Pseudoexfoliation (PEX) syndrome, which is an age-related, generalized elastotic matrix
process, currently represents the most common identifiable risk factor for open-angle
glaucoma. Dysregulated expression of proinflammatory cytokines has been implicated
in the initiation of various fibrotic disorders and in the pathophysiology of glaucoma.
Here we investigated the presence, expression, regulation, and functional significance
of proinflammatory cytokines in eyes with early and late stages of PEX syndrome/glaucoma
in comparison with normal and glaucomatous control eyes using multiplex bead analysis,
immunoassays, real-time PCR, Western blotting, immunohistochemistry, and cell culture
models. Early stages of PEX syndrome were characterized by approximately threefold
(P < 0.005) elevated interleukin (IL)-6 and IL-8 levels in the aqueous humor and a
concomitant approximately twofold (P < 0.001) increase in mRNA expression levels in
anterior segment tissues as compared with controls. In contrast, late stages of PEX
syndrome/glaucoma did not differ significantly from controls. IL-6, IL-6 receptor,
and phospho-signal transducer and activator of transcription 3 could be mainly localized
to walls of iris vessels and to the nonpigmented epithelium of ciliary processes.
IL-6 and IL-8 were significantly up-regulated by ciliary epithelial cells in response
to hypoxia or oxidative stress in vitro, whereas IL-6, but not IL-8, induced the expression
of transforming growth factor-beta1 and elastic fiber proteins. These findings support
a role for a stress-induced, spatially, and temporally restricted subclinical inflammation
in the onset of the fibrotic matrix process characteristic of PEX syndrome/glaucoma.