Diverse signaling pathways regulate fibroblast differentiation and transformation through Rho kinase activation

Publisher Website
Google Scholar
Abstract
This study examined the role of agonist‐induced Rho kinase (ROCK) involvement in the morphological outcome of pulmonary‐derived fibroblasts. Normal human lung fibroblasts (NHLF) spontaneously differentiate into network‐like structures in a two‐dimensional growth factor reduced Matrigel matrix‐based assay. Sphingosine 1‐phosphate (SPP), a bioactive phospholipid that regulates angiogenesis, inhibited fibroblast morphogenesis in a dose‐dependent manner, virtually eliminating the presence of multi‐cellular structures at 500 nM. Pretreatment with the Rho kinase‐specific inhibitor, H1152, eradicated the high dose SPP‐induced inhibition. Similarly, NHLFs transfected with Rho kinase siRNA prevented SPP‐induced inhibition of the fibroblast morphogenesis. Alternatively, transforming growth factor‐β1 (TGF‐β1), a cytokine recognized as a key mediator of wound healing, terminally differentiates NHLF into myofibroblasts as evidenced by the expression of the smooth muscle cell isoform of α‐actin (α‐SMA). H1152 suppressed TGF‐β1‐induced α‐SMA expression in a dose‐dependent manner. Similarly, treatment with Rho kinase siRNA reduced α‐SMA expression by greater than 50%. SPP treatment had no effect on TGF‐β1‐induced transformation into myofibroblasts, and TGF‐β1 treatment did not alter fibroblast morphogenesis. This study suggests a dual regulatory role for Rho kinase in cellular regulation of fibroblasts in which SPP‐induced Rho kinase activation via a G‐protein coupled receptor suppresses fibroblast morphogenesis while TGF‐β1‐induced Rho kinase activation through a serine/threonine kinase receptor culminates in transformation into myofibroblasts. J. Cell. Physiol. 211: 353–363, 2007.

This publication has 39 references indexed in Scilit: