Abstract
Idiopathic pulmonary fibrosis (IPF) is a disease of progressive scarring caused by excessive extracellular matrix (ECM) deposition and activation of α-SMA-expressing myofibroblasts. Human antigen R (HuR) is an RNA binding protein that promotes protein translation. Upon translocation from the nucleus to the cytoplasm, HuR functions to stabilize mRNA to increase protein levels. However, the role of HuR in promoting ECM production, myofibroblast differentiation and lung fibrosis is unknown. Human lung fibroblasts (HLFs) treated with TGFβ1 showed a significant increase in translocation of HuR from the nucleus to the cytoplasm. TGF-β-treated HLFs that were transfected with HuR siRNA had a significant reduction in α-SMA protein as well as the ECM proteins COL1A1, COL3A and FN1. HuR was also bound to mRNA for
ACTA2, COL1A1, COL3A1
and
FN
. HuR knock-down affected the mRNA stability of
ACTA2
but not that of the ECM genes
COL1A1, COL3A1
or
FN
. In mouse models of pulmonary fibrosis, there was higher cytoplasmic HuR in lung structural cells compared to control mice. In human IPF lungs, there was also more cytoplasmic HuR. This study is the first to show that HuR in lung fibroblast controls their differentiation to myofibroblasts and consequent ECM production. Further research on HuR could assist in establishing the basis for the development of new target therapy for fibrotic diseases such as IPF.