The effects of insulin-like growth factor 1 and growth hormone on human meibomian gland epithelial cells

JAMA Ophthalmol. 2014 May;132(5):593-9. doi: 10.1001/jamaophthalmol.2013.8295.

Abstract

Importance: 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.

Objectives: 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.

Intervention: Application of IGF-1 and growth hormone to human meibomian gland epithelial cells.

Main outcomes and measures: 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 and relevance: 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.

Publication types

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

MeSH terms

  • Antibodies, Monoclonal / pharmacology
  • Cell Count
  • Cell Survival
  • Cells, Cultured
  • Dry Eye Syndromes / drug therapy
  • Dry Eye Syndromes / metabolism
  • Dry Eye Syndromes / pathology
  • Electrophoresis, Polyacrylamide Gel
  • Epithelial Cells / drug effects
  • Epithelial Cells / metabolism*
  • Epithelial Cells / pathology
  • Female
  • Growth Hormone / drug effects
  • Growth Hormone / metabolism*
  • Humans
  • Immunoblotting
  • Insulin-Like Growth Factor I / antagonists & inhibitors
  • Insulin-Like Growth Factor I / metabolism*
  • Male
  • Meibomian Glands / drug effects
  • Meibomian Glands / metabolism*
  • Meibomian Glands / pathology
  • Signal Transduction

Substances

  • Antibodies, Monoclonal
  • Insulin-Like Growth Factor I
  • Growth Hormone
  • figitumumab