Transforming growth factor-beta initiates wound repair in rat liver through induction of the EIIIA-fibronectin splice isoform.
A prominent feature of the hepatic response to injury is production of a fetal isoform of fibronectin, a splice variant containing the EIIIA region, which appears very early after injury and derives from sinusoidal endothelial cells. Previous studies have shown that it is instrumental in initiating the cellular response to injury, specifically the conversion of resting stellate cells to myofibroblast-like cells. The present work describes the regulation of this change in fibronectin expression. Using sinusoidal endothelial cells from normal or injured liver in primary culture, we show that exogenous transforming growth factor beta (TGFbeta) stimulates [EIIIA]Fn expression. To assess the role of TGFbeta in vivo, we used a chimeric IgG containing the extracellular portion of the TGFbeta type II receptor as a competitive inhibitor of the cytokine. Administered to animals at the time of injury, the inhibitor reduced expression of [EIIIA]Fn mRNA by 50% as compared to controls (P < 0.01). There was a corresponding decrease in [EIIIA]Fn protein production as judged by immunohistochemistry. Cell fractionation experiments indicated that the changes observed in whole-liver extracts were localized to sinusoidal endothelial cells. We conclude that TGFbeta initiates wound repair in part by stimulating endothelial expression of [EIIIA]Fn. Results with the soluble inhibitor of the TGFbeta type II receptor suggest a novel strategy for modulating wound repair in vivo.
George
J
J
Liver Center and Department of Medicine, University of California, San Francisco, California 94143, USA.
Wang
S S
SS
Sevcsik
A M
AM
Sanicola
M
M
Cate
R L
RL
Koteliansky
V E
VE
Bissell
D M
DM
D000818:Animals; D019898:Autocrine Communication; D001652:Bile Ducts; D004274:DNA, Recombinant; D004727:Endothelium / Q000378:metabolism / Q000473:pathology; D005353:Fibronectins / Q000235:genetics*; D014644:Genetic Variation; D008026:Ligation; D008099:Liver / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology / Q000502:physiology; D008297:Male; D020033:Protein Isoforms / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D018125:Receptors, Transforming Growth Factor beta / Q000502:physiology; D016212:Transforming Growth Factor beta / Q000494:pharmacology* / Q000502:physiology; D015854:Up-Regulation; D014945:Wound Healing / Q000502:physiology*
D004274:DNA, Recombinant; D005353:Fibronectins; D020033:Protein Isoforms; D018125:Receptors, Transforming Growth Factor beta; D016212:Transforming Growth Factor beta