The influence of 13-cis retinoic acid on human meibomian gland epithelial cells

Invest Ophthalmol Vis Sci. 2013 Jun 26;54(6):4341-50. doi: 10.1167/iovs.13-11863.

Abstract

Purpose: Meibomian gland dysfunction (MGD) is a primary cause of dry eye disease. One of the risk factors for MGD is exposure to 13-cis retinoic acid (13-cis RA), a metabolite of vitamin A. However, the mechanism is not well understood. We hypothesize that 13-cis RA inhibits cell proliferation, promotes cell death, alters gene and protein expressions, and attenuates cell survival pathways in human meibomian gland epithelial cells.

Methods: To test our hypotheses, immortalized human meibomian gland epithelial cells were cultured with or without 13-cis RA for varying doses and time. Cell proliferation, cell death, gene expression, and proteins involved in proliferation/survival and inflammation were evaluated.

Results: We found that 13-cis RA inhibited cell proliferation, induced cell death, and significantly altered the expression of 6726 genes, including those involved in cell proliferation, cell death, differentiation, keratinization, and inflammation, in human meibomian gland epithelial cells. Further, 13-cis RA also reduced the phosphorylation of Akt and increased the generation of interleukin-1β and matrix metallopeptidase 9.

Conclusions: Exposure to 13-cis RA inhibits cell proliferation, increases cell death, alters gene expression, changes signaling pathways, and promotes inflammatory mediator and protease expression in meibomian gland epithelial cells. These effects may be responsible, at least in part, for the 13-cis RA-related induction of MGD.

Keywords: dry eye disease; meibomian gland dysfunction; retinoic acid.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Death / drug effects
  • Cell Line, Transformed
  • Cell Proliferation / drug effects
  • Cell Survival / drug effects
  • Dermatologic Agents / pharmacology
  • Dose-Response Relationship, Drug
  • Dry Eye Syndromes / pathology*
  • Epithelial Cells / drug effects
  • Epithelial Cells / metabolism
  • Epithelial Cells / pathology
  • Gene Expression / drug effects
  • Humans
  • In Situ Nick-End Labeling
  • Interleukin-1beta / genetics
  • Interleukin-1beta / metabolism
  • Isotretinoin / pharmacology*
  • Matrix Metalloproteinase 9 / genetics
  • Matrix Metalloproteinase 9 / metabolism
  • Meibomian Glands / drug effects*
  • Meibomian Glands / metabolism
  • Meibomian Glands / pathology*
  • Proto-Oncogene Proteins c-akt / metabolism
  • Signal Transduction / drug effects

Substances

  • Dermatologic Agents
  • Interleukin-1beta
  • AKT1 protein, human
  • Proto-Oncogene Proteins c-akt
  • MMP9 protein, human
  • Matrix Metalloproteinase 9
  • Isotretinoin