title: Amelioration of experimental autoimmune uveoretinitis with nuclear factor-{kappa}B Inhibitor dehydroxy methyl epoxyquinomicin in mice.
abstract: 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-kappaB (NF-kappaB), in the retina. The therapeutic effect of the NF-kappaB 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-kappaB 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-kappaB p65 subunit into the nuclei. Conclusions. Systemic administration of DHMEQ suppressed NF-kappaB translocation in the retina, which might have reduced the inflammation of ocular tissues. DHMEQ-mediated regulation of NF-kappaB p65 could be a therapeutic target for the control of endogenous ocular inflammatory diseases.
authors.affiliation: Departments of Ophthalmology, Hokkaido University Graduate School of Medicine, Sapporo, Japan.
authors.forename: Daiju
authors.initials: D
authors.lastname: Iwata
authors.forename: Nobuyoshi
authors.initials: N
authors.lastname: Kitaichi
authors.forename: Akiko
authors.initials: A
authors.lastname: Miyazaki
authors.forename: Kazuya
authors.initials: K
authors.lastname: Iwabuchi
authors.forename: Kazuhiko
authors.initials: K
authors.lastname: Yoshida
authors.forename: Kenichi
authors.initials: K
authors.lastname: Namba
authors.forename: Michitaka
authors.initials: M
authors.lastname: Ozaki
authors.forename: Shigeaki
authors.initials: S
authors.lastname: Ohno
authors.forename: Kazuo
authors.initials: K
authors.lastname: Umezawa
authors.forename: Kenichiro
authors.initials: K
authors.lastname: Yamashita
authors.forename: Satoru
authors.initials: S
authors.lastname: Todo
authors.forename: Susumu
authors.initials: S
authors.lastname: Ishida
authors.forename: Kazunori
authors.initials: K
authors.lastname: Onoé
mesh_terms: D000818:Animals; D000938:Antigen-Presenting Cells / Q000187:drug effects; D001327:Autoimmune Diseases / Q000139:chemically induced / Q000276:immunology / Q000517:prevention & control*; D001549:Benzamides / Q000008:administration & dosage*; D002467:Cell Nucleus / Q000378:metabolism; D003512:Cyclohexanones / Q000008:administration & dosage*; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D015536:Down-Regulation; D005260:Female; D019084:Fluorescent Antibody Technique, Indirect; D007274:Injections, Intraperitoneal; D008213:Lymphocyte Activation / Q000187:drug effects; D051379:Mice; D018613:Microscopy, Confocal; D012160:Retina / Q000378:metabolism; D012173:Retinitis / Q000139:chemically induced / Q000276:immunology / Q000517:prevention & control*; D013601:T-Lymphocytes / Q000276:immunology; D051996:Transcription Factor RelA / Q000037:antagonists & inhibitors* / Q000378:metabolism; D014605:Uveitis / Q000139:chemically induced / Q000276:immunology / Q000517:prevention & control*
chemical_list: D001549:Benzamides; D003512:Cyclohexanones; D016207:Cytokines; D051996:Transcription Factor RelA; C464444:dehydroxymethylepoxyquinomicin