title: The effects of insulin-like growth factor 1 and growth hormone on human meibomian gland epithelial cells.
abstract: OBJECTIVE
  A phase 1 study has reported that dry eye disease is the most common adverse effect of human exposure to the antibody figitumumab, an anticancer drug that prevents insulin-like growth factor 1 (IGF-1) from binding to its receptor. We hypothesized that the mechanism underlying this effect is the inhibition of IGF-1 action in epithelial cells of the meibomian gland.
  
  
  OBJECTIVE
  To test the hypothesis that IGF-1 stimulates meibomian gland function in vitro and to examine whether growth hormone, a closely related hormone of IGF-1, has the same effect. DESIGN, SETTING, AND MATERIAL: Immortalized human meibomian gland epithelial cells were cultured in the presence or the absence of IGF-1, growth hormone, and an IGF-1 receptor-blocking antibody. Signaling pathways, cell proliferation, neutral lipid staining, and a key protein involved in lipid biogenesis were evaluated.
  
  
  METHODS
  Application of IGF-1 and growth hormone to human meibomian gland epithelial cells.
  
  
  METHODS
  Immunoblotting, cell counting, and neutral lipid staining. RESULTS Insulin-like growth factor 1 activated the phosphoinositol 3-kinase/Akt and forkhead box O1 pathways (showing a dose-dependent effect on immunoblotting), stimulated cellular proliferation (about 1.8-fold increase in cell number), increased sterol regulatory element-binding protein 1 expression (about 3-fold increase on immunoblotting), and promoted lipid accumulation in human meibomian gland epithelial cells (about 2-fold increase in lipid staining). These IGF-1 actions, which may be blocked by cotreatment with the anti-IGF-1 antibody, were accompanied by inconsistent effects on extracellular signal-regulated kinase phosphorylation. We were not able to demonstrate activation of Akt, forkhead box O1, extracellular signal-regulated kinase, Janus kinase 2, or signal transducers and activators of transcription 5, induced cell proliferation, or lipid accumulation in these cells by growth hormone application.
  
  
  CONCLUSIONS
  Our results support the hypothesis that IGF-1 acts on human meibomian gland epithelial cells and may explain why treatment with figitumumab, the IGF-1 inhibitor, causes dry eye disease. Ophthalmic care for dry eye disease may be needed when patients with cancer undergo treatment with drugs that inhibit IGF-1 action.
authors.affiliation: Schepens Eye Research Institute, Massachusetts Eye and Ear, Boston 2Department of Ophthalmology, Harvard Medical School, Boston, Massachusetts.
authors.forename: Juan
authors.initials: J
authors.lastname: Ding
authors.affiliation: Schepens Eye Research Institute, Massachusetts Eye and Ear, Boston 2Department of Ophthalmology, Harvard Medical School, Boston, Massachusetts.
authors.forename: David A
authors.initials: DA
authors.lastname: Sullivan
mesh_terms: D000911:Antibodies, Monoclonal / Q000494:pharmacology; D002452:Cell Count; D002470:Cell Survival; D002478:Cells, Cultured; D015352:Dry Eye Syndromes / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D004591:Electrophoresis, Polyacrylamide Gel; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D005260:Female; D013006:Growth Hormone / Q000187:drug effects / Q000378:metabolism*; D006801:Humans; D015151:Immunoblotting; D007334:Insulin-Like Growth Factor I / Q000037:antagonists & inhibitors / Q000378:metabolism*; D008297:Male; D008537:Meibomian Glands / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D015398:Signal Transduction
chemical_list: D000911:Antibodies, Monoclonal; D007334:Insulin-Like Growth Factor I; D013006:Growth Hormone; C525021:figitumumab