Interleukin-1 stimulates and all-trans-retinoic acid inhibits collagenase gene expression through its 5' activator protein-1-binding site

Mol Endocrinol. 1990 Jul;4(7):973-80. doi: 10.1210/mend-4-7-973.


Collagenase production by synovial fibroblast-like cells (synoviocytes) plays a major role in cartilage and bone destruction in rheumatoid arthritis. Interleukin-1 (IL-1) increases collagenase secretion by elevating the steady state levels of collagenase mRNA in cultured rheumatoid synoviocytes, while all-trans-retinoic acid (RA) has the opposite effect. We have studied the regulation of collagenase gene transcription by IL-1 and RA in synoviocytes by transient transfection of plasmid constructs containing deletion mutants of the 5'-flanking region of the collagenase gene or the isolated phorbol ester-responsive element ligated to a chloramphenicol acetyltransferase reporter gene. We show that the phorbol ester-responsive element of the collagenase gene mediates both positive and negative regulatory effects, respectively, of IL-1 and RA on transcription. In addition, we show that IL-1 and 12-O-tetradecanoyl-phorbol-13-acetate transiently induce c-jun and c-fos expression and that retinoic acid inhibits IL-1 and 12-O-tetradecanoyl-phorbol-13-acetate induction of c-fos, but not c-jun. These results suggest that RA inhibits collagenase transcription at least in part through inhibition of c-fos.

MeSH terms

  • Binding Sites / drug effects
  • Cells, Cultured
  • DNA-Binding Proteins / metabolism
  • Epithelium / drug effects
  • Epithelium / enzymology
  • Gene Expression Regulation
  • Humans
  • Interleukin-1 / pharmacology*
  • Kinetics
  • Microbial Collagenase / biosynthesis
  • Microbial Collagenase / genetics*
  • Promoter Regions, Genetic
  • Proto-Oncogene Proteins / metabolism
  • Proto-Oncogene Proteins c-fos
  • Proto-Oncogene Proteins c-jun
  • RNA, Messenger / metabolism
  • Synovial Membrane / enzymology*
  • Tetradecanoylphorbol Acetate / pharmacology
  • Transcription Factors / metabolism
  • Tretinoin / pharmacology*


  • DNA-Binding Proteins
  • Interleukin-1
  • Proto-Oncogene Proteins
  • Proto-Oncogene Proteins c-fos
  • Proto-Oncogene Proteins c-jun
  • RNA, Messenger
  • Transcription Factors
  • Tretinoin
  • Microbial Collagenase
  • Tetradecanoylphorbol Acetate