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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
Kim, So YoungYeo, AreumNoh, HyemiJi, Yong WooSong, Jong SukKim, Hyeon ChangKim, Lark KyunLee, Hyung Keun
Issue Date
11월-2018
Publisher
ASSOC RESEARCH VISION OPHTHALMOLOGY INC
Keywords
corneal keratocyte; granular corneal dystrophy type 2; interleukin-7; TGF-beta; stromal dystrophy
Citation
INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE, v.59, no.13, pp.5693 - 5703
Indexed
SCIE
SCOPUS
Journal Title
INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE
Volume
59
Number
13
Start Page
5693
End Page
5703
URI
https://scholar.korea.ac.kr/handle/2021.sw.korea/72071
DOI
10.1167/iovs.18-25161
ISSN
0146-0404
Abstract
PURPOSE. Granular corneal dystrophy type 2 (GCD2) is caused by a point mutation (R124H) in the TGF-beta-induced gene (TGFBI). However, the mechanisms underlying the accumulation of TGF-beta-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 TGFbI 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-beta and TGFBI expression were reduced on IL-7 treatment in corneal fibroblasts. Interestingly, the interplay between TGF-beta 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-beta expression. The RANKL/RANK axis regulates TGF-beta and TGFBI expression via IL-7-mediated MT-MMP regulation in corneal fibroblasts. These findings improve our understanding of the pathogenesis of GCD2.
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