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Review
. 2016:2016:4083735.
doi: 10.1155/2016/4083735. Epub 2016 Jan 20.

The Role of the IL-20 Subfamily in Glaucoma

Mary K Wirtz  1 , Kate E Keller  1
Affiliations
Review

The Role of the IL-20 Subfamily in Glaucoma

Mary K Wirtz et al. Mediators Inflamm. 2016.

Abstract

Glaucoma is a common disease that leads to loss of peripheral vision and, if left untreated, ultimately to blindness. While the exact cause(s) of glaucoma is still unknown, two leading risk factors are age and elevated intraocular pressure. Several studies suggest a possible link between glaucoma and inflammation in humans and animal models. In particular, our lab recently identified a T104M mutation in IL-20 receptor-B (IL-20RB) in primary open angle glaucoma patients from a large pedigree. Several of the interleukin- (IL-) 20 family of cytokines and receptors are expressed in ocular tissues including the trabecular meshwork, optic nerve head, and retinal ganglion cells. The DBA/2J mouse develops high intraocular pressures with age and has characteristic optic nerve defects that make it a useful glaucoma model. IL-24 expression is significantly upregulated in the retina of these mice, while IL-20RA expression in the optic nerve is downregulated following pressure-induced damage. The identification of a mutation in the IL-20RB gene in a glaucoma pedigree and changes in expression levels of IL-20 family members in the DBA/2J mouse suggest that disruption of normal IL-20 signaling in the eye may contribute to degenerative processes associated with glaucoma.

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Figures

Figure 1
Figure 1
Schematic showing the anatomy of normal and glaucoma eyes. In glaucoma, a blockage in the aqueous humor outflow pathway in the anterior chamber (red) causes intraocular pressure to increase leading to loss of retinal ganglion cells and optic nerve damage at the back of the eye (orange). Images were slightly modified from those freely provided by the National Eye Institute, National Institute of Health.
Figure 2
Figure 2
(a) Schematic of the anterior chamber of the eye showing the location of the trabecular meshwork and the flow pattern of aqueous humor. Image was slightly modified from those freely provided by the National Eye Institute, National Institute of Health. (b) H&E stained radial section of a human trabecular meshwork. The TM is a triangular-shaped tissue comprised of a series of fenestrated beams around which the aqueous humor flows (red arrows) before draining into Schlemm's canal. For orientation purposes, the cornea is to the right and the ciliary body is toward the left. (c) Schematic of IL-20 signaling in normal cells. IL-20 or IL-24 binds to the IL-20RB receptor, which phosphorylates Janus kinase (JAK). JAK then phosphorylates STAT3, which translocates to the nucleus to promote transcription of inflammation-related target genes. This in turn increases MMP activity and ECM remodeling. (d) In glaucoma cells harboring the IL-20RB T104M mutation, the cytokine is unable to bind to the receptor so the JAK/STAT3 pathway is not activated. Therefore, higher expression of proinflammatory genes remains and elevated IOP would be sustained since MMP activity and ECM remodeling are not affected.
Figure 3
Figure 3
STAT3 activation in normal human dermal fibroblasts (white bars, n = 3) and patient fibroblasts with the IL-20RB T104M mutation (dark bars, n = 2) with and without cytokine stimulation: ∗ p < 0.05 between cytokine treated and untreated cells; ∗∗ p < 0.01 and ∗∗∗ p < 0.05 comparing fibroblasts with the T104M IL-20RB mutation versus wild-type cells with the same cytokine treatment (reprinted with copyright permission from Journal of Ocular Pharmacology and Therapeutics). IL-20 was added at 100 or 200 ng/mL and IL-19 and IL-24 were used at 100 ng/mL.
Figure 4
Figure 4
MMP activity in conditioned media from normal (white bars, n = 3) and patient fibroblasts with the IL-20RB T104M mutation (dark bars, n = 2) treated with cytokines ∗ p < 0.03 (reprinted with copyright permission from Journal of Ocular Pharmacology and Therapeutics). IL-20 was added at 100 or 200 ng/mL and IL-19 and IL-24 were used at 100 ng/mL.
See this image and copyright information in PMC

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