2006 Fiscal Year Final Research Report Summary
Regulation of Immunological homeostasis by dendritic cells
| Project/Area Number |
16043204
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| Research Category |
Grant-in-Aid for Scientific Research on Priority Areas
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| Allocation Type | Single-year Grants |
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| Review Section |
Biological Sciences
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| Research Institution | Akita University |
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Principal Investigator |
OHTAKI Toshiaki Akita University, School of Medicine, Professor, 医学部, 教授 (50233200)
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| Project Period (FY) |
2003 – 2006
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| Keywords | IL-15 / CpG / DC subsets / cross-talk / granuloma / endotoxin shock / chemokine / 1.Anew innate immune activation mechanismby dendritic cells / In response to CpQ wild-type mice produce IL-12 and become resistant to a lethal dose of Listeria / monocytogenes (LM). In contrast, CpG-treated IL-15-deficient mice produce little IL-12 and succumb to / LM. Further analysis revealed that IL-15-dependent cross-talk between cDCs and pDCs is essential for / CpG-induced immune activation. These results have been published in Nat. Immunol. and introduced in / News ＆ Views of the same issue (Nat. Immunol. 7:699-700 ( 2006 )). It is important to study whether the / similar cross-talk between DC subsets is involved in innate immune activation mediated by other TLR / ligands, which is in progress. / 2. Essential roles of DC-derived IL-15 as a mediator of inflammatory responses in vivo / Propionibacterium acnes, a causative bacteria for human sarcoidosis, and zymosan induce granuloma / formation in the liver of wild-type mice but not in those of IL-154" mice likely due to the impaired / activation of sequential IL-12-IFN-y-chemokine production pathway necessary for monocyte migration. / Likewise, lethal endotoxin shock was not induced in P acnes-and zymosan-primed IL-15+ mice. Further / analysis revealed that DC-derived IL-5 is essential for the induction of granuloma formation and endotoxin / shock in vivo. Importantly, we generated new mAbs to detect and block mouse IL-15 activity, and / succeeded to prevent wild-type mice from the lethal endotoxin shock by injecting the mAbs. These / results have been published in J. Exp. Med. / 3. Other DC-related studies / We also found that epithelial type-fatty acid binding protein negatively regulates DC-production of IL-12, / signals through Nod-like receptor and Toll-like receptor synergistically enhance DC-production of IL-12, / and virus infection-induced type I IFNs play a critical role in the induction of DC maturation. / IL-15 / CpG / DC subsets / cross-talk / granuloma / endotoxin shock / chemokine |
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| Research Abstract |
1.Anew innate immune activation mechanismby dendritic cells
In response to CpQ wild-type mice produce IL-12 and become resistant to a lethal dose of Listeria monocytogenes (LM). In contrast, CpG-treated IL-15-deficient mice produce little IL-12 and succumb to LM. Further analysis revealed that IL-15-dependent cross-talk between cDCs and pDCs is essential for CpG-induced immune activation. These results have been published in Nat. Immunol. and introduced in News ＆ Views of the same issue (Nat. Immunol. 7:699-700 ( 2006 )). It is important to study whether the similar cross-talk between DC subsets is involved in innate immune activation mediated by other TLR ligands, which is in progress.
2. Essential roles of DC-derived IL-15 as a mediator of inflammatory responses in vivo
Propionibacterium acnes, a causative bacteria for human sarcoidosis, and zymosan induce granuloma formation in the liver of wild-type mice but not in those of IL-15^<-/-> mice likely due to the impaired activation of sequential IL-12-IFN-γ-chemokine production pathway necessary for monocyte migration. Likewise, lethal endotoxin shock was not induced in P acnes-and zymosan-primed IL-15^<-/-> mice. Further analysis revealed that DC-derived IL-5 is essential for the induction of granuloma formation and endotoxin shock in vivo. Importantly, we generated new mAbs to detect and block mouse IL-15 activity, and succeeded to prevent wild-type mice from the lethal endotoxin shock by injecting the mAbs. These results have been published in J. Exp. Med.
3. Other DC-related studies
We also found that epithelial type-fatty acid binding protein negatively regulates DC-production of IL-12, signals through Nod-like receptor and Toll-like receptor synergistically enhance DC-production of IL-12, and virus infection-induced type I IFNs play a critical role in the induction of DC maturation.
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