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T Suzuki, DA Sullivan; Estrogen Stimulation of Cytokine Gene Expression in Human Corneal Epithelial Cells . Invest. Ophthalmol. Vis. Sci. 2002;43(13):90.
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© ARVO (1962-2015); The Authors (2016-present)
Purpose:Researchers have proposed that the synthesis and secretion of pro-inflammatory cytokines by corneal epithelial cells may contribute to the development of ocular surface inflammation in dry eye syndromes. We hypothesize that this cytokine production may be promoted by estrogens, given that: [a] dry eye syndromes occur predominantly in women; [b] estrogen therapy is associated with a significant increase in the prevalence of dry eye signs and symptoms; [c] corneal epithelial cells contain nuclear estrogen receptors; and [d] estrogens influence other aspects of corneal immunity. The purpose of this study was to test our hypothesis. Methods:Human corneal epithelial cells (gift from Santen Pharmaceutical, Japan) were cultured in serum-containing media until confluence, then switched to serum-free media (DMEM-ITS) containing insulin, transferrin, and sodium selenite for 2 days. Following this time period, cells were cultured in DMEM-ITS containing vehicle, lipopolysaccharide (LPS, 10 µg/ml, positive control), or either 10 nM or 0.1 nM 17ß-estradiol. After 6 or 24 hours of hormone exposure, cells were harvested and processed for total RNA isolation, cDNA synthesis and the analysis of IL-8, IL-6, IL-1ß and granulocyte-macrophage colony-stimulating factor (GM-CSF) mRNA levels by multiplex and real-time PCR methods. Results:Our results demonstrate that 17ß-estradiol induces a marked increase in the expression of pro-inflammatory cytokine genes in human corneal epithelial cells. Estrogen treatment increased the mRNA levels of IL-8, IL-6, IL-1ß and GM-CSF, as compared to those in vehicle-treated controls. This hormone effect, which was consistently observed in different experiments, occurred after 24 and/or 6 hours of 17ß-estradiol exposure and at both estrogen concentrations. A similar up-regulation of cytokine gene expression was found following cellular treatment with LPS. Conclusion:Our findings show that 17ß-estradiol enhances the expression of pro-inflammatory genes in human corneal epithelial cells. This hormone action may play a role in the pathogenesis of ocular surface inflammation in dry eye. Supported by NIH grants EY05612 and EY12523 and a postdoctoral fellowship award from Allergan, Japan.
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