title: The influence of 13-cis retinoic acid on human meibomian gland epithelial cells.
abstract: OBJECTIVE
  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.
authors.affiliation: Schepens Eye Research Institute, Massachusetts Eye and Ear, Department of Ophthalmology, Harvard Medical School, Boston, MA 02114, USA. juan_ding@meei.harvard.edu
authors.forename: Juan
authors.initials: J
authors.lastname: Ding
authors.forename: Wendy R
authors.initials: WR
authors.lastname: Kam
authors.forename: Julia
authors.initials: J
authors.lastname: Dieckow
authors.forename: David A
authors.initials: DA
authors.lastname: Sullivan
mesh_terms: D016923:Cell Death / Q000187:drug effects; D002461:Cell Line, Transformed; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D003879:Dermatologic Agents / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D015352:Dry Eye Syndromes / Q000473:pathology*; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D020287:In Situ Nick-End Labeling; D053583:Interleukin-1beta / Q000235:genetics / Q000378:metabolism; D015474:Isotretinoin / Q000494:pharmacology*; D020780:Matrix Metalloproteinase 9 / Q000235:genetics / Q000378:metabolism; D008537:Meibomian Glands / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D003879:Dermatologic Agents; D053583:Interleukin-1beta; C494918:AKT1 protein, human; D051057:Proto-Oncogene Proteins c-akt; C579270:MMP9 protein, human; D020780:Matrix Metalloproteinase 9; D015474:Isotretinoin
keywords: dry eye disease; meibomian gland dysfunction; retinoic acid