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ABSTRACT: In this study, we investigated whether Heracleum moellendorffii Hance-derived dehydrogeijerin and geijerin could be used to suppress lipopolysaccharide (LPS)-induced inflammatory responses in murine macrophage cell lines, Raw 264.7 cells. Dehydrogeijerin reduced nitric oxide (NO) and inducible nitric oxide synthase (iNOS) production from LPS-stimulated Raw 264.7 cells, but on the other hand, geijerin did not reduce NO production. Dehydrogeijerin, unlike geijerin, has a double bond at C2'-C3' with an oxo function at C1'. Pre-treatment of Raw 264.7 cells with dehydrogeijerin reduced the production of cyclooxigenase-2 (COX-2) and pro-inflammatory cytokines. These inhibitory effects were associated with decreases in the phosphorylation of mitogen-activated protein (MAP) kinases. Our results indicate that dehydrogeijerin significantly inhibits the inflammatory activity of activated macrophages, suggesting that dehydrogeijerin could be a potential candidate for the treatment of inflammatory disease.
International immunopharmacology 10/2012; · 2.21 Impact Factor
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ABSTRACT: In this study, we investigate the relationship between natural killer (NK) cell susceptibility and the surface markers of cancer cells. Through phenotypic analysis, we found evidence that more susceptible cancer cell lines (K562 and Jurkat) express more NKG2D ligands. Major histocompatibility complex (MHC) class I chain-related A/B (MIC-A/B) and UL16 binding protein (ULBP) 1-5 molecules are typical ligands of NKG2D. The high killing activity of NK cells against K562 was abolished through the addition of a NKG2D blocking antibody. Upon in vitro stimulation with quercetin, low susceptible cancer cells increased NKG2D ligand expression, leading to enhancement of NK cell cytolytic activity. These results suggested that the anti-cancer activity of NK cells is not dependent on the origin and growth style of the target cells, but is dependent on the surface markers of the target cells.
Cellular Immunology 05/2012; 276(1-2):122-7. · 1.97 Impact Factor
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ABSTRACT: Histone deacetylase inhibitors (HDACis) have recently been shown to suppress inflammatory responses at much lower concentrations than that the concentrations that produce an antitumor effect. In the current study, the inhibitory activity of T cell functions by three different HDACis was compared, and the mechanisms underlying the inhibitory activity were demonstrated. Trichostatin-A (TSA) and scriptaid (ST) had potent inhibitory effects on the proliferation of T cells. TSA suppressed the synthesis of the T cell-activating cytokine, interleukin (IL)-2, and the T cell-derived cytokines, interferon (IFN)-γ, IL-4, and IL-13. In addition, TSA induced inhibition of cell cycle progression and IL-2 receptor expression. On the whole, TSA had a stronger effect on T cell functions than other HDACis. Similarly, a longer duration of hyperacetylation was observed in the cells that had been exposed to TSA. Thus, the inhibition of histone deacetylation appears to be related to the inhibitory effect of TSA. These results are expected to serve as a guide for future studies on the ability of HDACis to inhibit acute and chronic inflammatory diseases provoked by T cells.
Archives of Pharmacal Research 05/2012; 35(5):929-36. · 1.59 Impact Factor
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Jae Kwon Lee
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ABSTRACT: Flavonoids have biological activities including anti-allergic, anti-inflammatory, antimicrobial and anticancer activities shown from in vitro studies. Of these biological activities, the anti-inflammatory capacity of flavonoids has long been emphasized in Chinese medicine. In this study, I investigated that what flavonoid can be applied to the suppression of lipopolysaccharide (LPS)-induced inflammatory responses in macrophages among the four similar structure flavonoids. Eriodictyol was found to reduce nitric oxide (NO) production from LPS-stimulated Raw 264.7 cells in non-cytotoxic concentrations. Moreover, eriodictyol strongly suppressed the phagocytic activity of activated macrophages. Pre-treatment of Raw 264.7 cells with eriodictyol reduced the expression of mRNA and the secretion of pro-inflammatory cytokines. These inhibitory effects were found to be caused by blockage of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) activation and phosphorylation of p38 mitogen-activated protein kinase (MAPK), extracellular signal-regulated kinases 1 and 2 (ERK1/2) and c-Jun N-terminal kinase (JNK).
Archives of Pharmacal Research 04/2011; 34(4):671-9. · 1.59 Impact Factor
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Saet Byoul Lee,
Kyungsu Kang,
Sarangerel Oidovsambuu,
Eun Hye Jho,
Ji Ho Yun,
Ji-Hye Yoo,
En-Ha Lee,
Cheol-Ho Pan, Jae Kwon Lee,
Sang Hoon Jung,
Chu Won Nho
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ABSTRACT: In the present study, we isolated a polyacetylene, gymnasterkoreayne B (GKB), from Gymnaster koraiensis and investigated the effect of GKB on the protection from oxidative stress-induced cytotoxicity through induction of the expression of cellular defense enzymes. GKB induced mRNA expression and enzyme activity of NAD(P)H:quinone oxidoreductase (NQO1) in vitro and in vivo, and potently increased expression of many cellular defense genes including glutathione-S-transferases, UDP-glucuronosyltransferase, and glutathione reductase (GSR) in normal rat liver. The nuclear factor erythroid 2-related factor 2 (Nrf2) which is known to induce various antioxidant and cytoprotective genes, and the genes containing the antioxidant response element (ARE), including NQO1, hemeoxygenease-1, GSR were induced by GKB in HepG2 human hepatocarcinoma cells. Pre-treatment of the cells with GKB accelerated the production of glutathione and mitigated menadione-induced cytotoxicity in HepG2 cells. Taken together, we found that GKB was a novel inducer of phase II detoxification enzymes and cellular defense enzymes, resulting in protection of the cells from oxidative stress and hepatotoxicity through regulation of detoxifying and antioxidant systems.
Food and chemical toxicology: an international journal published for the British Industrial Biological Research Association 11/2010; 48(11):3035-41. · 2.99 Impact Factor
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ABSTRACT: Schiandra chinensis is a well-known Chinese traditional medicine for the treatment of hepatic disease. In this study, we investigated whether the nine major compounds of Schiandra chinensis could be applied to suppress lipopolysaccharide (LPS)-induced inflammatory responses in murine macrophages (Raw 264.7 cells). Among the nine lignans, three, gomisin J, gomisin N, and schisandrin C, were found to reduce nitric oxide (NO) production from LPS-stimulated Raw 264.7 cells. These three lignans showed low cytotoxic effects in Raw 264.7 cells. Pre-treatment of Raw 264.7 cells with gomisin J, gomisin N, or schisandrin C reduced the expression of mRNA and the secretion of pro-inflammatory cytokines. These inhibitory effects were found to be caused by blockage of p38 mitogen-activated protein kinase (MAPK), extracellular signal-regulated kinases 1 and 2 (ERK 1/2), and c-Jun N-terminal kinase (JNK) phosphorylation.
Bioscience Biotechnology and Biochemistry 02/2010; 74(2):285-91. · 1.28 Impact Factor
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ABSTRACT: Once activated by infected pathogens, dendritic cells (DCs) undergo activation and release inflammatory mediators responsible for the signs of inflammation. Our aim was to elucidate whether histone deacetylase inhibitors (HDACIs), trichostatine-A (TSA), scriptaid (ST) and sodium butylate (SB) regulate the inflammatory response of DCs. Pre-treatment with TSA and ST reduced the syngeneic and allogeneic-antigen presenting activity of LPS-stimulated DCs in a dose dependent manner to statistical significance. SB also reduced the antigen presenting activity of DCs, but not significantly. HDACIs mediate their effects through the modulation of DC maturation and pre-treatment of the DCs with TSA or ST prior to treatment with LPS reduced the expressions of DC mature markers to the level of immature dendritic cells (iDCs). Moreover, TSA and ST reduced the IL-2 production from LPS-stimulated mature DCs. Our results suggest that HDACIs may actively modulate the DC-induced inflammatory response through inhibition of phenotypical or functional maturation.
Cellular Immunology 01/2010; 262(1):52-7. · 1.97 Impact Factor
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ABSTRACT: Histone deacetylase (HDAC) inhibitors were recently shown to suppress inflammatory responses in models of autoimmune and inflammatory diseases. In this study, the anti-inflammatory effects of five different HDAC inhibitors on lipopolysaccharide-(LPS)-stimulated macrophages were compared and the mechanisms of these effects were demonstrated. Trichostatin-A (TSA) and scriptaid, two of the five HDAC inhibitors, showed the most potent inhibitory effects on the nitric-oxide (NO) production of RAW264.7 cells and bone-marrow-derived macrophages (BMDMs). TSA significantly decreased the mRNA and protein levels of the proinflammatory cytokines, such as tumor necrosis factor (TNF)-alpha, interleukin (IL)-6, and IL-1beta, whereas the pretreatment with TSA increased the level of the immunosuppressive cytokine IL-10. TSA also reduced the cell surface markers of the maturity of the macrophages. Furthermore, a longer duration (up to 8 h) of hyperacetylation was observed in the cells that had been exposed to TSA, whereas the hyperacetylation induced by the other HDAC inhibitors was absent after 8 h. These results demonstrated that TSA is the most potent HDAC inhibitor of histone deacetylation and has the greatest ability to induce anti-inflammatory activity in cloned and naïve macrophages. These results are expected to serve as a guide for future studies on the ability of HDAC inhibitors to inhibit acute and chronic inflammatory diseases.
Archives of Pharmacal Research 05/2009; 32(4):613-24. · 1.59 Impact Factor
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ABSTRACT: Macrophages generated in vitro using macrophage-colony stimulating factor (M-CSF) and interleukin (IL)-6 from bone marrow cells (BM-Mp) are defective in antigen presenting cell (APC) function as shown by their ability to induce the proliferation of anti-CD3 mAb-primed syngeneic T cells. However, they do express major histocompatibility (MHC) class I and II molecules, accessory molecules and intracellular adhesion molecules. Here we demonstrate that the defective APC function of macrophages is mainly due to production of TGF-beta1 by BM-Mp.
Microarray analysis showed that TGF-beta1 was highly expressed in BM-Mp, compared to a macrophage cell line, B6D, which exerted efficient APC function. Production of TGF-beta1 by BM-Mp was confirmed by neutralization experiments of TGF-beta1 as well as by real time-polymerase chain reaction (PCR).
Addition of anti-TGF-beta1 monoclonal antibody to cultures of BM-Mp and anti-CD3 mAb-primed syngeneic T cells efficiently induced the proliferation of syngeneic T cells. Conversely, the APC function of B6D cells was almost completely suppressed by addition of TGF-beta1. Quantitative real time-PCR analysis also confirmed the enhanced expression of TGF-beta1 in BM-Mp.
The defective APC function of macrophages generated in vitro with M-CSF and IL-6 was mainly due to the production of TGF-beta1 by macrophages.
Immune Network 02/2009; 9(1):27-33.
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ABSTRACT: Tectorigenin (Tg) and tectoridin (Td) are the major compounds isolated from the rhizomes of iridaceous plant Belamcanda chinensis which is well known as a chinese traditional medicine for the treatment of inflammatory diseases. In this study we investigated whether tectorigenin and tectoridin can be applied to the suppression of interferon-gamma and lipopolysaccharide (IFN-gamma/LPS)-induced inflammatory responses in macrophages. Anti-inflammatory activities of tectorigenin and tectoridin were compared with genistein (Ge), well known isoflavonoid as a phytoestrogen and regarded as an emerging anti-inflammatory agent. Both compounds showed low cytotoxic effect. In Raw 264.7 cells activated with IFN-gamma/LPS, pre-treated tectorigenin was found to inhibit the expression of inducible nitric oxide synthase (iNOS), the production of nitric oxide (NO) and the secretion of interleukin (IL)-1beta dose-dependently. Tectorigenin also decreased the expression of cyclooxigenase (COX)-2 and the production of prostaglandin E(2) (PGE(2)) in dose-dependent manner. These inhibitory effects of tectorigenin were found to be caused by the blocking of nuclear factor kappa-B (NF-kappaB) activation. Compared with genistein and tectoridin, tectorigenin showed significant inhibitory effect for almost anti-inflammatory tests in this study. All these results clearly demonstrated that tectorigenin appears to have the potential to prevent inflammation.
Archives of Pharmacal Research 12/2008; 31(11):1447-56. · 1.59 Impact Factor
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ABSTRACT: Acharan sulfate isolated from the giant African snail, Achatina fulica, has been reported to have antitumor activity in vivo. In an effort to determine the mechanisms of its antitumor activity, we examined the effects of acharan sulfate on professional antigen presenting cells (APCs). Acharan sulfate increased the phagocytic activity, the production of cytokines such as TNF-alpha and IL-1beta, and the release of nitric oxide on a macrophage cell line, Raw 264.7 cells. In addition, acharan sulfate induced phenotypic and functional maturation of immature dendritic cells (DCs). Immature DCs cultured with acharan sulfate expressed higher levels of class II MHC molecules and major co-stimulatory molecules such as B7-1, B7-2, and CD40. Functional maturation of immature DCs cultured in the presence of acharan sulfate was confirmed by the increased allostimulatory capacity and IL-12 production. These results suggest that the antitumor activity of acharan sulfate is partly due to the activation of professional antigen presenting cells.
Archives of Pharmacal Research 08/2007; 30(7):866-70. · 1.59 Impact Factor
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ABSTRACT: Leukotactin-1 (Lkn-1), a human CC chemokine that binds to both CC chemokine receptor (CCR)1 and CCR3, is distinct from other human CC chemokines in that it has long amino acid residues preceding the first cysteine at the NH(2)-terminus. Serial deletion studies showed that at least three amino acid residues, alanine-alanine-aspartic acid (A-A-D), preceding the first cysteine at the NH(2)-terminus are essential for the biological activity of Lkn-1. Point mutation and deletion studies for the three amino acids were performed in the present study. Substitutions of the first alanine residue with other amino acids did not cause significant loss of biological activities. Deletion of the third amino acid, aspartic acid, resulted in more than 100-fold loss of the activity. Deletion of two amino acids, alanine-alanine (A-A) or alanine-aspartic acid (A-D), resulted in almost complete loss of the activity. Loss of agonistic activity by deletion of two amino acids was due to impaired binding to CCR1. These results identify that alanine-aspartic acid residues preceding the first cysteine at the NH(2)-terminus are essential for the binding and biological activity of Lkn-1.
Immunology Letters 07/2005; 99(1):63-8. · 2.53 Impact Factor
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ABSTRACT: Macrophages generated with macrophage-colony stimulating factor (M-CSF) are defective in antigen presenting cell (APC) function, although they do express major histocompatibility (MHC) class II molecules, numerous accessory molecules, and intercellular adhesion molecules. In the present study, we show evidence that the acquisition of APC function is influenced significantly by microenvironmental condition of development. Macrophages generated from bone marrow progenitor cells with M-CSF and interleukin (IL)-6 were defective in APC function as determined by their ability to induce anti-CD3 monoclonal antibody (mAb)-primed T cell proliferation. Macrophages generated in the presence of some of the CC chemokines such as leukotactin-1, macrophage inflammatory protein (MIP)-1alpha, and RANTES together with M-CSF and IL-6, however, induced proliferation of anti-CD3 mAb-primed T cells. Maximum level of APC function was obtained when developing macrophages were exposed with the chemokines at the late stage of maturation. Enhanced APC function of the macrophages appeared to be correlated with the expression of co-stimulatory molecules and the ability to produce cytokines. These results suggest that the acquisition of APC function of mature macrophage is modulated significantly by the microenvironmental condition during development.
Cellular Immunology 04/2005; 234(1):1-8. · 1.97 Impact Factor
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ABSTRACT: Hepatitis C virus (HCV) is remarkably efficient at establishing chronic infection. One of the reasons for this appears to be the suppression of the accessory cell function of professional antigen presenting cells. In the present study, the immunosuppressive activity of HCV protein was examined on dendritic cells (DCs) generated from mouse bone marrow progenitor cells in vitro. We found that the DCs forced to express HCV protein have defective allostimulatory ability. DCs expressing HCV protein were phenotypically indistinguishable from normal DCs. However, they were unable to produce IL-12 effectively when stimulated with lipopolysaccharide. The functional domain of the HCV protein essential for immunosuppression was determined using a series of NH2-and C-terminal deletion mutants of HCV core protein. We found that amino acid residues residing between the 21st and the 40th residues from the NH2-terminus of HCV core protein are required for immunosuppression. These findings suggest that HCV core protein suppresses the elicitation of protective Th1 responses by the inhibition of IL-12 production by DCs.
Archives of Pharmacal Research 07/2002; 25(3):364-9. · 1.59 Impact Factor
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ABSTRACT: Leukotactin-1 (Lkn-1) is a human CC chemokine that binds to both CC chemokine receptor 1 (CCR1) and CCR3. Structurally, Lkn-1 is distinct from other human CC chemokines in that it has long amino acid residues preceding the first cysteine at the NH(2) terminus, and contains two extra cysteines. NH(2)-terminal amino acids of Lkn-1 were deleted serially, and the effects of each deletion were investigated. In CCR1-expressing cells, serial deletion up to 20 amino acids (Delta20) did not change the calcium flux-inducing activity significantly. Deletion of 24 amino acids (Delta24), however, increased the agonistic potency approximately 100-fold. Deletion of 27 or 28 amino acids also increased the agonistic potency to the same level shown by Delta24. Deletion of 29 amino acids, however, abolished the agonistic activity almost completely showing that at least 3 amino acid residues preceding the first cysteine at the NH(2) terminus are essential for the biological activity of Lkn-1. Loss of agonistic activity was due to impaired binding to CCR1. In CCR3-expressing cells, Delta24 was the only form of Lkn-1 mutants that revealed increased agonistic potency. Our results indicate that posttranslational modification is a potential mechanism for the regulation of biological activity of Lkn-1.
Journal of Biological Chemistry 05/2002; 277(17):14757-63. · 4.77 Impact Factor
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ABSTRACT: Acemannan, a major carbohydrate fraction of Aloe vera gel, has been known to have antiviral and antitumoral activities in vivo through activation of immune responses. The present study was set out to define the immunomodulatory activity of acemannan on dendritic cells (DCs), which are the most important accessory cells for the initiation of primary immune responses. Immature DCs were generated from mouse bone marrow (BM) cells by culturing in a medium supplemented with GM-CSF and IL-4, and then stimulated with acemannan, sulfated acemannan, and LPS, respectively. The resultant DCs were examined for phenotypic and functional properties. Phenotypic analysis for the expression of class II MHC molecules and major co-stimulatory molecules such as B7-1, B7-2, CD40 and CD54 confirmed that acemannan could induce maturation of immature DCs. Functional maturation of immature DCs was supported by increased allogeneic mixed lymphocyte reaction (MLR) and IL-12 production. The differentiation-inducing activity of acemannan was almost completely abolished by chemical sulfation. Based on these results, we propose that the adjuvant activity of acemannan is at least in part due to its capacity to promote differentiation of immature DCs.
International Immunopharmacology.
