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Tissue-Specific Stem Cells
Version of Record online: 30 DEC 2010
Copyright © 2010 AlphaMed Press
Volume 28, Issue 12, pages 2172–2181, December 2010
How to Cite
Bian, F., Qi, H., Ma, P., Zhang, L., Yoon, K.-C., Pflugfelder, S. C. and Li, D.-Q. (2010), An Immunoprotective Privilege of Corneal Epithelial Stem Cells Against Th17 Inflammatory Stress by Producing Glial Cell-Derived Neurotrophic Factor. STEM CELLS, 28: 2172–2181. doi: 10.1002/stem.539
Author contributions: F.B.: conception and design, provision of study material, collection and/or assembly of data, data analysis and interpretation, manuscript writing; H.Q.: conception and design, provision of study material, collection and/or assembly of data, data analysis and interpretation, manuscript writing; P.M.: provision of study material, collection and/or assembly of data; L.Z.: provision of study material or patients, collection and/or assembly of data; K.-C.Y.: provision of study material or patients, collection and/or assembly of data; S.C.P.: conception and design, financial support, manuscript writing; D.-Q.L.: conception and design, financial support, collection and/or assembly of data, data analysis and interpretation, manuscript writing, final approval of manuscript. F.B. and H.Q. contributed equally to this work.
First published online in STEM CELLS EXPRESS October 8, 2010.
Disclosure of potential conflicts of interest is found at the end of this article.
- Issue online: 30 DEC 2010
- Version of Record online: 30 DEC 2010
- Accepted manuscript online: 8 OCT 2010 02:17PM EST
- Manuscript Accepted: 20 SEP 2010
- Manuscript Received: 5 AUG 2010
- Department of Defense CDMRP PRMRP Grant. Grant Number: FY06 PR064719
- National Institutes of Health Grant. Grant Number: EY11915
- National Natural Science Foundation of China. Grant Number: 30872813
- Oshman Foundation
- William Stamps Farish Fund
- Glial cell-derived neurotrophic factor;
- Adult stem cell;
- Corneal epithelium
Adult stem cells are well known for their self-renewal and regenerative capacity. The mechanisms protecting these cells from inflammatory damage have not been well elucidated. This study investigated the immunoprotective properties of corneal epithelial stem cells from inflammation by producing glial cell-derived neurotrophic factor (GDNF). Primary human limbal epithelial cells (HLECs) cultured from limbal explants were treated with interleukin (IL)-17A, tumor necrosis factor (TNF)-α, or hyperosmotic media, with or without GDNF or nuclear factor kappa B (NF-κB) inhibitor (NF-κB-I) for 4–48 hours. Inflammatory mediators and Th17-inducing cytokines were determined by real-time polymerase chain reaction, enzyme-linked immunosorbent assay, and immunobead assays. NF-κB activation was detected by p65 phosphorylation, immunostaining and Western blotting. GDNF and its receptor, GDNF family receptor α-1, were exclusively immunolocalized in the basal layer of limbal epithelium, whereas IL-17 receptor was negative in these cells. Exogenous IL-17A stimulated the expression and production of inflammatory cytokines (TNF-α, IL-6, and IL-1β) and chemokine IL-8 by HLECs. Th17-inducing cytokines, transforming growth factor (TGF)-β1, IL-6, IL-23, and IL-1β, were significantly increased at mRNA and protein levels by HLECs exposed to TNF-α or hyperosmotic media. IL-17 activated NF-κB by p65 phosphorylation at serine 536 and nuclear translocation. GDNF or NF-κB-I blocked IL-17-induced NF-κB p65 activation and production of inflammatory mediators. Furthermore, GDNF suppressed the production of Th17-inducing cytokines through inhibiting NF-κB activation. These findings demonstrate that limbal progenitor cell-produced neurotrophic factor GDNF suppresses IL-17-mediated inflammation via NF-κB signaling pathway. This may represent a unique immunoprotective property of limbal stem cells against inflammatory challenges on the ocular surface. STEM CELLS 2010;28:2172–2181