A conserved TGFβ1/HuR feedback circuit regulates the fibrogenic response in fibroblasts

Persistent fibroblast activation in wound repair is believed to be the key reason for fibrosis and transforming growth factor (TGF)beta is considered as one of the key mediators for the fibrogenic response, with the detailed mechanism largely unknown. Here we found that TGF beta 1 treatment could induce a significant increase of endogenous TGF beta 1 expression by enhancing the mRNA stability in cardiac fibroblasts. Further study revealed that TGF beta 1 treatment translocated the nuclear HuR into cytoplasm, which in turn bound the ARE in the 3'UTR of TGF beta 1 and increased the mRNA stability as seen from the RNA-IP and reporter assay. Knockdown of HuR decreased the endogenous expression of TGF beta 1 under exogenous TGF beta 1 treatment, simultaneously with the decrease of Con a, Col3a and fibronectin expression. Our study here established a TGF beta 1/HuR feedback circuit regulating the fibrogenic response in fibroblasts, and targeting this feedback loop is of great potential to control fibrosis. (c) 2012 Elsevier Inc. All rights reserved.