphorylation of ERK1/2. Although detailed mechanisms of NHDF proliferation via RKIP are yet unknown, it will be important to investigate the molecular status of RKIP in certain proliferative diseases, such as keloids, in which TGF-β1 has been reported to play a pathogenic role by inducing hyperproliferation of dermal fibroblasts