Abstract
IL-22 is a pro- and anti-inflammatory cytokine that is mainly produced by T cells and NK cells. Recent studies have reported the increased number of IL-22 producing T cells in patients with autoimmune noninfectious uveitis; however, the correlation between IL-22 and uveitis remains unclear. In this study, we aimed to determine the specific role of IL-22 and its receptor in the pathogenesis of uveitis. Serum concentration of IL-22 was significantly increased in uveitis patients. IL-22Rα was expressed in the retinal pigment epithelial cell line, ARPE-19. To examine the effect of IL-22, ARPE-19 was treated with recombinant IL-22. The proliferation of ARPE-19 and the production of monocyte chemoattractant protein (MCP)-1 from ARPE-19 were clearly elevated. IL-22 induced MCP-1 which facilitated the migration of inflammatory cells. Moreover, IL-22 increased the IL-22Rα expression in ARPE-19 through the activation of PI3K/Akt. Experimental animal models of uveitis induced by interphotoreceptor retinoid binding protein 1–20 (IRBP1-20) exhibited elevation of hyperplasia RPE and IL-22 production. When CD4+ T cells from the uveitis patients were stimulated with IRBP1-20, the production of IL-22 definitely increased. In addition, we examine the regulatory role of cysteamine, which has an anti-inflammatory role in the cornea, in uveitis through the down-regulation of IL-22Rα expression. Cysteamine effectively suppressed the IRBP1-20-induced IL-22Rα expression and prevented the development of IRBP1-20-induced uveitis in the experimental animal model. These finding suggest that IL-22 and its receptor have a crucial role in the development and pathogenesis of uveitis by facilitating inflammatory cell infiltration, and that cysteamine may be a useful therapeutic drug in treating uveitis by down-regulating IL-22Rα expression in RPE.
Highlights
Uveitis is an inflammatory disease that develops in uvea which is the middle layer of tissue in the eye wall
Because IL-22Rα expression was shown to be upregulated in the liver of concanavalin A injected mice in a previous study, [25] we investigated whether IRBP1-20 and cysteamine regulated the expression of IL-22Rα in ARPE-19 cells
We found that IL-22Rα expression is increased in ARPE-19 by stimulation with IRBP1-20, and its expression was inhibited by pre-treatment with cysteamine, even though it is known that IRBP1-20 does not have a stimulatory effect on ARPE-19 [1, 39]
Summary
Uveitis is an inflammatory disease that develops in uvea which is the middle layer of tissue in the eye wall. It is a very serious disease because of its sudden development and quick progression. EAU may be a consequence of a Th1/Th17 dominant immune response. Supporting this idea, the numbers of Th17 cells along with elevated levels of particular subsets of IL-17 have been reported to be increased in EAU, suggesting a mechanism by which Th17 cells may contribute to uveitis [6]
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