Downregulation of IL-7 and IL-7R reduces membrane-type matrix metalloproteinase 14 in granular corneal dystrophy type 2 keratocyte

So Young Kim, Areum Yeo, Hyemi Noh, Yong Woo Ji, Jong Suk Song, Hyeon Chang Kim, Lark Kyun Kim, Hyung Keun Lee

Research output: Contribution to journalArticlepeer-review

2 Citations (Scopus)


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.

Original languageEnglish
Pages (from-to)5693-5703
Number of pages11
JournalInvestigative Ophthalmology and Visual Science
Issue number13
Publication statusPublished - 2018 Nov

Bibliographical note

Funding Information:
Supported by Science Research Program Grant No. NRF-2018R1A2B3001110 and Grant No. NRF-2017M3A7B4041798 through the National Research Foundation of Korea.

Publisher Copyright:
© 2018 The Authors.

All Science Journal Classification (ASJC) codes

  • Ophthalmology
  • Sensory Systems
  • Cellular and Molecular Neuroscience


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