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Uesato, Ryoko ; Ishibashi, Yasuyuki ; Ohshika, Shusa ; Naraoka, Takuya ; Toh, Satoshi
概要:
Proteoglycans are one of the most important components of the extracellular matrix in the cartilage and the levels of proteoglycans. such as versican and aggrecan, increase during chondrogenesis. The purpose of this study was to
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investigate the effect of exogenous proteoglycans from salmon nasal cartilage on chondrogenesis of mesenchymal stem cells. Mesenchymal stem cells derived from bone marrow aspiration of rabbit femurs were induced to chondrogenic lineage using a pellet culture technique. Pellets were cultured in the medium with or without cell growth factors. with or without proteoglycans. or a combination of these agents. Pellets treated with cell growth factors became hypertrophic and showed lacuna formation. and synthesis of cartilage matrix was recognized histologically. The expression of type II collagen and aggrecan mRNA were decreased in pellets incubated with a combination of cell growth factors and proteoglycans, compared to those incubated with only cell growth factors. Exogenous proteoglycans may down-regulate the expression of cartilage-specific mRNA directly, or may interact with growth factors in the culture medium. As the increase of glycoprotein during chondrogenesis is important for determining the direction and degree of differentiation. exogenous proteoglycans may have a similar effect.
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| 2.
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Nakai, Makoto ; Yoshihara, Shuichi ; Morohashi, Hajime ; Ishido, Keinosuke ; Sasaki, Mutsuo
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Hyaluronan (HA) is a major component of the pericellular matrix, and is implicated in cell adhesion, invasion. and tumor metastasis. We have reported that 4-methylumbelliferone (MU) inhibits HA synthesis by cultured skin
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fibroblasts, melanoma cells, and pancreatic cancer cells. We focused in the present study, on mesothelioma which has an extremely poor prognosis, and in which no effective therapy has yet been established. We investigated dealing with this neoplasm whether MU and 4-methylesculetin (ME), a MU derivative, are able to inhibit HA synthesis by the mesothelioma cell line NCI-H2052. MU inhibited HA synthesis by about 20%, and ME by about 40%, in comparison with the control group. MU inhibited the adhesion of NCI-H2052 cells by about 30%, and ME by about 50%, compared with the untreated control. MU inhibited cell locomotion by about 30%. and ME by about 40%. It is suggested through these results suggest that MU and ME inhibit HA synthesis. adhesion, and locomotion by human mesothelioma cells and weaken their pericellular matrix, and that the inhibitory effect of ME on HA synthesis is stronger than that of MU. It is presumed that both MU and ME may have potential as new therapeutic or prophylactic medicines against mesothelioma.
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| 3.
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Matsukura, Daisuke ; Yokoyama, Yoshihito ; Tanaka, Kanji ; Ozaki, Takashi ; Mizunuma, Hideki
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The changes in proteoglycan (PG) expression and glycosaminoglycan (GAG) constituents in the intervillous space of the pregnancy-induced hypertension (PIR) placenta were investigated. PGs and GAGs were purified from the extract of
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the placental intervillous space by the DEAE-Sephacel column and salt-concentration gradient method. and the GAG sugar chains were released by the actinase and cellulase treatments. The sugar chains from the placentas of normal pregnancy and PIR were compared by cellulose-acetate membrane electrophoresis. No difference was observed in the expressions of hyaluronic acid. heparan sulfate, and chondroitin sulfate. but a clear increase in the expression of dermatan sulfate (DS) in the placenta of the PIR was confirmed. An increase of the DS that specifically activates anticoagulants can be a body reaction to counteract the hemostatic condition observed in PIR.
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| 4.
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Maruyama, Ikuro ; Ito, Takashi ; Hashiguchi, Teruto
概要:
Responses to stimuli in cellar level are diverse and such hierarchical as secretion of stored factors,synthesis of lipid
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mediators and protein synthesis through genomic transcription. However, how can the cellsrespond in the case of necrosis? Recently a characteristic intranuclear protein, high-mobility group box 1 protein（HMGB1） is released from necrotic cells. The protein is an abundant nuclear protein with a dual functionboth inside and outside the cells. In physiological state, HMGB1 is present in the nucleus, and binds to DNA,playing a variety of crucial functions, including transcription and keeping the characteristic DNA architecture.However, the protein is released to extracellular space from most of necrotic cells, activated macrophages anddendritic cells. Out of the cells, HMGB1 acts as a signal of tissue damage and can promote infl ammation, immuneresponses, and results tissue regeneration. During sepsis and/or disseminated intravascular coagulation （DIC）,however, massive accumulation of HMGB1 in the systemic circulation will cause multiple organ failure （MOF）and subsequent lethal outcome. Thus HMGB1 in the systemic circulation has been considered as a lethalmediator of sepsis, and a promising therapeutic target for sepsis. Recently we identified that thrombomodulin（TM）, a natural anticoagulant glycoprotein expressed on the surface of endothelial cells, plays an importantrole in sequestering HMGB1. TM may prevent HMGB1 from reaching remote organs, thereby restrictingthe spectrum of HMGB1 action in the site of injury. Here we review recent progress made in defining thephysiological and pathological roles of HMGB1 and therapeutic strategies aimed at blocking circulatory HMGB1.
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Sasaki, Takeshi
概要:
Human parvovirus B19 （B19） is single stranded DNA virus, that causes erythema infectinosum in infantand/or acute onset p
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olyarthritis in adult. We present the evidence showing the role of B19 on the etiopathogy ofrheumatoid arthritis（ RA）.（ 1） B19 DNA could be frequently amplifi ed in the samples from rheumatoid joints. Thedetection B19 RNA and B19 protein VP1 was specific for RA, and positive at T cells, B cells, macrophages andfollicular dendritic cells in rheumatoid synovium. （ 2） B19 infection or transduction of B19 NS1gene caused TNFα,IL-6 and IL-8 production through activating AP1 and AP2 in macrophages or macrophage celll line U937. We alsofound Ku80 as a novel receptor for B19 on T cells, macrophages or erythroblasts. B19 used clathrin on the surface attheir cell entry and caused enhanced actin polymerization, resulting in the migration of T cells. （ 3） B19-transgenicmice became susceptible to type II collagen-induced polyarthritis that is a model of RA. We also experienced 12cases who developed RA after acute B19 infection. （ 4） Half of RA cases had a defective neutralizing ability to B19.
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Kido, Hiroshi ; Mizuno, Dai ; Le, Quang Trong ; Chida, Junji ; Yamada, Hiroshi ; Okumura, Yuushi ; Yano, Mihiro
概要:
Human infl uenza virus causes an annual epidemic infection. After infl uenza virus infection in the airway,infection som
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etimes spreads with severe neurologic complication and multiple organ failure, resulting in highmortality. In the process of viral spread from the lungs to other organs, signifi cant up-regulated trpsin was observedin various organs. Up-regulated trypsin eff ectively converted precursor of the viral envelope hemagglutinin（ HA） intoHA1 and HA2 subunits. The proteolytic activation of HA is a prerequisite for virus multiplication. Administration ofthe inhibitors of trypsin as new approaches for the treatment of infl uenza virus infection eff ectively suppressed viralmultiplication. Almost vaccines for infl uenza virus infection are administered i.m. or s.c., which induce IgG-mediatedprotection in the systemic immune compartment, but this immunization off ers insuffi cient protection on the mucosalsurface at the initial site of viral multiplication. To improve protective mucosal immunity, intranasal vaccinationhas been studied. The powerful mucosal adjuvants reported are toxin based, such as cholera toxin and Escherichiacoli heat-labile toxin, but these enterotoxins cause severe side eff ects. We recently found natural mucosal adjuvant,pulmonary surfactant, in the lungs. Intranasal administration of infl uenza vaccine combined with Surfacten, a modifi edpulmonary surfactant free of antigenic c-type lectins, induced high protective mucosal immunity in the airway andsystemic immune responses in the blood, the effi cacy of both protective immunities by Surfacten being equivalent tothose by cholera toxin. In this symposium, we reported the eff ects of Surfacten on mucosal and systemic immunities.
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| 7.
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Kurachi, Makoto ; Kakimi, Kazuhiro ; Ueha, Satoshi ; Matsushima, Kouji
概要:
Memory CD8+ T cells generated during an immune response are long-lived and self-renewing, off eringenhanced host protect
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ion against re-infection. However, how an antigen-specific population of memory T cells ismaintained throughout repetitive infections over potentially a lifetime is not known. Here we review the generationand maintenance of antigen-specifi c CD8+ T cells and introduce our recent data showing dynamic turnover of anantigen-specific memory T cell population during repeated antigen challenge in vivo. We demonstrated that aprimary response potentially occurs upon every recall response and fi nd that the skewed T-cell receptor （TCR）repertoire of pre-existing memory T cells is partly corrected by diversity in a newly formed （primary） population.Importantly, memory T cells generated in a more recent antigen encounter expand more vigorously in a subsequentrecall response. A primary response during re-challenge therefore restores both the TCR diversity and proliferativepotential of the memory T cell population. These findings indicate that memory T cell populations evolve overmultiple challenges, favoring memory T cells generated in more recent encounters, and suggest that these primarypopulations have essential roles in the perpetuation of antigen-specifi c T cell populations.
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| 8.
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Ohteki, Toshiaki ; Kuwajima, Seiichi
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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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| 9.
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Seya, Tsukasa ; Matsumoto, Misako ; Ebihara, Takashi ; Akazawa, Takashi
概要:
Double-stranded （ds）RNA-recognition receptors reside in the cytoplasm and membranes of cells. Thesereceptors are implica
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ted in the differential screening of microbes by the host. Myeloid dendritic cells （mDCs）recognize and respond to polyI:C, an analog of dsRNA, by endosomal TLR3 and cytoplasmic MDA5. NK cells areinduced in vivo by the administration of polyI:C to mice and in vitro are reciprocally activated by mDCs, although themolecular mechanisms as yet undetermined. Here, we show that the TLR adapter TICAM-1 （TRIF） participates inmDC-derived antitumor NK activation. In a syngeneic mouse tumor implant model, intraperitoneal administration ofpolyI:C led to the retardation of tumor growth, which eff ect relied largely on NK activation. This NK-dependent tumorregression did not occur in TICAM-1-/- or IFNAR-/- mice, while a normal NK antitumor response was induced in PKR-/-,MyD88-/-, IFN-β-/- and wild-type mice. IFNAR was a prerequisite for the induction of IFN-α/β and TLR3. The lackof TICAM-1 did not aff ect IFN production but resulted in unresponsiveness to IL-12 production, mDC maturation andpolyI:C-mediated antitumor activity. This NK activation required NK-mDC contact in in vitro transwell analysis. NKantitumoractivity was successfully introduced into tumor-implanted mice by transferring mDCs expressing TICAM-1.Implanted tumor growth in IFNAR-/- mice was retarded by adoptively transferring polyI:C-treated TICACM-1-positivemDCs but not TICAM-1-/- mDCs. Thus, TICAM-1 rather than MDA5 in mDCs critically facilitated mDC-NK contactand activation of antitumor NK, resulting in the regression of low MHC-expressing tumors
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| 10.
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Fujita, Takashi
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Recent studies show the involvement of cytoplasmic RNA helicase family, RIG-I, MDA5 and LGP2 inantiviral innate immune r
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esponses. RIG-I and MDA5 are primarily responsible for the detection of viral infectionand triggering activation cascade for type I interferon genes in many cell types. RIG-I consists of N-terminalCAspase Recruitment Domain (CARD) and a domain with signatures of DExD/H box helicase (helicase domain).Functional analyses revealed that the helicase domain detects viral RNA and CARD triggers the activation ofdownstream signaling cascade, including activation of transcription factors, NF-κB, IRF-3 and IRF-7. RIG-I bindsto double stranded (ds)RNA, however it does not simply function as a binding receptor for dsRNA, since RIG-Iwith disrupted ATP binding site is incapable of signaling. A model is proposed that in the absence of dsRNA,RIG-I forms “closed” conformation and upon binding to dsRNA, it conforms into “open” structure exposing CARD.We produced recombinant RIG-I protein using Baculo virus system and purified it to homogeneity. Biochemicalproperties, including dsRNA binding activity, ATPase activity and helicase activity, of recombinant RIG-I wereinvestigated. The results suggested that RIG-I requires certain structure of ligand RNA that is specifi c to viral (ornon-self) origin. Furthermore, we found evidence that RIG-I conforms a certain structure upon binding to dsRNA inthe presence of ATP. These results were consistent with the above model for activation of RIG-I. Furthermore, weobserved that RIG-I forms oligomers in virus-infected cells and artifi cial oligomerization of RIG-I CARD mimics virusinducedsignaling, resulting in the activation of interferon and other cytokine genes. These results highlight how viralreplication in cytoplasm is detected by RIG-I helicase and switch on signal cascades for initial antiviral responses.
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