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 journalArticle

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.

Original languageEnglish
Pages (from-to)5693-5703
Number of pages11
JournalInvestigative ophthalmology & visual science
Volume59
Issue number13
DOIs
Publication statusPublished - 2018 Nov 1

Fingerprint

Membrane-Associated Matrix Metalloproteinases
Matrix Metalloproteinase 14
Interleukin-7
Down-Regulation
Fibroblasts
Cornea
Eye Banks
Polymerase Chain Reaction
Penetrating Keratoplasty
Corneal Transplantation
Corneal dystrophy Avellino type
Point Mutation
Flow Cytometry
Western Blotting
Enzyme-Linked Immunosorbent Assay
Cytokines
Mutation

ASJC Scopus subject areas

  • Ophthalmology
  • Sensory Systems
  • Cellular and Molecular Neuroscience

Cite this

Downregulation of IL-7 and IL-7R Reduces Membrane-Type Matrix Metalloproteinase 14 in Granular Corneal Dystrophy Type 2 Keratocyte. / Kim, So Young; Yeo, Areum; Noh, Hyemi; Ji, Yong Woo; Song, Jong-Suk; Kim, Hyeon Chang; Kim, Lark Kyun; Lee, Hyung Keun.

In: Investigative ophthalmology & visual science, Vol. 59, No. 13, 01.11.2018, p. 5693-5703.

Research output: Contribution to journalArticle

Kim, So Young ; Yeo, Areum ; Noh, Hyemi ; Ji, Yong Woo ; Song, Jong-Suk ; Kim, Hyeon Chang ; Kim, Lark Kyun ; Lee, Hyung Keun. / Downregulation of IL-7 and IL-7R Reduces Membrane-Type Matrix Metalloproteinase 14 in Granular Corneal Dystrophy Type 2 Keratocyte. In: Investigative ophthalmology & visual science. 2018 ; Vol. 59, No. 13. pp. 5693-5703.
@article{0682301b1a954af5be9e2c793216ee35,
title = "Downregulation of IL-7 and IL-7R Reduces Membrane-Type Matrix Metalloproteinase 14 in Granular Corneal Dystrophy Type 2 Keratocyte",
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.",
author = "Kim, {So Young} and Areum Yeo and Hyemi Noh and Ji, {Yong Woo} and Jong-Suk Song and Kim, {Hyeon Chang} and Kim, {Lark Kyun} and Lee, {Hyung Keun}",
year = "2018",
month = "11",
day = "1",
doi = "10.1167/iovs.18-25161",
language = "English",
volume = "59",
pages = "5693--5703",
journal = "Investigative Ophthalmology and Visual Science",
issn = "0146-0404",
publisher = "Association for Research in Vision and Ophthalmology Inc.",
number = "13",

}

TY - JOUR

T1 - Downregulation of IL-7 and IL-7R Reduces Membrane-Type Matrix Metalloproteinase 14 in Granular Corneal Dystrophy Type 2 Keratocyte

AU - Kim, So Young

AU - Yeo, Areum

AU - Noh, Hyemi

AU - Ji, Yong Woo

AU - Song, Jong-Suk

AU - Kim, Hyeon Chang

AU - Kim, Lark Kyun

AU - Lee, Hyung Keun

PY - 2018/11/1

Y1 - 2018/11/1

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=85057559592&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85057559592&partnerID=8YFLogxK

U2 - 10.1167/iovs.18-25161

DO - 10.1167/iovs.18-25161

M3 - Article

VL - 59

SP - 5693

EP - 5703

JO - Investigative Ophthalmology and Visual Science

JF - Investigative Ophthalmology and Visual Science

SN - 0146-0404

IS - 13

ER -