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Daiju Iwata, Nobuyoshi Kitaichi, Akiko Miyazaki, Kazuya Iwabuchi, Kazuhiko Yoshida, Kenichi Namba, Michitaka Ozaki, Shigeaki Ohno, Kazuo Umezawa, Kenichiro Yamashita, Satoru Todo, Susumu Ishida, Kazunori Onoé; Amelioration of Experimental Autoimmune Uveoretinitis with Nuclear Factor-κB Inhibitor Dehydroxy Methyl Epoxyquinomicin in Mice. Invest. Ophthalmol. Vis. Sci. 2010;51(4):2077-2084. doi: 10.1167/iovs.09-4030.
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Experimental autoimmune uveoretinitis (EAU), a Th1/Th17 cell-mediated autoimmune disease induced in mice, serves as a model of human endogenous uveitis. In this model, proinflammatory cytokines and various stimuli activate the transcriptional factor, nuclear factor-κB (NF-κB), in the retina. The therapeutic effect of the NF-κB inhibitor, dehydroxy methyl epoxyquinomicin (DHMEQ), was examined on EAU.
EAU was induced in B10.BR mice by K2 peptide immunization. DHMEQ (40 mg/kg/d) was administered daily by intraperitoneal injection. Clinical severity and histopathologic severity were assessed. Translocation of NF-κB p65 into the nucleus in EAU retina was assessed. T cells were collected from draining lymph nodes of the K2-immunized mice to examine antigen (Ag)-specific T-cell active responses and cytokine production in vitro.
Disease onset was significantly delayed in DHMEQ-treated mice (15.6 days) compared with untreated mice (12.6 days; P < 0.01). Histologic severity was significantly milder in DHMEQ-treated mice (score, 1.13) than in controls (score, 2.33; P < 0.05). DHMEQ suppressed the Ag-specific T-cell active responses and downregulated the productions of Th-1 type cytokines in vitro in a dose-dependent manner. Alternation was not observed in Th-2 type cytokines. Pretreatment of primed T cells or Ag-presenting cells with DHMEQ reduced T-cell activation and Th1/Th17 cytokine production. DHMEQ treatment suppressed the translocation of the NF-κB p65 subunit into the nuclei.
Systemic administration of DHMEQ suppressed NF-κB translocation in the retina, which might have reduced the inflammation of ocular tissues. DHMEQ-mediated regulation of NF-κB p65 could be a therapeutic target for the control of endogenous ocular inflammatory diseases.
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