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Downregulation of IL-7 and IL-7R Reduces Membrane-Type Matrix Metalloproteinase 14 in Granular Corneal Dystrophy Type 2 Keratocyte

Authors
 So Young Kim  ;  Areum Yeo  ;  Hyemi Noh  ;  Yong Woo Ji  ;  Jong Suk Song  ;  Hyeon Chang Kim  ;  Lark Kyun Kim  ;  Hyung Keun Lee 
Citation
 Investigative Ophthalmology & Visual Science, Vol.59(13) : 5693-5703, 2018 
Journal Title
 Investigative Ophthalmology & Visual Science 
ISSN
 0146-0404 
Issue Date
2018
Abstract
Purpose: Granular corneal dystrophy type 2 (GCD2) is caused by a point mutation (R124H) in the TGF-β-induced gene (TGFBI). However, the mechanisms underlying the accumulation of TGF-β-induced protein (TGFBIp) are poorly understood. Therefore, we evaluated the signaling cascade affecting the expression of TGFBIp using patient-derived cells. Methods: Keratocyte primary cultures were prepared from corneas from the eye bank or from heterozygous or homozygous patients with GCD2 after penetrating or lamellar keratoplasty. GCD2 diagnoses were based on the results of a DNA analysis for the R124H TGFβI mutation. Keratocytes were treated with various cytokines and then analyzed using quantitative PCR (qPCR) array, qPCR, flow cytometry, ELISA, and Western blotting. Results: TGFBI expression was counterregulated by IL-7 in corneal fibroblasts. IL-7 expression was significantly reduced in corneal fibroblasts from patients with GCD2. TGF-β and TGFBI expression were reduced on IL-7 treatment in corneal fibroblasts. Interestingly, the interplay between TGF-β and IL-7 was regulated by the RANKL/RANK signaling cascade. Also, IL-7 regulates the expression of a membrane-type matrix metalloproteinase (MT-MMP), which plays a crucial role in migration and neovascularization in the cornea. Conclusions: These studies demonstrate that impaired IL-7 expression in patients with GCD2 affects disease pathogenesis via a failure to control TGF-β expression. The RANKL/RANK axis regulates TGF-β and TGFBI expression via IL-7-mediated MT-MMP regulation in corneal fibroblasts. These findings improve our understanding of the pathogenesis of GCD2.
Full Text
https://iovs.arvojournals.org/article.aspx?articleid=2717202
DOI
10.1167/iovs.18-25161
Appears in Collections:
1. College of Medicine (의과대학) > BioMedical Science Institute (의생명과학부) > 1. Journal Papers
1. College of Medicine (의과대학) > Dept. of Preventive Medicine and Public Health (예방의학교실) > 1. Journal Papers
1. College of Medicine (의과대학) > Dept. of Ophthalmology (안과학교실) > 1. Journal Papers
Yonsei Authors
김락균(Kim, Lark Kyun) ORCID logo https://orcid.org/0000-0001-5983-4470
김현창(Kim, Hyeon Chang) ORCID logo https://orcid.org/0000-0001-7867-1240
이형근(Lee, Hyung Keun) ORCID logo https://orcid.org/0000-0002-1123-2136
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URI
https://ir.ymlib.yonsei.ac.kr/handle/22282913/167134
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