Retinoic acid inhibition of transforming growth factor-beta-induced collagen production by human lung fibroblasts.
Transforming growth factor-beta (TGF-beta)-stimulated collagen production plays an important role in the pathogenesis of the fibrotic response seen in chronic inflammatory lung disorders. Retinoids are vitamin A analogues that are potent immunomodulators and have been shown to modulate stromal cell collagen production in a variety of nonpulmonary systems. We hypothesized that retinoids might also modulate lung fibroblast collagen production. To test this hypothesis, we determined whether all-trans retinoic acid (RA) and several other retinoid compounds regulate the production of types I and III collagen by unstimulated and TGF-beta 1-stimulated human lung fibroblasts. Unstimulated cells produced modest quantities of types I and III collagen, and TGF-beta 1 increased the production of these matrix molecules 2- to 4-fold. Preincubation with 10(-5) M RA caused a significant decrease in the basal levels of types I and III collagen produced by these cells. RA preincubation also totally abrogated the collagen inductive effects of TGF-beta 1. At 10(-5) M, RA preincubation caused a 97% decrease in the stimulation of type I collagen and a 115% decrease in the stimulation of type III collagen caused by TGF-beta 1. These inhibitory effects were dose dependent. Significant inhibition of type I and III collagen production was appreciated with doses of RA as low as 10(-9) and 10(-8), respectively. These inhibitory effects were not unique to RA since 13-cis-retinoic acid, 9-cis-retinoic acid, etretinate, all-trans etretin, and the water-soluble retinoids, retinoyl beta-glucuronide and retinyl-beta-glucuronide, also inhibited TGF-beta 1-stimulated type I collagen production.(ABSTRACT TRUNCATED AT 250 WORDS)
Redlich
C A
CA
Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut 06510-8057.
Delisser
H M
HM
Elias
J A
JA
D002460:Cell Line; D002478:Cells, Cultured; D003094:Collagen / Q000096:biosynthesis*; D005347:Fibroblasts / Q000378:metabolism; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D066298:In Vitro Techniques; D017370:Interleukin-11 / Q000235:genetics; D008168:Lung / Q000166:cytology / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics; D014158:Transcription, Genetic / Q000187:drug effects; D016212:Transforming Growth Factor beta / Q000494:pharmacology*; D014212:Tretinoin / Q000494:pharmacology*
D017370:Interleukin-11; D012333:RNA, Messenger; D016212:Transforming Growth Factor beta; D014212:Tretinoin; D003094:Collagen