Inhibition of type III TGF-β receptor aggravates lung fibrotic process

Transforming growth factor-beta (TGF-beta) is a multifunctional cytokine that regulates cell proliferation, death, development or differentiation. In addition, TGF-beta is considered a key mediator in fibrogenic processes, and signals either directly or indirectly through types I, II and III (T beta RI, II, and III) receptor complexes. The type III TGF-beta (T-beta RIII or betaglycan) is a transmembrane proteoglycan without a functional kinase domain, and is considered as a coreceptor to increase the affinity of ligand binding to T beta RII. Little is studied on TGF-beta and T beta RIII (or betaglycan) signaling, while it is well known about TGF-beta ligand and T beta RII signaling. In this study, we investigated the effects of T beta RIII expression on TGF beta induced differentiation, in view of the finding that T beta RIII is significantly downregulated during TGF-beta-induced differentiation in fibroblasts. TGF-beta induced alpha-SMA and Procollagen Type I expression were markedly inhibited in fibroblasts stably expressing T beta RIII. Endogenous T beta RIII expression did not alter the T beta RI or TpRII levels, but inhibited Smad 2/3, Akt and ERK phosphorylation. The molecular mechanism of T beta RIII action in TGF-beta-induced differentiation is associated with both Smad-dependent and Smad-independent pathways. Our results suggest that T beta RIII is a novel molecular target for regulation of TGF-beta signaling in myofibroblast differentiation. (C) 2010 Elsevier Masson SAS. All rights reserved.