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ABSTRACT: Lipopolysaccharide (LPS) is recognized by CD14 with Toll-like receptor 4 (TLR4), and initiates 2 major pathways of TLR4 signaling, the MyD88-dependent and TRIF-dependent signaling pathways. The MyD88-dependent pathway induces inflammatory responses such as the production of TNF-α, IL-6, and IL-12 via the activation of NFκB and MAPK. The TRIF-dependent pathway induces the production of type-I IFN, and RANTES via the activation of IRF-3 and NFκB, and is also important for the induction of adaptive immune responses. CD14 plays a critical role in initiating the TRIF-dependent signaling pathway response to LPS, to support the internalization of LPS via endocytosis. Here, we clearly demonstrate that intracellular delivery of LPS by LPS-formulated liposomes (LPS-liposomes) initiate only TRIF-dependent signaling via clathrin-mediated endocytosis, independent of CD14. In fact, LPS-liposomes do not induce the production of TNF-α and IL-6 but induce RANTES production in peritoneal macrophages. Additionally, LPS-liposomes could induce adaptive immune responses effectively in CD14-deficient mice. Collectively, our results strongly suggest that LPS-liposomes are useful as a TRIF-dependent signaling-based immune adjuvant without inducing unnecessary inflammation.
PLoS ONE 01/2013; 8(4):e60078. · 4.09 Impact Factor
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ABSTRACT: We previously showed that formation of pulmonary granulomas in mice in response to a mycobacterial glycolipid, trehalose 6,6'-dimycolate (TDM) is due to the action of TNF-α and not of IFN-γ. However, the mechanisms of formation and maintenance of pulmonary granulomas are not yet clear. The purpose of the present study is to evaluate the mechanisms of granuloma formation by TDM at the early phase. Histological analysis showed that inflammatory cells infiltrated the murine pulmonary interstitium on day 2 after an intravenous injection with TDM as a w/o/w emulsion. Clear granuloma formation was observed on day 7 after the injection. The mRNA expression of IL-17, IFN-γ and macrophage inflammatory protein 2 was found in lung mononuclear cells at the day after TDM injection. The major IL-17-producing cells were T-cell receptor (TCR) γδ T cells expressing Vγ6. In mice depleted of γδ T cells by treatment with anti-TCR γδ monoclonal antibody, the number of TDM-induced granuloma was decreased, but the size of granuloma was not affected. Our results suggest that the mycobacterial glycolipid TDM causes activation of IL-17-producing TCR γδ T cells and stimulates chemotaxis of inflammatory cells including neutrophils in to lung.
Immunopharmacology and Immunotoxicology 10/2012; 34(5):815-23. · 1.83 Impact Factor
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Current topics in medicinal chemistry 04/2011; 11(14):1750-1. · 4.47 Impact Factor
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ABSTRACT: Oxidative stress and inflammatory responses sustained for a long period of time cause many diseases. A proinflammatory cytokine, tumor necrosis factor α (TNF-α), plays a pivotal role in the pathogenesis of chronic and auto-immune diseases. The present review, supplemented by hitherto unpublished data of the authors and their coworkers, shows that the intake of polyphenols contained in natural sources, such as hydroxytyrosol, tyrosol, oleuropein (olives), naringin and hesperidin (Citrus fruits), resveratrol, procyanidins or oligomeric procyanidin (grapes or grape seed extracts), (-)-epigallocatechin gallate (green tea) and quercetin (grapes, green tea) etc., are able to modulate chronic inflammatory diseases, such as type 2 diabetes, rheumatoid arthritis, inflammatory bowel disease, and affect the formation and interaction of advanced glycation end products with their respective receptors. Furthermore, potent activities of fermented grape marc, prepared as a fine lyophilized powder from fresh skin and seeds of a Japanese grape strain (Koshu) and then fermented with Lactobacillus plantarum, are described. Finally, the bioavailability of representative polyphenols will be discussed.
Current topics in medicinal chemistry 04/2011; 11(14):1767-79. · 4.47 Impact Factor
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ABSTRACT: Rheumatoid arthritis (RA) is closely related to the pathogenesis of tumor necrosis factor α in lesions. We investigated the suppressive effects of a Citrus flavanone naringin on inflammatory responses in mice with collagen-induced arthritis (CIA), a mouse model for RA. To investigate potential preventive and therapeutic effects of naringin, mice were given naringin orally three times a week from the second immunization with collagen (day 21) and from day 31, when symptoms of CIA had reached a plateau, respectively. In both cases, inflammation-related clinical scores for knee joints were significantly reduced by administration of naringin. Histological analyses demonstrated that representative phenomena, such as damage to interchondral joints, infiltration of inflammatory cells and pannus formation, were significantly depressed by treatment with naringin. In addition, increases in the expression of high-mobility group box-1 protein in the joints of mice with CIA were suppressed by naringin. These results suggest that oral administration of naringin might be effective for treating human patients with RA.
Immunopharmacology and Immunotoxicology 04/2011; 33(4):723-9. · 1.83 Impact Factor
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ABSTRACT: To investigate the antiallergic effects of fermented grape marc from Negroamaro (N-FGM), we examined antigen (Ag)-induced degranulation of rat basophilic leukemia (RBL-2H3) cells. Among supernatants of N-FGM suspensions in water, ethanol, and dimethyl sulfoxide (DMSO), supernatants of DMSO-suspended N-FGM but not of nonfermented Negroamaro grape marc (N-GM) markedly suppressed the Ag-induced degranulation and phosphorylation of Syk in RBL-2H3 cells. Supernatants of DMSO-suspended N-FGM did not reduce the expression of FcepsilonRI on RBL-2H3 cells. Analyses of supernatants of N-FGM suspensions in water, ethanol, and DMSO by high-performance liquid chromatography revealed higher amounts of quercetin in supernatants of DMSO-suspended N-FGM than those in the other supernatants. Quercetin also suppressed the Ag-induced degranulation and phosphorylation of Syk but did not reduce the expression of FcepsilonRI on RBL-2H3 cells. These results suggest that inhibition of the Ag-induced degranulation and Syk phosphorylation by N-FGM might be due to the action of quercetin, as an active component in N-FGM.
Immunopharmacology and Immunotoxicology 09/2010; 32(3):454-61. · 1.83 Impact Factor
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ABSTRACT: We investigated the inhibitory effects of fermented grape marc (FGM), lyophilized fine powder of skin, and seeds of Vitis vinifera Koshu grape prepared by fermentation with Lactobacillus plantarum, on type-I allergic responses in mice. Repeated oral administration of FGM, but not non-fermented grape marc (GM), to BALB/c mice primed with ovalbumin (OVA) resulted in a significant reduction of serum IgE levels, compared with those of immunized controls. After OVA challenge, increased numbers of eosinophils in bronchial alveolar lavage fluids (BALF) significantly decreased by treatment with FGM but not with GM. For passive cutaneous anaphylaxis (PCA) reaction, BALB/c mice received intradermal sensitization with anti-OVA IgE serum and were challenged intravenously with OVA containing Evans blue at 24 h after IgE sensitization. Oral administration of FGM at 30 min before OVA challenge significantly suppressed the PCA reaction. On the other hand, Lactobacillus alone and non-fermented GM did not show any suppressive effects. Interestingly, FGM samples prepared from grapes for red wine, such as Negroamaro (rich in resveratrol) or Tannat (rich in oligomeric procyanidin), did not suppress the reaction. These results indicate that oral administration of FGM, prepared from Koshu grape for white wine but not from grapes for red wine, could suppress both phases of type-I allergic responses. A fraction extractable with acetone was responsible for the suppressive effects of FGM.
Immunopharmacology and Immunotoxicology 02/2010; 32(4):593-9. · 1.83 Impact Factor
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ABSTRACT: Glycosphingolipids (GSLs) are components of the outer membrane of Sphingomonas species, commonly classified into two types, alpha-glucuronosyl ceramide (alpha-GlcACer) and alpha-galacturonosyl ceramide (alpha-GalACer), respectively. GSL-7 from S. yanoikuyae and GSL-13 from S. terrae, with alpha-GalACer-type structure, possess dihydrosphingosine but with a different ratio of C21cyclopropane to C20:1, while other parts remain similar. We therefore examined if this difference in the ratio of C21cyclopropane to C20:1 in the two ceramides may influence activation of, not only invariant natural killer T (iNKT) cells, but also other cells involved in innate immunity. GSL-7 with a large proportion of C21cyclopropane induced stronger activation of iNKT cells, natural killer cells, dendritic cells, and macrophages than GSL-13 with a large proportion of C20:1. The results show that a higher ratio of C21cyclopropane to C20:1 in the dihydrosphingosine molecule allows a more optimal activation of iNKT cells and other cell types.
Immunopharmacology and Immunotoxicology 06/2009; 31(3):363-9. · 1.83 Impact Factor
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The Japanese journal of antibiotics 03/2009; 62 Suppl A:23-6.
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ABSTRACT: Natural killer T (NKT) cells recognize lipid antigens, such as glycosphingolipids (GSLs), via CD1d and contribute to host defense against various pathogens. Here, we demonstrate that GSLs isolated from Sphingomonas bacteria and inserted into liposomes (GSL-liposomes) enhance the activation of NKT cells and dendritic cells (DCs). GSL-liposomes remarkably enhanced the production of IFN-gamma from splenocytes in vitro and this enhancement depended on the content of the pH-sensitive lipid dioleoyl-phosphoethanolamine (DOPE) in the liposomes. GSL-liposomes containing DOPE were clearly broken in late endosomes and this may facilitate effective loading of GSLs onto CD1 molecules. Treatment with GSL-liposomes also activated NKT cells and DCs in vivo. Collectively, our results strongly suggest that GSL-liposomes can effectively induce NKT cell-mediated immune responses and may be useful as an immune adjuvant for inducing protective immunity.
Journal of Controlled Release 10/2008; 133(1):18-23. · 5.73 Impact Factor
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ABSTRACT: Quercetin (QUER) and luteolin (LUTE) are dietary flavonoids capable of regulating the production of cytokines, such as tumor necrosis factor-alpha (TNF-alpha), and interleukin-6 (IL-6). However, their mechanisms of action are not fully understood. In lipopolysaccharide-triggered (LPS)-triggered signaling via Toll-like receptor 4 (TLR4), QUER and LUTE suppresses not only the degradation of the inhibitor of kappaB (IkappaB), with resultant activation of nuclear factor-kappaB (NF-kappaB), but also the phosphorylation of p38 and Akt in bone marrow-derived macrophages that have been stimulated with LPS. We report here that, in TNF-alpha-induced signaling, QUER and LUTE significantly suppressed the production of IL-6 and activation of NF-kappaB. Accumulation of lipid rafts, the initial step in the signaling pathway, was significantly inhibited when macrophages were treated with QUER or with LUTE prior to exposure to LPS. Similarly, the accumulation of lipid rafts was inhibited by the flavonoids when B cells were activated via the membrane IgM and when T cells were activated via CD3. In contrast, QUER and LUTE did not inhibit the activation of phorbol myristate acetate-induced NF-kappaB in macrophages. Our observations suggest that QUER and LUTE interact with receptors on the cell surface and suppress the accumulation of lipid rafts that occurs downstream of the activation of the receptors.
Immunopharmacology and Immunotoxicology 09/2008; 30(4):867-82. · 1.83 Impact Factor
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ABSTRACT: We showed in a previous study that hot-water extracts of Agaricus blazei (Agaricus extracts) had anti-tumor activity to Meth A fibrosarcoma, but it remains unclear whether the Agaricus extracts ameliorate the skewed balance of type-1 T helper (Th1) and type-2 T helper (Th2) cells. We examined whether Agaricus extracts effect the skewed Th1/Th2 balance in tumor-bearing and asthma-induced mice. When Meth A-bearing mice were given orally either Agaricus extracts or water once a day starting 5 days after tumor implantation, spleen T cells, prepared from tumor-bearing mice treated with Agaricus extracts, in response to anti-CD3 monoclonal antibody produced significantly higher levels of interferon gamma (IFN-gamma) than that of controls. The mRNA expression of IFN-gamma-inducing protein 10 and the frequency of CD69(+) or CD49d(+) cells, among activated T cells infiltrated into tumors, significantly increased in Agaricus-treated mice, compared with those of tumor-controls. In asthma-induced mice, treatment with the Agaricus extracts caused significant downregulation of OVA-specific antibody responses of IgG1 and IgE but not of IgG2a, and significantly decreased total cell numbers, levels of interleukin 5, and eosinophil numbers in bronchial alveolar lavage fluids. IFN-gamma production by anti-CD3-stimulated spleen cells, obtained from Agaricus-treated mice, significantly increased. Our results strongly suggest that oral administration of Agaricus extracts ameliorates the Th1/Th2 balance from the Th2-skewed conditions.
Immunopharmacology and Immunotoxicology 09/2008; 30(4):747-60. · 1.83 Impact Factor
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ABSTRACT: Tumor necrosis factor-alpha (TNF-alpha) is important for the induction of systemic inflammatory responses that lead to lethal shock. Quercetin and luteolin, which differ by one hydroxyl group, are known to suppress the lipopolysaccharide-induced production of TNF-alpha in vitro. We show differing inhibitory effects of quercetin and luteolin on the induction of lethal shock in Salmonella typhimurium aroA-infected mice. In a time- and dose-dependent manner, quercetin reduced the plasma levels of TNF-alpha, lowered bacterial titers in livers, prevented liver damage and prolonged survival, while luteolin had little or no effect. Compared with luteolin, quercetin increased the infiltration of Gr-1(+)CD69(+) neutrophils into the peritoneal cavity and lowered heat shock protein 70 expression. Obviously, the additional hydroxyl group in quercetin is important for suppressing infection-induced lethal shock in mice.
FEMS Immunology & Medical Microbiology 07/2008; 53(3):306-13. · 2.44 Impact Factor
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ABSTRACT: Hesperidin (Hsp) is an abundant flavonoid in citrus fruits, and the oral administration of Hsp has been recently reported to suppress collagen-induced arthritis in mice. Therefore, we sought to determine whether alpha-glucosylhesperidin (Hsp-G), which is an Hsp derivative with enhanced water-solubility, is effective on treating arthritis in both mice and humans. Hsp-G was orally administered to mice with collagen-induced arthritis, and its effects were evaluated clinically and histologically. Oral administration of Hsp-G improved collagen-induced arthritis when administered before the onset of arthritis as well as when administered after its onset. A decrease in tumor necrosis factor-alpha production was found to cause this improvement. In the human study, 19 patients with rheumatoid arthritis (RA) were enrolled in a 12-week double-blind, placebo-controlled trial. Patients were administered beverages containing 3 g Hsp-G (n = 9) or placebo (n = 10) every morning for the duration of the 3-month trial. Additionally, patients received standard therapy from a physician every 4 weeks. As a result, 3 of 9 patients in the Hsp-G group improved, while only 1 of 10 patients in the placebo group improved; this was in accordance with the American College of Rheumatology criteria. The present study revealed that the food material Hsp-G was effective when administered with standard anti-rheumatoid therapy in ameliorating RA in mice and humans without any adverse effects and may improve the quality of life for patients with RA as a complementary/alternative medicine.
Immunopharmacology and Immunotoxicology 02/2008; 30(1):117-34. · 1.83 Impact Factor
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ABSTRACT: The effects of isoflavones and of a derivative of soybeans fermented with Bacillus subtilis, designated Nattoesse, on the lipopolysaccharide (LPS)-induced production of tumor necrosis factor-alpha (TNF-alpha) and fibrinolysis were investigated in vivo. The dietary supplement Nattoesse contains several isoflavones. Therefore, we examined the effects of individual isoflavones (daidzein, daidzin, genistein, and genistin) on the LPS-induced production of TNF-alpha. Intraperitoneal injections of daidzein, daidzin, and genistin (but not of genistein before a challenge with LPS) resulted in significant depression of serum levels of TNF-alpha in mice. Daidzein had the strongest activity in this assay. Oral administration of daidzein to mice also had a significant suppressive effect, as compared with that of the Citrus flavanone naringin. In galactosamine-sensitized mice, by contrast, the suppression of LPS-induced lethal shock by daidzein was very weak. Nattoesse did not inhibit the production of TNF-alpha nor did it prevent lethal shock. However, oral administration of Nattoesse to mice significantly suppressed LPS-induced increases in scores of the fibrin degradation product, and the effect was both dose- and time-dependent. Thus, it appears that Nattoesse has fibrinolytic activity during LPS-induced circulatory failure.
Immunopharmacology and Immunotoxicology 02/2007; 29(2):323-33. · 1.83 Impact Factor
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ABSTRACT: The preventive and therapeutic effects of the Citrus flavonoid hesperidin (HES) on the development of collagen-induced arthritis (CIA), a mouse model of rheumatoid arthritis (RA), were investigated. Mice were administered orally HES three times a week starting from either the onset (day 21) of secondary immunization or on day 31, when the CIA development had reached a plateau. In both cases, treatment with HES resulted in a significant suppression of clinical scores and improvement of histological features. These results suggest that oral administration of HES could be effective for treating human RA patients.
Planta Medica 05/2006; 72(5):477-9. · 2.15 Impact Factor
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ABSTRACT: We previously reported that glycopeptidolipid (GPL) isolated from Mycobacterium avium serovar 4 inhibited phagosome-lysosome (P-L) fusion when macrophages phagocytosed heat-killed Staphylococcus aureus (SA). In the present study we analyzed the underlying inhibitory mechanism of GPL coated on SA. Elimination of oligosaccharide from GPL abrogated its inhibitory activity. GPL did not inhibit P-L fusion of opsonized SA phagocytosed via complement receptors. The inhibitory activity of GPL was competitively reduced by the presence of alpha-methyl-D-mannoside and anti-mannose receptor antibody, suggesting that inhibition of P-L fusion by GPL is mediated through mannose receptor. Recruitment of early endosome antigen 1 and Ca2+/calmodulin kinase II in human macrophage-like THP-1 cells were significantly suppressed by GPL, indicating that GPL inhibits steps for leading to the P-L fusion.
Microbiology and Immunology 02/2006; 50(3):243-51. · 1.30 Impact Factor
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ABSTRACT: Flavonoids have beneficial activities which modulate oxidative stress, allergy, tumor growth and viral infection, and which stimulate apoptosis of tumor cells. In addition to these activities, dietary flavonoids are able to regulate acute and chronic inflammatory responses. Here we describe new aspects of regulatory mechanisms by which flavonoids suppress production of tumor necrosis factor-alpha (TNF-alpha) by macrophages, microglial cells and mast cells stimulated with lipopolysaccharide (LPS) and others via toll-like receptors (TLRs), and TNF-alpha-mediated acute and chronic inflammatory responses. Treatment with flavonoids such as luteolin, apigenin, quercetin, genistein, (-)-epigallocatechin gallate, and anthocyanidin resulted in significant downregulation of LPS-elicited TNF-alpha and nitric oxide (NO) production and diminished lethal shock. In chronic diseases, pathogenesis of collagen-induced arthritis (CIA), a mouse model of rheumatoid arthritis which is triggered by TNF-alpha, was improved by the oral administration of flavonoids after the onset of CIA. Here, we discuss that inhibitory effects of flavonoids on acute and chronic inflammation are due to regulation of signaling pathways, including the nuclear factor kappaB (NF-kappaB) activation and mitogen-activated protein (MAP) kinase family phosphorylation. FcetaRI expression by NF-kappaB activation was also reduced by flavonoids; while accumulation of lipid rafts, which is the critical step for signaling, was blocked by flavonoids. The intake of dietary flavonoids reduces acute and chronic inflammation due to blocking receptor accumulation and signaling cascades, and would assist individuals at high-risk from life-style related diseases.
Current pharmaceutical design 02/2006; 12(32):4271-9. · 4.41 Impact Factor
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ABSTRACT: The mechanisms by which immunoglobulin A (IgA) production up-regulates in the intestine of Toll-like receptor-4 (TLR4)-mutated mice were investigated. When TLR4-mutated, C3H/HeJ and BALB/lps(d) mice received oral administration of cholera toxin (CT), not only CT-specific IgA levels in the intestinal lavage but also the number of IgA-producing cells in intestinal lamina propria (iLP) significantly increased compared with those of the wild-type C3H/He and BALB/c mice. Interleukin (IL)-5-producing cells and CD86+ cells in iLP also significantly increased in C3H/HeJ mice. The expression of major histocompatibility complex class II and CD86 on cells present in Peyer's patches (PPs) of C3H/HeJ mice was higher than those of C3H/He mice. In non-immunized C3H/HeJ mice, the expression of transforming growth factor-beta (TGF-beta) mRNA and the percentages of IL-10-producing cells in PPs but not in spleen increased when compared with those in C3H/He mice. The suppressor of cytokine signalling-1 (SOCS-1) was expressed in PPs of C3H/He mice but not C3H/HeJ mice. These results indicate that high IgA levels in the intestine of TLR4-mutated mice are due to up-regulation of TGF-beta and IL-10 and the lack of regulation by SOCS-1.
Immunology 10/2005; 116(1):64-70. · 3.32 Impact Factor
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ABSTRACT: Immunomodulating activity of glycopeptidolipids (GPL), separated from different serovars of Mycobacterium avium complex (MAC), on macrophage functions was compared. When peripheral blood mononuclear cells (PBMC), from healthy donors showing strongly positive reactions to mycobacterial purified protein derivatives (PPD), were incubated with heat-killed Staphylococcus aureus coated with GPL serovar 4, phagocytosis of monocytes increased in dose-dependent manner. However, coating with GPL serovar 9 did not show any effects. After phagocytosis of heat-killed S. aureus, the phagosome-lysosome (P-L) fusion in monocytes was inhibited dose-dependently by coating of S. aureus with GPL serovar 4, but not serovar 9. These results indicate that GPL serovar 4 facilitates invasion of MAC into monocytes and renders resistance to bactericidal reactions due to the inhibition of P-L fusion. Regarding accessory function of macrophages in proliferative responses of T cells, the addition of GPL serovar 4 to cultures resulted in significant inhibition of anti-CD3 monoclonal antibody (mAb)-induced proliferation, whereas both serovar GPLs did not cause reduction of cell viability. Furthermore, the PPD-specific T cell proliferative response was downregulated markedly by GPL serovar 4, but weakly suppressed by GPL serovar 9. These results indicated that the immunomodulating activity of GPL on macrophage functions is serovar-dependent.
Biological & Pharmaceutical Bulletin 03/2005; 28(2):335-9. · 1.66 Impact Factor
