Inhibition of collagen type I synthesis by skin fibroblasts of graft versus host disease and scleroderma patients: effect of halofuginone.
The effect of halofuginone (a plant alkaloid) on collagen alpha 1(I) gene expression and collagen synthesis was evaluated in human skin fibroblasts from patients with chronic graft-versus-host disease (cGvHD) or scleroderma and from a normal individual. Halofuginone caused a dose-dependent inhibition in collagen alpha 1(I) gene expression and collagen synthesis in all cultures tested, the cGvHD fibroblasts being the least sensitive. In normal and scleroderma fibroblasts, concentrations of halofuginone as low as 10(-10) M and 10(-9) M were sufficient to cause a significant reduction in collagen alpha 1(I) gene expression and collagen synthesis, respectively. In addition, halofuginone also inhibited the transforming growth factor beta-induced collagen synthesis. Three days after halofuginone removal, collagen gene expression returned to control levels. The reduction of collagen mRNA transcript levels by halofuginone appeared to be dependent on new protein synthesis because simultaneous treatment of fibroblasts with protein synthesis inhibitors prevents the suppressive effect of halofuginone on collagen alpha 1(I) mRNA gene expression. The ability of extremely low concentrations of halofuginone to inhibit collagen alpha 1(I) synthesis specifically and transiently at the transcriptional level suggests that this material may be an important tool for studying collagen alpha 1(I) gene regulation and may be used as a novel and promising antifibrotic therapy.
Halevy
O
O
Department of Animal Science, Faculty of Agriculture, Hebrew University of Jerusalem, Rehovot, Israel.
Nagler
A
A
Levi-Schaffer
F
F
Genina
O
O
Pines
M
M
D000328:Adult; D003049:Coccidiostats / Q000494:pharmacology*; D003094:Collagen / Q000096:biosynthesis / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D005260:Female; D005347:Fibroblasts / Q000187:drug effects*; D006086:Graft vs Host Disease / Q000188:drug therapy*; D006801:Humans; D008875:Middle Aged; D010880:Piperidines; D011799:Quinazolines / Q000494:pharmacology*; D052999:Quinazolinones; D013997:Time Factors
D003049:Coccidiostats; D010880:Piperidines; D011799:Quinazolines; D052999:Quinazolinones; D003094:Collagen; C010176:halofuginone