Abstract
Bortezomib is a proteasome inhibitor used for hematologic cancer treatment. Since it can suppress NF-κB activation, which is critical for the inflammatory process, bortezomib has been found to possess anti-inflammatory activity. In this study, we evaluated the effect of bortezomib on experimental autoimmune uveitis (EAU) in mice and investigated the potential mechanisms related to NF-κB inactivation. High-dose bortezomib (0.75 mg/kg), low-dose bortezomib (0.15 mg/kg), or phosphate buffered saline was given after EAU induction. We found that the EAU is ameliorated by high-dose bortezomib treatment when compared with low-dose bortezomib or PBS treatment. The DNA-binding activity of NF-κB was suppressed and expression of several key inflammatory mediators including TNF-α, IL-1α, IL-1β, IL-12, IL-17, and MCP-1 was lowered in the high-dose bortezomib-treated group. These results suggest that proteasome inhibition is a promising treatment strategy for autoimmune uveitis.
Highlights
Uveitis is among the most important causes of blindness and severe visual impairment worldwide
Our study demonstrated that bortezomib, a 26S proteasome inhibitor, is active in suppressing Nuclear factor-kappa B (NF-κB) activation and is effective in inhibiting ocular inflammation and reducing the production of inflammatory mediators in experimental autoimmune uveitis (EAU)
Our results indicate that inhibition of proteasome may be a promising approach to treating autoimmune uveitis
Summary
Uveitis is among the most important causes of blindness and severe visual impairment worldwide. Posterior uveitis tends to damage the photoreceptor cells and lead to permanent blindness. This severe intraocular inflammatory disease is often associated with autoimmune responses to unique retinal proteins [2]. Current therapies for uveitis are based largely on immunosuppressive treatment including corticosteroids, antimetabolites, and alkylating agents. Due to the nonspecific nature and the dose-limiting side effects of these drugs, the results of current treatment for autoimmunemediated uveitis remain unsatisfactory [3]. Novel approaches to control the inflammatory process in uveitis are being keenly developed both in humans and in animal models [4]
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