Phorbol ester-induced inhibition of collagen accumulation by human lung fibroblasts.
The effect of phorbol 12-myristate 13-acetate (PMA) on collagen accumulation by human embryonic lung fibroblasts was determined. PMA (10 nM) dramatically inhibited collagen formation in cultures that were unstimulated or stimulated with transforming growth factor-beta (TGF-beta). Collagen accumulation was decreased by 50% in unstimulated cultures and by 80% in TGF-beta-treated cultures. This inhibition was associated with a marked decrease in steady-state levels for alpha 1(I) collagen mRNA and decreases in alpha 1(I) gene transcription as determined by nuclear run-off assays. The PMA-mediated decrease in alpha 1(I) collagen mRNA was not affected by the addition of cycloheximide or indomethacin. Prolonged treatment with PMA (100 nM) resulted in down-regulation of protein kinase C (PKC) activity to less than 3% of untreated cultures. When PKC activity was down-regulated, treatment with PMA did not block TGF-beta-stimulated collagen formation, and prostaglandin E2-induced inhibition of protein formation was still evident. These results suggests that PKC activity modulates the level of transcription of collagen genes and collagen accumulation in lung fibroblast cultures.
Goldstein
R H
RH
Pulmonary Center, Boston University School of Medicine, Massachusetts.
Fine
A
A
Farnsworth
L J
LJ
Poliks
C
C
Polgar
P
P
D002460:Cell Line; D003094:Collagen / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics*; D003513:Cycloheximide / Q000494:pharmacology; D015232:Dinoprostone / Q000494:pharmacology; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism; D006657:Histones / Q000235:genetics; D006801:Humans; D007213:Indomethacin / Q000494:pharmacology; D007700:Kinetics; D008168:Lung / Q000378:metabolism*; D012333:RNA, Messenger / Q000187:drug effects / Q000235:genetics; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D014158:Transcription, Genetic / Q000187:drug effects; D015291:Transforming Growth Factors / Q000494:pharmacology
D006657:Histones; D012333:RNA, Messenger; D015291:Transforming Growth Factors; D003094:Collagen; D003513:Cycloheximide; D015232:Dinoprostone; D013755:Tetradecanoylphorbol Acetate; D007213:Indomethacin