Abstract
The appearance of myofibroblasts is generally thought to be the underlying cause of the fibrotic changes that underlie idiopathic pulmonary fibrosis. However, the cellular/molecular mechanisms that account for the fibroblast-myofibroblast differentiation/activation in idiopathic pulmonary fibrosis remain poorly understood. We investigated the functional role of hyaluronan receptor CD44V6 (CD44 containing variable exon 6 (v6)) for differentiation of lung fibroblast to myofibroblast phenotype. Increased hyaluronan synthesis and CD44 expression have been detected in numerous fibrotic organs. Previously, we found that the TGFβ1/CD44V6 pathway is important in lung myofibroblast collagen-1 and α-smooth-muscle actin synthesis. Because increased EGR1 (early growth response-1) expression has been shown to appear very early and nearly coincident with the expression of CD44V6 found after TGFβ1 treatment, we investigated the mechanism(s) of regulation of CD44V6 expression in lung fibroblasts by TGFβ1. TGFβ1-mediated CD44V6 up-regulation was initiated through EGR1 via ERK-regulated transcriptional activation. We showed that TGFβ1-induced CD44V6 expression is through EGR1-mediated AP-1 (activator protein-1) activity and that the EGR1- and AP-1-binding sites in the CD44v6 promoter account for its responsiveness to TGFβ1 in lung fibroblasts. We also identified a positive-feedback loop in which ERK/EGR1 signaling promotes CD44V6 splicing and found that CD44V6 then sustains ERK signaling, which is important for AP-1 activity in lung fibroblasts. Furthermore, we identified that HAS2-produced hyaluronan is required for CD44V6 and TGFβRI co-localization and subsequent CD44V6/ERK1/EGR1 signaling. These results demonstrate a novel positive-feedback loop that links the myofibroblast phenotype to TGFβ1-stimulated CD44V6/ERK/EGR1 signaling.
Highlights
The appearance of myofibroblasts is generally thought to be the underlying cause of the fibrotic changes that underlie idiopathic pulmonary fibrosis
transforming growth factor 1 (TGF1)-induced activation of ERK/EGR1 signaling depends on CD44V6 and stimulates CD44V6 expression—To investigate whether CD44v6 is important for activation of ERK/EGR1 signaling in response to specific cytokines, we examined the effects of TGF1 on human normal lung fibroblasts (HNLFbs)
To investigate whether CD44V6 is important for activation of ERK/EGR1 signaling in response to TGF1, we examined the effects of TGF1 on HNLFbs
Summary
The appearance of myofibroblasts is generally thought to be the underlying cause of the fibrotic changes that underlie idiopathic pulmonary fibrosis. Because increased EGR1 (early growth response-1) expression has been shown to appear very early and nearly coincident with the expression of CD44V6 found after TGF1 treatment, we investigated the mechanism(s) of regulation of CD44V6 expression in lung fibroblasts by TGF1. We identified a positive-feedback loop in which ERK/EGR1 signaling promotes CD44V6 splicing and found that CD44V6 sustains ERK signaling, which is important for AP-1 activity in lung fibroblasts. We identified that HAS2-produced hyaluronan is required for CD44V6 and TGFRI co-localization and subsequent CD44V6/ ERK1/EGR1 signaling These results demonstrate a novel positive-feedback loop that links the myofibroblast phenotype to TGF1-stimulated CD44V6/ERK/EGR1 signaling. Expression and regulation of CD44v6 are stimulated in response to the hepatocyte growth factor, in particular by the Ras/ERK pathway [10], or through activation of EGR1 [11] or AP-1 [12]. The role of EGR1 and/or AP-1 in TGF1-induced CD44V6 expression/activity has not been defined in any cell type
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
