Purchase this article with an account.
C.-H. Yang, Y.-C. Liu; Inhibitory Effects of Proteasome Inhibitor Bortezomib on Endotoxin-Induced Uveitis in Lewis Rats. Invest. Ophthalmol. Vis. Sci. 2010;51(13):827.
Download citation file:
© ARVO (1962-2015); The Authors (2016-present)
Nuclear factor-kappa B (NF-ΚB) is a major regulator of pivotal proinflammatory cytokines in uveitis pathogenesis. Bortezomib inhibits NF-ΚB activation by blocking the degradation of the NF-ΚB inhibitor, I-ΚB. In this study, we investigated the efficacy of bortezomib on endotoxin-induced uveitis (EIU) in rats
EIU was induced in male Lewis rats by subcutaneous injection of 200 µg lipopolysaccharide. Proteasome inhibitor bortezomib (0.2 mg/kg or 0.05 mg/kg) or MG132 (10 mg/kg) was administered intraperitoneally 30 minutes before LPS treatment. The aqueous humor was collected at 24 hours after LPS injection, the number of infiltrating cells, the protein concentration, and the levels of nitric oxide (NO), tumor necrosis factor (TNF)-α, interleukin (IL)-6, monocyte chemoattractant protein- 1 (MCP-1), and macrophage inflammatory protein (MIP)-2 in the aqueous humor were determined. Immunohistochemical (IHC) staining with a monoclonal antibody against activated nuclear factor (NF)-ΚB and electrophoretic mobility shift assay (EMSA) were performed to evaluate the effect of bortezomib on NF-ΚB activation in the iris-ciliary body (ICB) of rats. A mouse macrophage cell line (RAW264.7 cells) was stimulated with LPS in the presence of bortezomib or MG132. Expression of inducible NO synthase (iNOS) and degradation of inhibitor ΚB (IΚB) were analyzed by Western blot analysis.
Bortezomib suppressed the inflammatory cellular infiltration of rats with EIU in a dose dependent fashion. Treatment with bortezomib reduced the concentrations of NO, TNF- α, IL-6, MCP-1, and MIP-2 in aqueous humor. IHC staining and EMSA demonstrated bortezomib inhibited NF-ΚB activation in the ICB of rats wit EIU. In vitro study showed that bortezomib suppressed IΚB degradation and inhibited NF-ΚB activation in RAW cells. Bortezomib also dose dependently suppressed the production of NO and chemokines in the condition medium of RAW264.7 cells stimulated by LPS.
These findings indicate that the proteasome inhibitor bortezomib has anti-inflammatory effects on EIU by inhibiting the NF-ΚB dependent signaling pathway and the subsequent production of proinflammatory mediators
This PDF is available to Subscribers Only