Thymosin-beta4 (Tbeta4) blunts PDGF-dependent phosphorylation and binding of AKT to actin in hepatic stellate cells.

摘要

Hepatic stellate cell transdifferentiation is a key event in the fibrogenic cascade. Therefore, attempts to prevent and/or revert the myofibroblastic phenotype could result in novel therapeutic approaches to treat liver cirrhosis. The expression of platelet-derived growth factor (PDGF)-beta receptor and the proliferative response to platelet-derived growth factor-betabeta (PDGF-betabeta) are hallmarks of the transdifferentiation of hepatic stellate cells (HSC). In this communication, we investigated whether thymosin-beta4 (Tbeta4), a chemokine expressed by HSC could prevent PDGF-BB-mediated proliferation and migration of cultured HSC. Using early passages of human HSC, we showed that Tbeta4 inhibited cell proliferation and migration and prevented the expression of PDGF-beta receptor (PDGF-betar), alpha-smooth muscle actin and alpha1(I) collagen mRNAs. Tbeta4 also inhibited the reappearance of PDGF-betar after its PDGF-BB-dependent degradation. These PDGF-dependent events were associated with the inhibition of AKT phosphorylation at both T308 and S473 amino acid residues. The lack of AKT phosphorylation was not due to the inhibition of PDGF-betar phosphorylation, the activation of phosphoinositide 3-kinase (PI3K), pyruvate dehydrogenase kinase isozyme 1 (PDK1), and mammalian target of rapamycin (mTOR). We found that PDGF-BB induced AKT binding to actin, and that Tbeta4 prevented this effect. Tbeta4 also prevented the activation of freshly isolated HSC cultured in the presence of Dulbecco's modified Eagle's medium or Dulbecco's minimal essential medium containing 10% fetal bovine serum. In conclusion, overall, our findings suggest that Tbeta4 by sequestering actin prevents binding of AKT, thus inhibiting its phosphorylation. Therefore, Tbeta4 has the potential to be an antifibrogenic agent.