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論文
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Ohteki, Toshiaki ; Kuwajima, Seiichi
概要:
Unmethylated CpG oligodeoxynucleotides （CpG） prevalent in bacteria and DNA viruses bind Toll-likereceptor（ TLR） 9 and di
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rectly stimulate DCs, thereby activating the innate and adaptive immune responses. CpG ispotentially a powerful reagent for protective immunity against infection by a wide variety of pathogens, for cancerand allergy therapies, and for the development of prophylactic and therapeutic vaccines. Here we investigated therole of interleukin （IL）-15 in the activation of CpG-induced immune responses. We show that upon CpG-priming,both wild-type（ WT） and NK cell-depleted WT mice produce interleukin（ IL）-12 p70 and become resistant to a lethaldose of Listeria monocytogenes（ LM）, whereas IL-15-/- mice impair IL-12 p70 production and succumb to the infection.Notably, CpG-stimulated conventional dendritic cells （cDCs） are the major producer of both IL-15 and IL-12 p70,but cDCs do not produce IL-12 in the absence of plasmacytoid DCs（ pDCs） in vivo. Importantly, cDC-derived IL-15induces CD40 expression on cDCs, which interacts with CD40 ligand on pDCs, leading to CD40 cross-linking and IL-12production. Collectively, these fi ndings show that IL-15-dependent cross-talk between cDCs and pDCs is essential forCpG-induced immune activation（ recently published in Nat Immunol 2006;7:740-6）
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| 2.
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論文
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Sashinami, Hiroshi ; Kageyama, Kazunori ; Suda, Toshihiro ; Nakane, Akio
概要:
It is well known that corticotropin releasing factor （CRF） modulates immune response duringinfl ammation. We investigate
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d the eff ect of CRF family peptides on host resistance to Listeria monocytogenes infectionin mice. The numbers of L. monoctyogenes in the organs of Ucn2-treated mice were dramatically increased comparedwith CRF- or Ucn-treated mice. CRF receptor type 2 is involved in the suppressive eff ect of Ucn2 on L. monocytogenesinfection. Interferon （IFN）-γ and tumor necrosis factor （TNF）-α production were decreased and interleukin （IL）-10 production was signifi cantly increased in the spleens of Ucn2-treated mice compared with those in Ucn2-untreatedcontrol mice. The eff ect of Ucn2 was canceled by depleting endogenous IL-10 using anti-IL-10 monoclonal antibodyand in IL-10 deficient mice. The expression and activation of signal transducers and activators of transcription3 （STAT3） were up-regulated and the expression and activation of STAT1 were down-regulated in the spleensfrom Ucn2-treated mice compared with vehicle-treated mice. Moreover, suppression of TNF-α production andaugmentation of IL-10 production and expression and activation of STAT3 by Ucn2 treatment were observed in heatkilledL. monocytogenes-stimulated macrophages. These results suggested that Urn2 suppresses host resistance to L.monocytogenes infection via up-regulation of IL-10 production.
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| 3.
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Sashinami, Hiroshi ; Hu, Dong-Liang ; Li, Sheng-Jun ; Mitsui, Toshihito ; Hakamada, Kenichi ; Ishiguro, Yoh ; Fukuda, Shinsaku ; Nakane, Akio
概要:
We investigated the eff ect of p60 that is one of virulence factors of Listeria monocytogenes on host immune response in
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vitro and in vivo. C57BL/6 mice immunized with p60 showed antigen-specifi c T-helper I type immune response. Mouse macrophage RAW264.7 cells produced tumor necrosis factor alpha （TNF-α）, interleukin-12 and interferon beta （IFN-β） in response to stimulation with recombinant p60. Administration of p60 prior to a sublethal infection with L. monocytogenes enhanced innate host resistance in naïve mice. TNF-α and IFN-β production from RAW264.7 cells and bone marrow-derived macrophages were Toll-like receptor 4 （TLR4）-dependent. The enhanced clearance of L. monocytogenes by p60 administration was not shown in C3H/HeJ mice. Our fi ndings demonstrated that p60 enhances host resistance against L. monocytngenes infection through both activation and attenuation of host innate immune response in the TLR4-dependent manner.
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| 4.
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Osanai, Arihiro ; Li, Sheng-Jun ; Nakane, Akio
概要:
Peptidoglycan recognition proteins （PGRPs） are pattern recognition receptors which are conserved from insects to humans.
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PGRPs can recognize bacteria and their cell wall components, peptidoglycans. Human PGRPs have bactericidal activities that can be accomplished by their amidase activities. Insect PGRPs consist of 16 subtypes and some have eff ector functions as the activation of Toll pathway （PGRP-SA）, the activation of Imd pathway （PGRPLC）and induction of autophagosome formation （PGRP-LE）, thus contribute to the elimination of bacteria. However, the role of mammalian PGRPs in bacterial infection remains unclear. In this study, we report the function of mouse PGRP-S, the homologue of PGRP-SA, in bacterial infection. The recombinant protein was produced in Escherichia coli overexpression system and used for specifi cantibody production. We investigated the role of PGRP-S in infection with Listeria monocytogenes, a facultative Gram-positive bacterium that can grow intracellularly. The administration of recombinant PGRP-S before L. monocytogenes infection decreased the number of bacteria in the organs of infected mice. When endogenous PGRP-S was neutralized by antibodies specifi c to PGRP-S, the bacterial number increased. The levels of proinfl ammatory cytokines that are essential in the protection against L. monocytogenes infection were lower when the specific antibody was administered prior to infection. Together with these, it is suggested that PGRP-S plays a role in the protection against L. monocytogenes infection.
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| 5.
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Tanaka, Nahoko ; Hiraga, Hiroto ; Sakuraba, Hirotake ; Murai, Yasuhisa ; Maeda, Takato ; Watanabe, Rina ; Ota, Shinji ; Akemoto, Yui ; Hasui, Keisuke ; Yoshida, Shukuko ; Asano, Krisana ; Nakane, Akio ; Fukuda, Shinsaku
概要:
Vitamin A is essential for maintenance of homeostasis, and it also regulates various immune mechanisms.Listeria monocyto
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genes is a gram-positive bacillus that invades the cytoplasm of phagocytes and performs intracellular multiplication, and is often used as a tool for functional analysis of macrophages. In this study, we investigated the changes of macrophages under vitamin A deficiency（ VAD） using L. monocytogenes. During L. monocytogenes infection,apoptosis was increased in CD11b-positive splenocytes of VAD mice compared with vitamin A sufficient （VAS）mice. A similar result was obtained with peritoneal exudate cells （PECs）. Significant increase of apoptosis due to the administration of Ro41-5253, an inhibitor of retinoic acid receptor, was also observed in the macrophage cell line RAW264.7. Furthermore, in VAD mice, the number of bacteria in the spleens and livers was significantly increased.These results suggest that excessive apoptosis of macrophages occurs under VAD condition, leading to impaired host resistance to L. monocytogenes. Taken together, vitamin A contributes to the maintenance of homeostasis by regulating macrophage functions, indicating the importance of vitamin A supplementation.
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