The Effects of Insulin-like Growth Factor 1 and Growth Hormone on Human Meibomian Gland Epithelial Cells

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 MEASURESImmunoblotting, 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 RELEVANCEOur 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.

The Combined Effect of Azithromycin and Insulin-Like Growth Factor-1 on Cultured Human Meibomian Gland Epithelial Cells

“…This result is consistent with previous reports. 12,22 Our data indicate that AZM and IGF-1, although both promoting lipid accumulation in IHMGECs, may actually act through separate mechanisms, thereby allowing an additive effect on lipid accumulation and composition. The increase in these neutral and phospholipids, which are major components of meibum, is highly significant, because MGD is characterized by a reduced quantity and quality of meibum.…”

“…The SREBP-1 and cyclins B1 and D1 were analyzed by immunoblot as described earlier. 12 Primary antibodies were diluted at the concentration of 1:500 (SREBP-1, H-160; Santa Cruz), 1:1000 (cyclins B1 and D1; Cell Signaling Technology, Danvers, MA, USA) and 1:10,000 (b-actin; Cell Signaling Technology). Horseradish peroxidase-conjugated secondary antibodies, goat anti-rabbit IgG, and Fc-specific goat anti-mouse IgG were diluted 1:5000 (Sigma-Aldrich).…”

“…[9][10][11] In addition, we have discovered that insulin-like growth factor-1 (IGF-1) is essential for meibomian gland health and promotes both cell proliferation and lipid accumulation. 12 Given these findings, we hypothesize that the combination of AZM and IGF-1 will promote cell differentiation and lipid accumulation while preserving the normal cell proliferation in HMGECs. We further hypothesize that the combination will modulate lipid composition, and the expression of a key lipogenesis factor (sterol regulatory element-binding protein 1 [SREBP-1]).…”

Age-Related Dry Eye Lactoferrin and Lactobionic Acid

“…Their secretion declines over time, until only low levels can be detected in individuals aged over 60 years [25]. This results in the inhibition of the Foxo1 gene, which in turn leads to decreased proliferation and lipogenesis in meibomian gland cells, increased apoptosis and delayed turnover [26].…”

Differentiation Patterns of Immortalized Human Meibomian Gland Epithelial Cells in Three-Dimensional Culture

“…14 Previous studies, including some from our group, showed the functional influence of cultivation conditions, 15,16 neurotransmitters, 17,18 growth factors, 19,20 x-3 fatty acids, 21 sex hormones, 22,23 and pharmacologic substances 24 on HMGEC. However, all of these studies rely on 2D cell culture conditions or limited animal experiments.…”