Promoter competitors as novel antifibrotics that inhibit transforming growth factor-β induction of collagen and noncollagen protein synthesis in fibroblasts
✍ Scribed by Natalie T. Meisler; Jen-Fu Chiu; Kenneth R. Cutroneo
- Publisher
- John Wiley and Sons
- Year
- 1999
- Tongue
- English
- Weight
- 201 KB
- Volume
- 75
- Category
- Article
- ISSN
- 0730-2312
No coin nor oath required. For personal study only.
✦ Synopsis
A single-stranded 27-mer phosphorothioate oligodeoxynucleotide (ssPT) containing the transforming growth factor- (TGF-) response element was synthesized. Rat fetal lung fibroblasts were stably transfected with the ColCat 3.6 plasmid, which contains a portion of the 5Ј-flanking region of the pro␣1(I) collagen gene linked to the chloramphenicol acetyltransferase (CAT) gene. The cells were transiently transfected with the modified oligodeoxynucleotides in both the presence and absence of bleomycin, a fibrogenic antineoplastic agent. At 50 µg ssPT, the bleomycininduced increase in CAT activity was abrogated. The ability of ssPT to inhibit collagen synthesis in rat fetal lung fibroblasts was determined. Single-stranded PTs inhibited both collagen synthesis and noncollagen protein synthesis induced by TGF-1, the mediator of the bleomycin fibrogenic effect. Inflamed granulation tissue fibroblasts were prepared from polyvinyl alcohol sponges implanted in the backs of rats. These fibroblasts were treated with various doses of ssPTs in the presence and absence of TGF-1. Single-stranded PTs also blocked both the TGF-1-induced increase in collagen synthesis and noncollagen synthesis in these fibroblasts. However, the TGF-1-induced increase in collagen and noncollagen protein synthesis was not blocked by ssPTs containing a mutated TGF- response element. In addition, ssPT did not significantly alter the basal levels of collagen and noncollagen protein synthesis in rat lung fibroblasts or in granuloma derived fibroblasts. Since dexamethasone was also able to block the TGF-1-induced increase in collagen and noncollagen protein synthesis (Meisler et al., [1997]