Overexpression of c-Met and CD44v6 receptors contributes to autocrine TGF {beta}1 signaling in interstitial lung disease [Molecular Bases of Disease]
December 9th, 2013 by Ghatak, S., Bogatkevich, G. S., Atanelishvili, I., Akter, T., Feghali-Bostwick, C. A., Hoffman, S., Fresco, V. M., Fuchs, J. C., Visconti, R. P., Markwald, R. R., Padhye, S. B., Silver, R. M., Hascall, V. C., Misra, S.
The hepatocyte growth factor (HGF) and the HGF receptor Met pathway are important in the pathogenesis of interstitial lung disease (ILD). Alternatively spliced isoforms of CD44 containing variable exon 6 (CD44v6) and its ligand hyaluronan (HA), alter cellular function in response to interaction between CD44v6 and HGF. TGF β1 is the crucial cytokine that induces fibrotic action in ILD-fibroblasts (ILDFbs). We have identified an autocrine TGF β1-signaling that upregulates both Met and CD44v6 mRNA and protein expression. Western blot analysis, flow cytometry and immunostaining revealed that CD44v6 and Met colocalize in fibroblasts and in tissue sections from ILD patients and in lungs of bleomycin-treated mice. Interestingly, cell proliferation induced by TGF β1 is mediated through Met and CD44v6. Further, cell proliferation mediated by TGF β1/CD44v6 is Erk dependent. In contrast, action of Met on ILDFb proliferation does not require Erk, but does require p38MAPK. ILDFbs were sorted into CD44v6+/Met+ and CD44v6-/Met+ subpopulations. HGF inhibited TGF β1-stimulated collagen-1 and α-smooth muscle actin (α-SMA) expression in both of these subpopulations by interfering with TGF β1 signaling. HGF alone markedly stimulated CD44v6 expression that in turn regulated collagen-1 synthesis. Our data with primary lung fibroblast cultures with respect to collagen-1, CD44v6 and Met expressions were supported by immunostaining of lung sections from bleomycin treated mice and from ILD patients. These results define the relationships between CD44v6, Met and autocrine TGF β1 signaling, and the potential modulating influence of HGF on TGF β1-induced CD44v6 dependent fibroblast function in ILD fibrosis.