title: Apurinic/Apyrimidinic Endonuclease 1/Redox Factor-1 (Ape1/Ref-1) Modulates Antigen Presenting Cell-mediated T Helper Cell Type 1 Responses.
abstract: Apurinic/apyrimidinic endonuclease 1/redox factor-1 (Ape1/Ref-1) is a multifunctional protein possessing DNA repair, redox control, and transcriptional regulatory activities. Although Ape1/Ref-1 plays multiple roles in the immune system, its functions in helper T (Th) cell activation and differentiation are largely unknown. In this study, the function of Ape1/Ref-1 in Th cell activation was analyzed using an Ape1/Ref-1 redox-specific inhibitor, E3330. When splenocytes from OT-II mice, which are ovalbumin (OVA)-specific T-cell receptor transgenic mice, were activated with OVA in the presence of E3330, the induction of IFN-γ-producing OT-II T cells was significantly increased. In contrast, E3330 did not enhance IFN-γ production from plate-bound anti-CD3 antibody-stimulated CD4+T cells in the absence of antigen presenting cells (APCs). Furthermore, E3330-pretreated and OVA-pulsed APCs also enhanced the IFN-γ production from OT-II T cells. These results suggested that E3330 enhances Th1 responses by modifying APC function. E3330 did not alter the surface expression of MHC-II or the co-stimulatory molecules CD80 and CD86 on APCs. On the other hand, E3330 up-regulated the IL-12 p35 and p40 gene expression, and IL-12 surface retention, but decreased the IL-12 secretion from Toll-like receptor (TLR) ligand-stimulated APCs. These results were confirmed with Ape1/Ref-1 knockdown experiments. Taken together, our findings indicated that the suppression of Ape1/Ref-1 redox function leads to an increased cell surface retention of IL-12 and enhances Th1 responses. This is the first study to demonstrate that Ape1/Ref-1 modulates the IL-12 production and secretion from APCs and controls Th1 immune responses.
authors.affiliation: From the Department of Immunology, Yamagata University Faculty of Medicine, 2-2-2 Iida-Nishi, Yamagata 990-9585.
authors.forename: Nasrin
authors.initials: N
authors.lastname: Akhter
authors.affiliation: From the Department of Immunology, Yamagata University Faculty of Medicine, 2-2-2 Iida-Nishi, Yamagata 990-9585.
authors.forename: Yuji
authors.initials: Y
authors.lastname: Takeda
authors.affiliation: From the Department of Immunology, Yamagata University Faculty of Medicine, 2-2-2 Iida-Nishi, Yamagata 990-9585.
authors.forename: Hidetoshi
authors.initials: H
authors.lastname: Nara
authors.affiliation: From the Department of Immunology, Yamagata University Faculty of Medicine, 2-2-2 Iida-Nishi, Yamagata 990-9585.
authors.forename: Akemi
authors.initials: A
authors.lastname: Araki
authors.affiliation: the Department of Microbiology and Immunology, Tohoku University Graduate School of Medicine, 2-1 Seiryo-Machi, Aoba-Ku, Sendai 980-8075, and.
authors.forename: Naoto
authors.initials: N
authors.lastname: Ishii
authors.affiliation: WPI-Advanced Institute for Materials Research, Tohoku University, Sendai 980-8577, Japan.
authors.forename: Naoki
authors.initials: N
authors.lastname: Asao
authors.affiliation: From the Department of Immunology, Yamagata University Faculty of Medicine, 2-2-2 Iida-Nishi, Yamagata 990-9585, asao-h@med.id.yamagata-u.ac.jp.
authors.forename: Hironobu
authors.initials: H
authors.lastname: Asao
mesh_terms: D000818:Animals; D000938:Antigen-Presenting Cells / Q000166:cytology / Q000187:drug effects / Q000276:immunology*; D016227:Benzoquinones / Q000494:pharmacology; D002478:Cells, Cultured; D043603:DNA-(Apurinic or Apyrimidinic Site) Lyase / Q000037:antagonists & inhibitors / Q000276:immunology*; D007111:Immunity, Cellular / Q000187:drug effects; D007371:Interferon-gamma / Q000276:immunology; D018664:Interleukin-12 / Q000276:immunology; D008810:Mice, Inbred C57BL; D010084:Oxidation-Reduction / Q000187:drug effects; D011422:Propionates / Q000494:pharmacology; D018417:Th1 Cells / Q000166:cytology / Q000187:drug effects / Q000276:immunology*
chemical_list: D016227:Benzoquinones; D011422:Propionates; C075569:E 3330; D018664:Interleukin-12; D007371:Interferon-gamma; C486216:Apex1 protein, mouse; D043603:DNA-(Apurinic or Apyrimidinic Site) Lyase
keywords: Ape1/Ref-1; IL-12; T helper cells; antigen presenting cell; cytokine; dendritic cell; differentiation; redox regulation