Abstract
Complement factor H (CFH) is a central regulator of the complement system and has been implicated in the etiology of age-related macular degeneration (AMD), a leading cause of blindness in the elderly. In view of previous studies showing that reduced expression of CFH in the retina is a risk factor for developing AMD, there is significant interest in understanding how CFH expression is regulated in the retina. In this study, we have shown that the anti-inflammatory cytokine, IL-27, induced CFH expression in mouse retinal cells and human retinal pigmented epithelial cells (RPE) through STAT1-mediated up-regulation of Interferon Regulatory Factor-1 (IRF-1) and IRF-8. We further show that cells in the ganglion and inner-nuclear layers of the retina constitutively express IRF-1 and IRF-8 and enhanced CFH expression in the retina during ocular inflammation correlated with significant increase in the expression of IRF-1, IRF-8 and IL-27 (IL-27p28 and Ebi3). Our data thus reveal a novel role of IL-27 in regulating complement activation through up-regulation of CFH and suggest that defects in IL-27 signaling or expression may contribute to the reduction of CFH expression in the retina of patients with AMD.
Highlights
The vertebrate eye is comprised of highly specialized tissues of the retina, cornea, lens, iris, ciliary body, choroid, sclera, aqueous humor and vitreous body and its primary function is to receive and convert incident light rays into visual images
We further show that IL-27 induced the increase of complement factor H (CFH) expression in ARPE-19 through activation of STAT1 and STAT3 pathways (Fig. 1F)
Recent studies using the ARPE-19 cell line suggest that IFN-g regulates CFH expression in retinal pigment epithelia (RPE) cells through activation of STAT1 [12,19], factors that activate the STAT1 required for CFH transcription in the retina are unknown since retinal cells do not produce the proinflammatory cytokine, IFN-g
Summary
The vertebrate eye is comprised of highly specialized tissues of the retina, cornea, lens, iris, ciliary body, choroid, sclera, aqueous humor and vitreous body and its primary function is to receive and convert incident light rays into visual images. The uncontrolled activation of the complement pathway in the eye is dangerous as it is potentially injurious to terminally differentiated photoreceptors and neurons of the neuroretina. This calamity is obviated by the production of a family of complement control proteins of which complement factor H (CFH) is a prominent member
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