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Collaborative Action of NF-B and p38 MAPK Is Involved in CpG DNA-Induced IFN- and Chemokine Production in Human Plasmacytoid Dendritic Cells¹

Youko Osawa^*, Sumiko Iho^2,, Rumiko Takauji, Hisakazu Takatsuka, Saburo Yamamoto^¶, Takayuki Takahashi^||, Satomi Horiguchi^#, Yoshimasa Urasaki, Takasumi Matsuki and Shigeharu Fujieda^*

^* Department of Otorhinolaryngology-Head and Neck Surgery, Department of Pathological Sciences, Department of Forensic Medicine and Human Genetics, and Department of Hematology and Cardiology, Faculty of Medical Sciences, University of Fukui, Fukui, Japan; ^¶ Department of Bacterial Pathogenesis and Infection Control, National Institute of Infectious Diseases, Tokyo, Japan; ^|| Department of Hematology and Clinical Immunology, Kobe City General Hospital, Kobe, Japan; and ^# Department of Molecular Neurobiology and Pharmacology, Graduate School of Medicine, University of Tokyo, Tokyo, Japan

CpG DNA induces plasmacytoid dendritic cells (pDC) to produce type I IFN and chemokines. However, it has not been fully elucidated how the TLR9 signaling pathway is linked to these gene expressions. We examined the mechanisms involving the TLR9 and type I IFN signaling pathways, in relation to CpG DNA-induced IFN-, IFN regulatory factor (IRF)-7, and chemokines CXCL10 and CCL3 in human pDC. In pDC, NF-B subunits p65 and p50 were constitutively activated. pDC also constitutively expressed IRF-7 and CCL3, and the gene expressions seemed to be regulated by NF-B. CpG DNA enhanced the NF-B p65/p50 activity, which collaborated with p38 MAPK to up-regulate the expressions of IRF-7, CXCL10, and CCL3 in a manner independent of type I IFN signaling. We then examined the pathway through which IFN- is expressed. Type I IFN induced the expression of IRF-7, but not of IFN-, in a NF-B-independent way. CpG DNA enabled the type I IFN-treated pDC to express IFN- in the presence of NF-B/p38 MAPK inhibitor, and chloroquine abrogated this effect. With CpG DNA, IRF-7, both constitutively and newly expressed, moved to the nuclei independently of NF-B/p38 MAPK. These findings suggest that, in CpG DNA-stimulated human pDC, the induction of IRF-7, CXCL10, and CCL3 is mediated by the NF-B/p38 MAPK pathway, and that IRF-7 is activated upstream of the activation of NF-B/p38 MAPK in chloroquine-sensitive regulatory machinery, thereby leading to the expression of IFN-.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported in part by a Grant-in-Aid for Scientific Research (13670266, 16590355, and 17390458) from the Japan Society for the Promotion of Science and for young scientists (17791165) from Ministry of Education, Culture, Sports, Science and Technology; Research on Allergic Disease and Immunology of Ministry of Health, Labor and Welfare (17220101); Research on Health Sciences focusing on Drug Innovation (International Collaborative Research Project SH54212 and SH54411) from the Japan Health Science Foundation; and Smoking Research Foundation.

² Address correspondence and reprint requests to Dr. Sumiko Iho, Department of Pathological Sciences, Faculty of Medicine, University of Fukui, 23-3 Matsuoka-Shimoaizuki, Eiheiji-cho, Yoshida-gun, Fukui 910-1193, Japan. E-mail address: ihosumik{at}fmsrsa.fukui-med.ac.jp

³ Abbreviations used in this paper: DC, dendritic cell; pDC, plasmacytoid DC; ISRE, IFN-stimulated response element; IRF, IFN regulatory factor; TRAF6, TNF receptor-associated factor 6; ODN, oligonucleotide; Act D, actinomycin D; CHX, cycloheximide; PDTC, pyrrolidinedithiocarbamate; CAPE, caffeic acid phenethyl ester; DEX, dexamethasone; PMX, polymixin B; BDCA, blood DC Ag; SR, scavenger receptor.

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