All-trans retinoic acid enhances differentiation and influences permeability of intestinal Caco-2 cells under serum-free conditions

Dev Growth Differ. 2004 Dec;46(6):503-14. doi: 10.1111/j.1440-169x.2004.00765.x.


Vitamin A and retinoids are essential nutrients for the differentiation of epithelia. Vitamin A deficiency is accompanied by an impairment in intestinal integrity. We investigated whether retinoids influence the differentiation and permeability of Caco-2 cells under serum-free culture conditions as a model for the intestinal epithelium. Treatment of the Caco-2 cells with retinoic acids (RA) resulted in an increased specific activity, enhanced mRNA expression, and induction of the 5'-flanking promoter activity of the marker enzyme for the differentiation intestinal alkaline phosphatase. Surprisingly, permeability of the Caco-2 monolayer, as measured by transepithelial electric resistance and [3H]-mannitol flux, was found to be enhanced by RA. Treatment with RA had only a slight effect on the mRNA expression of the tight junction-associated proteins occludin, ZO-1, claudin-1, -3, and -4, but enhanced the expression of claudin-2, which was recently suggested to form a paracellular ion channel. The role of retinoids as potent inducers of epithelial differentiation was confirmed for the Caco-2 cells under serum-free culture conditions and it was concluded that IAP is a target gene of RA. The inverse regulation of the permeability by RA under these serum-free conditions showed that other mechanisms, which are essential to regulate intestinal epithelial integrity with respect to decreased permeability, have to be identified.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alkaline Phosphatase / genetics
  • Alkaline Phosphatase / metabolism
  • Caco-2 Cells
  • Cell Differentiation / drug effects
  • Cell Differentiation / physiology
  • Cell Membrane Permeability / drug effects
  • Culture Media, Serum-Free
  • Humans
  • Intestinal Mucosa / cytology*
  • Intestinal Mucosa / drug effects
  • Intestinal Mucosa / metabolism*
  • Membrane Proteins / metabolism
  • RNA, Messenger / analysis
  • RNA, Messenger / metabolism
  • Tight Junctions / drug effects
  • Tight Junctions / metabolism
  • Tretinoin / pharmacology
  • Tretinoin / physiology*
  • Vitamin A / pharmacology


  • Culture Media, Serum-Free
  • Membrane Proteins
  • RNA, Messenger
  • Vitamin A
  • Tretinoin
  • Alkaline Phosphatase