Journal
MOLECULAR PHARMACEUTICS
Volume 6, Issue 3, Pages 772-779Publisher
AMER CHEMICAL SOC
DOI: 10.1021/mp9000469
Keywords
siRNA; shRNA; transforming growth factor beta 1 (TGF-beta 1); hepatic stellate cells; liver fibrosis
Funding
- NIH [R01 EB003922, R01 DK064633]
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Small interfering RNA (siRNA) and short hairpin RNA (shRNA) targeting different regions of transforming growth factor beta 1 (TGF-beta 1) mRNA were designed and the silencing effect was determined after transfection into immortalized rat liver stellate cells (HSC-T6). There was not only significant decrease in TGF-beta 1, tissue inhibitor of metalloproteinase 1 (TIMP-1), alpha-smooth muscle actin (alpha-SMA) and type 1 collagen after transfection with TGF-beta 1 siRNAs, but also synergism in gene silencing when siRNAs targeting two different start sites were used as a pool for transfection. The two siRNA sequences which efficiently inhibited TGF-beta 1 gene expression were converted to shRNAs via cloning into the pSilencer1.0. There was significant decrease in TGF-beta 1 and TIMP-1 when HSC-T6 cells were transfected with pshRNA targeting the same regions of TGF-beta 1 mRNA as siRNAs. Furthermore, TGF-beta 1 gene silencing in HSC-T6 cells significantly decreased the levels of inflammatory cytokines, such as tumor necrosis factor-alpha (TNF-alpha) and interleukin-1 beta (IL-1 beta). In conclusion, both siRNA and shRNA showed sequence-specific and dose dependent TGF-beta 1 gene silencing and have the potential to treat liver fibrosis.
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