| Co-Investigator(Kenkyū-buntansha) |
WATANABE Norihiko Chiba University Hospital, Allergy and Clinical Immunology, Assistant Professor, 医学部附属病院, 講師 (20375653)
KAGAMI Shin-ichiro Chiba University, Molecular Genetics, Assistant Professor, 大学院医学研究院, 助手 (30375654)
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| Budget Amount *help |
¥3,500,000 (Direct Cost: ¥3,500,000)
Fiscal Year 2006: ¥1,500,000 (Direct Cost: ¥1,500,000)
Fiscal Year 2005: ¥2,000,000 (Direct Cost: ¥2,000,000)
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| Research Abstract |
Cytokine environment is critical for the differentiation and commitment of immune cells. For example, IL-4, a representative Th2 cytokine, induces further Th2 cell differentiation, whereas a Th1 cytokine IFN-γ in coordination with IL-12 induces Th1 cell differentiation. While these positive-feedback mechanisms are essential for the profound differentiation of T helper cells, the immune system also has a number of intrinsic and extrinsic machinery to antagonize the excessive differentiation of immune cells.
We show in this research that IL-4 induces IFN-γ production in B22O^+ plasmacytoid dendritic cells (PDCs). By searching for cell populations that produce IFN-γ upon IL-4 stimulation, we found that PDCs were a major IFN-γ-producing cell upon IL-4 stimulation in wild-type and Rag-2^<-/-> splenocytes. Isolated PDCs, but not CD11b^+ DCs or CD8^+ DCs, produced IFN-γ upon IL-4 stimulation. In vivo, the depletion of PDCs by anti-Ly6G/C antibody prevented IFN-γ production induced by IL-4 administration. We also found that IL-4 induced IFN-γ production, but not IL-12 or IFN-α production, in PDCs and also strongly enhanced CpG ODN-induced IFN-γ production, but not CpG ODN-induced IL-12 or IFN-a production. However, IL-4 did not induce IFN-γ production in Stat6^<-/->PDCs. Moreover, IL-4 induced Stat4 expression in PDCs through a Stat6-dependent mechanism and only the Stat4-expressing PDCs produced IFN-γ. Furthermore, IL-4 did not induce IFN-γ production in Stat4^<-/->PDCs. These results indicate that PDCs preferentially produce IFN-γ upon IL-4 stimulation by Stat6- and Stat4-dependent mechanisms.
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