TGFβ Mediated Proinflammatory-To-Profibrotic State Transition of Corneal Fibroblasts Through Modulation of Histone Acetylation

Abstract

 

Purpose:

 

Corneal fibroblasts exhibit different phenotypes in differentphases of corneal wound healing. In the inflammatory phase,the cells assume a proinflammatory phenotype and produce largeamounts of cytokines and chemokines, but in the proliferativeand remodeling phases, the cells adapt a profibrotic state asindicated by differentiation into myofibroblasts and increasedextracellular matrix protein synthesis, secretion and deposition.In the present study, the molecular mechanisms underlying suchtransition of corneal fibroblasts were investigated.

 

Methods:

 

Corneal fibroblasts were prepared from human corneas and treatedwith TGFβ, a known profibrotic and anti-inflammatory factorin wound healing, in the absence or presence of trichostatinA (TSA), a histone deacetylase (HDAC) inhibitor.

 

Results:

 

TGFβ induced corneal fibroblasts to gain a profibroticstatus as shown by increased extracellular matrix synthesis,morphological changes and assembly of actin filaments. cDNAmicroarray, real time PCR and ELISA assay revealed that proinflammatorygene expressions of corneal fibroblasts were downregulated inTGFβ-treated cells. Moreover, TSA reversed the TGFβ-mediatedproinflammatory-to-profibrotic transition of corneal fibroblastsas well as the histone deacetylations induced by TGFβ.

 

Conclusions:

 

TGFβ suppressed the production of proinflammatory factorsand enhanced the expression of matrix remodeling genes duringthe proinflammatory-to-profibrotic state,transition of cornealfibroblasts, and the roles of TGFβ on corneal fibroblastsmight be mediated by modulating histone acetylation.  

 

 

Keywords: cornea: stroma and keratocytes • cornea: basic science • wound healing