PENTOXIFYLLINE, PENTIFYLLINE, AND INTERFERONS DECREASE TYPE-I AND TYPE-III PROCOLLAGEN MESSENGER-RNA LEVELS IN DERMAL FIBROBLASTS - EVIDENCE FOR MEDIATION BY NUCLEAR FACTOR-1 DOWN-REGULATION
Mr. Duncan et al., PENTOXIFYLLINE, PENTIFYLLINE, AND INTERFERONS DECREASE TYPE-I AND TYPE-III PROCOLLAGEN MESSENGER-RNA LEVELS IN DERMAL FIBROBLASTS - EVIDENCE FOR MEDIATION BY NUCLEAR FACTOR-1 DOWN-REGULATION, Journal of investigative dermatology, 104(2), 1995, pp. 282-286
Pentoxifylline (PTX) is a methylxanthine that exhibits multiple biolog
ic activities, including the inhibition of collagen synthesis by derma
l fibroblasts. Because some PTX activities have recently been linked t
o transcription factor-mediated regulation of gene transcription, we h
ave investigated if PTX acts to inhibit collagen synthesis at a transc
riptional locus by measuring procollagen mRNA levels and by assaying f
or the presence of an activator fo procollagen gene promoters, nuclear
factor (NF)-1. The effects of another methylxanthine, pentifylline (P
TF), shown herein to be a tenfold more potent inhibitor of collagen sy
nthesis than PTX, and interferon-alpha, -beta, and -gamma were studied
in parallel. Analysis of extracellular protein and RNA from 48-h-trea
ted fibroblasts showed that PTX, PTF, and interferons decreased alpha
1(I), alpha 2(I), and alpha 1(III) procollagens by reducing the steady
-state levels of the corresponding procollagen mRNA transcripts. Reduc
tion of procollagen mRNA levels appeared to be dependent on new protei
n synthesis, as it was prevented by treatment with cycloheximide. Assa
y for the presence of nuclear NF-1 by gel mobility shift analysis show
ed that extracts from interferon, PTX, and PTF-treated fibroblasts lac
ked proteins recognizing the consensus DNA binding sequence for NF-1.
Taken together, these observations suggest interferons and methylxanth
ines may inhibit fibroblast collagen synthesis by a common mechanism r
equiring new protein synthesis that suppresses procollagen gene transc
ription through down-regulation of NF-1.