production involves p38 MAPK-dependent STAT1 phosphorylation in human plasmacytoid dendritic cell precursors
Departments of
* Forensic Medicine and
Immunology and Medical Zoology and
# Division of Transfusion Medicine, Faculty of Medicine, Fukui Medical University, Japan;
Department of Bacterial and Blood Products, National Institute of Infectious Diseases, Tokyo, Japan;
Department of Hematology and Clinical Immunology, Kobe City General Hospital, Japan;
|| Chemicals Development Group, Emori & Co., Ltd., Fukui, Japan; and
** Department of Microbiology and Immunology, Aichi Medical University School of Medicine, Japan
Correspondence: Dr. Takasumi Matsuki, Department of Forensic Medicine, or Dr. Sumiko Iho, Department of Immunology and Medical Zoology, Faculty of Medicine, Fukui Medical University, 23 Shimoaizuki, Matsuoka-cho, Yoshida-gun, Fukui 910-1193, Japan. E-mails: tmatsuki@fmsrsa.fukui-med.ac.jp or ihosumik{at}fmsrsa.fukui-med.ac.jp
Human plasmacytoid or CD4+CD11c- type 2 dendritic cell precursors (PDC) were identified as natural type I interferon (IFN)-producing cells in response to viral and bacterial infection. They represent effector cells of innate immunity and link it to the distinct adaptive immunity by differentiating into mature DC. It has been reported that oligodeoxyribonucleotides containing unmethylated CpG motifs (CpG DNA) stimulate PDC to produce IFN-
, but the molecular mechanisms involved remain unknown. We found that CpG-DNA-induced IFN- production in PDC was completely impaired by the inhibitor of the p38 mitogen-activated protein kinase (MAPK) pathway. Expression of IFN regulatory factor (IRF)-7 was enhanced by CpG-DNA treatment, which was preceded by the phosphorylation of signal transducer and activator of transcription (STAT)1 on Tyr-701, as well as its enhanced phosphorylation on Ser-727. All of these events were also suppressed by the p38 MAPK inhibitor. STAT1, STAT2, and IRF-9, components of IFN-stimulated gene factor 3 (ISGF3), were recognized in the nuclear fraction of CpG-DNA-treated cells. Neither anti-IFN-/ß antibodies (Ab) nor anti-IFNAR Ab suppressed STAT1 phosphorylation, enhancement of IRF-7 expression, or IFN- production in the early phase of the culture. These results suggest that CpG DNA induces p38 MAPK-dependent phosphorylation of STAT1 in a manner independent of IFN-/ß, which may cause ISGF3 formation to increase the transcription of the IRF-7 gene, thereby leading to IFN- production in human PDC.
Key Words: IRF-7 • STAT2 • IRF-9 • TLR-9
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