Amelioration of Experimental Autoimmune Uveoretinitis with Nuclear Factor-kappa B Inhibitor Dehydroxy Methyl Epoxyquinomicin in Mice

作者：Iwata Daiju; Kitaichi Nobuyoshi^*; Miyazaki Akiko; Iwabuchi Kazuya; Yoshida Kazuhiko; Namba Kenichi; Ozaki Michitaka; Ohno Shigeaki; Umezawa Kazuo; Yamashita Kenichiro; Todo Satoru; Ishida Susumu; Onoe Kazunori

来源：Investigative Ophthalmology & Visual Science, 2010, 51(4): 2077-2084.

DOI：10.1167/iovs.09-4030

PURPOSE. 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-kappa B (NF-kappa B), in the retina. The therapeutic effect of the NF-kappa B inhibitor, dehydroxy methyl epoxyquinomicin (DHMEQ), was examined on EAU.
METHODS. 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-kappa B 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.
RESULTS. 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-kappa B p65 subunit into the nuclei.
CONCLUSIONS. Systemic administration of DHMEQ suppressed NF-kappa B translocation in the retina, which might have reduced the inflammation of ocular tissues. DHMEQ-mediated regulation of NF-kappa B p65 could be a therapeutic target for the control of endogenous ocular inflammatory diseases. (Invest Ophthalmol Vis Sci. 2010; 51: 2077-2084) DOI:10.1167/iovs.09-4030

• 出版日期2010-4
• 单位河北医科大学