Retinoic acid induces corneal epithelial CYP4B1 gene expression and stimulates the synthesis of inflammatory 12-hydroxyeicosanoids

J Ocul Pharmacol Ther. 2004 Feb;20(1):65-74. doi: 10.1089/108076804772745473.


Injury to the ocular surface provokes an inflammatory response that is mediated, at least in part, by corneal epithelial derived 12-hydroxyeicosanoids (HETEs) including 12-HETE and 12-HETrE; both metabolites exhibit potent inflammatory and angiogenic properties and are formed by a cytochrome P450 (CYP) 4B1. Retinoids are known to mediate wound-healing processes in many tissues and, as such, are integral components of the inflammatory response. We studied the effect of various retinoids on corneal synthesis of 12-hydroxyeicosanoids and on activation of CYP4B1 gene expression. Corneal organ cultures were used to assess the effect of retinoic acid on epithelial metabolism of arachidonic acid to 12-hydroxyeicosanoids. Luciferase reporter vectors containing different lengths of the CYP4B1 3.4 kb-5'-untranslated region were used to examine the effect of vitamin D and retinoids (9-cis-retinoic acid and all-trans retinoic acid) on transcriptional activation of CYP4B1 in transient transfection experiments with HepG2 cells. Vitamin D had no effect on CYP4B1 promoter activity, but 9-cis and all-trans retinoic acids increased promoter activity by up to 70% over control. Addition of both 9-cis and all-trans retinoic acids resulted in an additive effect increasing promoter activity by 2-fold. The increased promoter activity correlated with the presence of RAR/RXR binding motifs. Incubation of corneal organ culture for 24 hours in the presence of 9-cis and all-trans retinoic acids increased the synthesis of 12-HETE and 12-HETrE by 2-fold. The finding that retinoic acid increases the expression of the CYP4B1 gene and enhances production of the inflammatory 12-hydroxyeicosanoids in the corneal epithelium may provide a linkage between wound healing and inflammation in the ocular surface.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Alitretinoin
  • Animals
  • Aryl Hydrocarbon Hydroxylases / genetics*
  • Cell Line, Tumor
  • Epithelium, Corneal / drug effects*
  • Epithelium, Corneal / enzymology
  • Female
  • Gene Expression / drug effects*
  • Humans
  • Hydroxyeicosatetraenoic Acids / biosynthesis*
  • Luciferases / genetics
  • Male
  • Organ Culture Techniques
  • Oxygen / metabolism
  • Plasmids
  • Polymerase Chain Reaction
  • Promoter Regions, Genetic / drug effects
  • Rabbits
  • Transcriptional Activation / genetics
  • Tretinoin / pharmacology*
  • Vitamin D / pharmacology


  • Hydroxyeicosatetraenoic Acids
  • Vitamin D
  • Alitretinoin
  • Tretinoin
  • Luciferases
  • Aryl Hydrocarbon Hydroxylases
  • cytochrome P-450 CYP4B1
  • Oxygen