TGFbeta mediated transition of corneal fibroblasts from a proinflammatory state to a profibrotic state through modulation of histone acetylation.
Corneal fibroblasts exhibit different phenotypes in different phases of corneal wound healing. In the inflammatory phase, the cells assume a proinflammatory phenotype and produce large amounts of cytokines and chemokines, but in the proliferative and remodeling phases, they adapt a profibrotic state, differentiate into myofibroblasts and increase extracellular matrix protein synthesis, secretion, and deposition. In the present study, the molecular mechanisms regulating the transition of corneal fibroblasts from the proinflammatory state to the profibrotic state were investigated. Corneal fibroblasts were treated with TGFbeta, a known profibrotic and anti-inflammatory factor in wound healing, in the absence or presence of trichostatin A (TSA), a histone deacetylase (HDAC) inhibitor. The results revealed that TGFbeta induced the profibrotic transition of corneal fibroblasts, including increased extracellular matrix synthesis, morphological changes, and assembly of actin filaments. Meanwhile, proinflammatory gene expressions of corneal fibroblasts were down-regulated with the treatment of TGFbeta, as confirmed by cDNA microarray, real time PCR and ELISA. Moreover, TSA reversed the TGFbeta-mediated transition of corneal fibroblasts from the proinflammatory state to the profibrotic state, as accompanied by histone hyperacetylations. In conclusion, TGFbeta suppressed the production of proinflammatory factors and enhanced the expression of matrix remodeling genes of corneal fibroblasts in the transition from the proinflammatory state to the profibrotic state, and the dual roles of TGFbeta on the phenotype regulations of corneal fibroblasts were mediated by altered histone acetylation.
Zhou
Qingjun
Q
State Key Laboratory Cultivation Base, Shandong Provincial Key Laboratory of Ophthalmology, Shandong Eye Institute, Qingdao, China.
Yang
Lingling
L
Wang
Yao
Y
Qu
Mingli
M
Chen
Peng
P
Wang
Ye
Y
Xie
Lixin
L
Zhao
Jing
J
Wang
Yiqiang
Y
D000107:Acetylation; D008841:Actin Cytoskeleton / Q000378:metabolism; D048430:Cell Shape; D054338:Cell Transdifferentiation; D002478:Cells, Cultured; D003315:Cornea / Q000378:metabolism* / Q000473:pathology; D004797:Enzyme-Linked Immunosorbent Assay; D016326:Extracellular Matrix Proteins / Q000096:biosynthesis; D005347:Fibroblasts / Q000378:metabolism* / Q000473:pathology; D005355:Fibrosis; D020869:Gene Expression Profiling / Q000379:methods; D005786:Gene Expression Regulation; D051548:Histone Acetyltransferases / Q000378:metabolism; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology; D006657:Histones / Q000378:metabolism*; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology; D007249:Inflammation / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D018836:Inflammation Mediators / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis; D010641:Phenotype; D016133:Polymerase Chain Reaction; D016212:Transforming Growth Factor beta / Q000378:metabolism*
D016326:Extracellular Matrix Proteins; D056572:Histone Deacetylase Inhibitors; D006657:Histones; D006877:Hydroxamic Acids; D018836:Inflammation Mediators; D016212:Transforming Growth Factor beta; C012589:trichostatin A; D051548:Histone Acetyltransferases