Imunoterapia: acesso aberto
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Abstrato

The Effect of Histone Deacetylase Inhibitor Trichostatin A on IL- 17A-Induced Transformation of MRC5 into Myofibroblasts and its Mechanism

Shuo Li*, Jie Cao*,Qian Zhang, Zexin Guo, Jing Zhang, Wei Zhou, Yueqing Wu, Lixia Dong, Jing Feng

Objective: To elucidate potential IL-17A- and TSA-mediated regulation of fibroblasts transformation.

Method: MTT assay, HDAC1 activity assay, cell immunofluorescence and Western blot were employed to detect the expression of related indicators.

Results: MRC5 cells expressed only a small amount of Vimentin. IL-17A treatment up regulated MRC5 cell proliferation, in a concentration-dependent manner. TSA treatment, however, suppressed MRC5 cell proliferation. IL-17A treatment also upregulated HDAC1 activity in MRC5 cells, in a concentration-dependent manner. Using immunofluorescence, we demonstrated that IL-17A-treated MRC5 cells had markedly elevated Vimentin, Collagen-I and a-SMA levels, compared to controls. However, a combined treatment of IL-17A and TSA resulted in markedly reduced levels of the Vimentin, Collagen-I and a-SMA, compared to IL-17A alone, yet the amount was higher than controls. Using western blot analysis, we also revealed that the IL-17A-treated MRC5 cells had markedly elevated levels of Vimentin, a-SMA, HDAC1, p-Smad2, and p-Smad3, and markedly reduced level of Smad7, compared to controls. In TSA intervention group, the expression effect of the above protein was opposite. Moreover, no discernible difference was observed in the levels of Smad2 and Smad3 among the treated and un-treated groups.

Conclusion: IL-17A stimulates proliferation of MRC5 cells and increases HDAC1 activity and protein expression. It also transforms MRC5 cells into myofibroblasts via activation of the TGF-β1/Smads signaling network. TSA, on the other hand, strongly suppresses TGF -β1/Smads pathway-mediated fibrosis by ceasing HDAC1 activity and protein expression.