• Title/Summary/Keyword: Costimulatory molecules

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MCP-1 Derived from Stromal Keratocyte Induces Corneal Infiltration of CD4+ T Cells in Herpetic Stromal Keratitis

  • Lee, Sun Kyoung;Choi, Beom Kyu;Kang, Woo Jin;Kim, Young Ho;Park, Hye Young;Kim, Kwang Hui;Kwon, Byoung S.
    • Molecules and Cells
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    • v.26 no.1
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    • pp.67-73
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    • 2008
  • Herpetic stromal keratitis (HSK) is an inflammatory disorder induced by HSV-1 infection and characterized by T cell-dependent destruction of corneal tissues. It is not known what triggers $CD4^+$ T cell migration into the stroma of HSV-1-infected corneas. The keratocyte is a fibroblast-like cell that can function as an antigen-presenting cell in the mouse cornea by expressing MHC class II and costimulatory molecules after HSV-1 infection. We hypothesized that chemokines produced by stromal keratocytes are involved in $CD4^+$ T cell infiltration into the cornea. We found that keratocytes produce several cytokines and chemokines, including MCP-1, RANTES, and T cell activation (TCA)-3. HSV-1 infection increased the production of MCP-1 and RANTES by keratocytes, and these acted as chemoattractants for HSV-1-primed $CD4^+$ T cells expressing CCR2 and CCR5. ExpreHerpetic stromal keratitis (HSK) is an inflammatory disorder induced by HSV-1 infection and characterized by T cell-dependent destruction of corneal tissues. It is not known what triggers $CD4^+$ T cell migration into the stroma of HSV-1-infected corneas. The keratocyte is a fibroblast-like cell that can function as an antigen-presenting cell in the mouse cornea by expressing MHC class II and costimulatory molecules after HSV-1 infection. We hypothesized that chemokines produced by stromal keratocytes are involved in $CD4^+$ T cell infiltration into the cornea. We found that keratocytes produce several cytokines and chemokines, including MCP-1, RANTES, and T cell activation (TCA)-3. HSV-1 infection increased the production of MCP-1 and RANTES by keratocytes, and these acted as chemoattractants for HSV-1-primed $CD4^+$ T cells expressing CCR2 and CCR5. Expression of MCP-1 in the corneal stroma was confirmed in vivo. Finally, when HSV-1-primed $CD4^+$ T cells were adoptively transferred into wild type and MCP-1-deficient mice that had been sublethally irradiated to minimize chemokine production from immune cells, infiltration of $CD4^+$ T cells was markedly reduced in the MCP-1-deficient mice, suggesting that it is the MCP-1 from HSV-1-infected keratocytes that attracts $CD4^+$ T cells into the cornea.

Modulatory Effect of Kaempferitrin, a 3,7-Diglycosylflavone, on the LPS-Mediated Up-regulation of Surface Co-stimulatory Molecules and CD29-Mediated Cell-cell Adhesion in Monocytic- and Macrophage-like Cells (활성화된 단핵구 및 대식세포의 항원제시기능에 대한 Kaempferitrin의 조절 효과)

  • Kim, Byung-Hun;Cho, Dong-Ha;Cho, Jae-Youl
    • YAKHAK HOEJI
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    • v.51 no.6
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    • pp.482-489
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    • 2007
  • Kaempferitrin, isolated from Kenaf (Hibiscus cannabinus), was examined to evaluate its modulatory effects on antigen-presenting cell functions of macrophages/monocytes such as phagocytosis of foreign materials, up-regulation of costimulatory molecules (CD40, CD80 and CD86), adhesion molecule activation, and antigen processing and presentation. Kaempferitrin strongly blocked up-regulation of CD40, CD80 and CD86, but not pattern recognition receptor (PRR) (e.g., TLR2). It also suppressed functional activation of CD29 (${\beta}1$-integrins), as assessed by cell-cell adhesion assay, required for T cell-antigen-presenting cell (APC) interaction. Furthermore, this compound did not block a simple activation of CD29, as assessed by cell-fibronectin adhesion assay. However, the compound did not diminish phagocytic uptake, an initial step for antigen processing, and ROS generation in RAW264.7 cells. In particular, to understand molecular mechanism of kaempferitrin-mediated inhibition, the regulatory role of LPS-induced signaling events was examined using immunoblotting analysis. Interestingly, this compound dose dependently suppressed the phosphorylation of $I{\kappa}B{\alpha}$, Src, Akt and Syk, demonstrating that it can negatively modulate the activation of these signaling enzymes. Therefore, our data suggested that kaempferitrin may be involved in regulating APC function-relevant immune responses of macrophages and monocytes by regulating intracellular signaling.

Lactoferrin Induces Tolerogenic Bone Marrow-Derived Dendritic Cells

  • Hui-Won Park;Sun-Hee Park;Hyeon-Ju Jo;Tae-Gyu Kim;Jeong Hyun Lee;Seung-Goo Kang;Young-Saeng Jang;Pyeung-Hyeun Kim
    • IMMUNE NETWORK
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    • v.20 no.5
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    • pp.38.1-38.12
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    • 2020
  • Dendritic cells (DCs) are professional antigen-presenting cells (APCs) that initiate both T-cell responses and tolerance. Tolerogenic DCs (tDCs) are regulatory DCs that suppress immune responses through the induction of T-cell anergy and Tregs. Because lactoferrin (LF) was demonstrated to induce functional Tregs and has a protective effect against inflammatory bowel disease, we explored the tolerogenic effects of LF on mouse bone marrow-derived DCs (BMDCs). The expression of CD80/86 and MHC class II was diminished in LF-treated BMDCs (LF-BMDCs). LF facilitated BMDCs to suppress proliferation and elevate Foxp3+ induced Treg (iTreg) differentiation in ovalbumin-specific CD4+ T-cell culture. Foxp3 expression was further increased by blockade of the B7 molecule using CTLA4-Ig but was diminished by additional CD28 stimulation using anti-CD28 Ab. On the other hand, the levels of arginase-1 and indoleamine 2,3-dioxygenase-1 (known as key T-cell suppressive molecules) were increased in LF-BMDCs. Consistently, the suppressive activity of LF-BMDCs was partially restored by inhibitors of these molecules. Collectively, these results suggest that LF effectively causes DCs to be tolerogenic by both the suppression of T-cell proliferation and enhancement of iTreg differentiation. This tolerogenic effect of LF is due to the reduction of costimulatory molecules and enhancement of suppressive molecules.

Ginsenoside fractions regulate the action of monocytes and their differentiation into dendritic cells

  • Lee, Yeo Jin;Son, Young Min;Gu, Min Jeong;Song, Ki-Duk;Park, Sung-Moo;Song, Hyo Jin;Kang, Jae Sung;Woo, Jong Soo;Jung, Jee Hyung;Yang, Deok-Chun;Han, Seung Hyun;Yun, Cheol-Heui
    • Journal of Ginseng Research
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    • v.39 no.1
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    • pp.29-37
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    • 2015
  • Background: Panax ginseng (i.e., ginseng) root is extensively used in traditional oriental medicine. It is a modern pharmaceutical reagent for preventing various human diseases such as cancer. Ginsenosidesd-the major active components of ginsengd-exhibit immunomodulatory effects. However, the mechanism and function underlying such effects are not fully elucidated, especially in human monocytes and dendritic cells (DCs). Methods: We investigated the immunomodulatory effect of ginsenosides from Panax ginseng root on $CD14^+$ monocytes purified from human adult peripheral blood mononuclear cells (PBMCs) and on their differentiation into DCs that affect $CD4^+$ T cell activity. Results: After treatment with ginsenoside fractions, monocyte levels of tumor necrosis factor (TNF)-${\alpha}$, interleukin (IL)-6, and IL-10 increased through phosphorylation of extracellular signal-regulated kinase (ERK)1/2 and c-Jun N-terminal kinase (JNK), but not p38 mitogen-activated protein kinase (MAPK). After treatment with ginsenoside fractions, TNF-${\alpha}$ production and phosphorylation of ERK1/2 and JNK decreased in lipopolysaccharide (LPS)-sensitized monocytes.We confirmed that DCs derived from $CD14^+$ monocytes in the presence of ginsenoside fractions (Gin-DCs) contained decreased levels of the costimulatory molecules CD80 and CD86. The expression of these costimulatory molecules decreased in LPS-treated DCs exposed to ginsenoside fractions, compared to their expression in LPS-treated DCs in the absence of ginsenoside fractions. Furthermore, LPS-treated Gin-DCs could not induce proliferation and interferon gamma (IFN-${\gamma}$) production by $CD4^+$ T cells with the coculture of Gin-DCs with $CD4^+$ T cells. Conclusion: These results suggest that ginsenoside fractions from the ginseng root suppress cytokine production and maturation of LPS-treated DCs and downregulate $CD4^+$ T cells.

Expression of Co-stimulatory Molecules and STAT/SOCS Signaling Factors in the Splenocytes of Mice Tolerized against Arthritis by Oral Administration of Type II Collagen (제2형 콜라겐으로 경구관용을 유도한 관절염 모델 마우스의 비장림프구내의 보조자극인자 및 STAT/SOCS 신호전달 인자의 발현 양상조사)

  • Lee, Kang-Eun;Hwang, Sue-Yun;Min, So-Youn;Kim, Ho-Youn
    • IMMUNE NETWORK
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    • v.3 no.3
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    • pp.248-254
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    • 2003
  • Oral administration of antigen has long been used in the induction of immune tolerance in various animal models of autoimmune diseases including rheumatoid arthritis (RA). Alleveation of arthritogenic symptoms has been reported from RA patients who received oral administration of type II collagen (CII) without side effects, however its rather inconsistent therapeutic efficacy and variation among patients calls for more detailed investigation on the mechanism of oral tolerance to be settled as regular treatment for RA. In an attempt to understand the immunogenic processes underpinning tolerance induction by orally administered CII, we analyzed changes in the expression of costimulatory molecules and STAT/SOCS signaling messengers in the mouse model of collagen induced arthritis (CIA). We found thatin the spleen of CIA mice, that has been undergone repeated oral feeding of CII prior to the induction of arthritis, showed increased promortion of CTLA4 expressing lymphocytes than in the spleen of PBS fed control. On the other hand, cells expressing CD28 or ICOS were decreased in the spleen of tolerized mice. Tolerance induction by oral CII administration also enhanced the expression of STAT6 in both RNA and protein level, while not affecting the expression of STAT3. The expression of SOCS3, which hasbeen known to transmit STAT-mediated signals from Th2 type cytokines, remained unchanged in the spleen of tolerized mice. Interestingly transcript of SOCS1, which has been associated with Th1 related pathways, was only visible in the spleen of tolerized but not of control mice, suggesting that as in the case of IL-6 signaling, it may exert a feed back inhibition toward the Th1 type stimulation.

20S-dihydroprotopanaxadiol, a ginsenoside derivative, boosts innate immune responses of monocytes and macrophages

  • Kim, Mi-Yeon;Cho, Jae Youl
    • Journal of Ginseng Research
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    • v.37 no.3
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    • pp.293-299
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    • 2013
  • 20S-dihydroprotopanaxadiol (2H-PPD) is a derivative of protopanaxadiol, a glycone of ginsenosides prepared from Panax ginseng. Although ginsenosides and acidic polysaccharides are known to be major active ingredients in ginseng, the immunopharmacological activities of their metabolites and derivatives have not been fully explored. In this study, we aimed to elucidate the regulatory action of 2H-PPD on the function of monocytes and macrophages in innate immune responses. 2H-PPD was able to boost the phagocytic uptake of fluorescein isothiocyanate-dextran in macrophages and enhance the generation of radicals (reactive oxygen species) in sodium nitroprusside-treated RAW264.7 cells. The surface levels of the costimulatory molecules such as CD80 and CD86 were also increased during 2H-PPD treatment. In addition, this compound boosted U937 cell-cell aggregation induced by CD29 and CD43 antibodies, but not by cell-extracellular matrix (fibronectin) adhesion. Similarly, the surface levels of CD29 and CD43 were increased by 2H-PPD exposure. Therefore, our results strongly suggest that 2H-PPD has the pharmacological capability to upregulate the functional role of macrophages/monocytes in innate immunity.

Cancer Vaccines (암백신)

  • Son, Eun-Wha;In, Sang-Whan;Pyo, Suhk-Neung
    • IMMUNE NETWORK
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    • v.5 no.2
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    • pp.55-67
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    • 2005
  • Cancer vaccine is an active immunotherapy to stimulate the immune system to mount a response against the tumor specific antigen. Working as a stimulant to the body's own immune system, cancer vaccines help the body recognize and destroy targeted cancers and may help to shrink advanced tumors. Research is currently underway to develop therapeutic cancer vaccines. It is also possible to develop prophylactic vaccines in the future. The whole cell approach to eradicate cancer has used whole cancer cells to make vaccine. In an early stage of this approach, whole cell lysate or a mixture of immunoadjuvant and inactivated cancer cells has been used. Improved vaccines are being developed that utilize cytokines or costimulatory molecules to mount an attack against cancer cells. In case of melanoma, these vaccines are expected to have a therapeutic effect of vaccine. Furthermore, it is attempting to treat stomach cancer, colorectal cancer, pancreatic cancer, and prostate cancer. Other vaccines are being developing that are peptide vaccine, recombinant vaccine and dendritic cell vaccine. Out of them, reintroduction of antigen-specific dendritic cells into patient and DNA vaccine are mostly being conducted. Currently, research and development efforts are underway to develop therapeutic cancer vaccine such as DNA vaccine for the treatment of multiple forms of cancers.

Regulatory Effect of Ginsenosides Rh1 on Monocytic U937 Cell Adhesion (홍삼유래 ginsenosides Rh1의 단핵구 U937 세포 유착조절 효과)

  • Kim, Byung-Hun;Cho, Jae-Youl
    • Journal of Ginseng Research
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    • v.33 no.4
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    • pp.324-329
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    • 2009
  • Cell-cell adhesion managed by various adhesion molecules is known to be one of pathophysiological phenomena found in numerous immunological diseases such as rheumatoid arthritis and allergic diseases. In this study, we examined the regulatory role of ginsenosides (G)- Rh1, reported to display anti-inflammatory and anti-allergic effects, on CD29-mediated cell adhesion. G-Rh1 significantly suppressed U937 cell-cell adhesion mediated by CD29 but not CD43. It also blocked U937 cell-fibronectin adhesion, mediated by activated CD29, up to 30%. In agreement, this compound also significantly decreased the surface level of CD29 but not CD43 as well as other costimulatory molecules such as CD69, CD80, and CD86. Therefore, these results suggest that G-Rh1 may have inhibitory function on CD29-mediated cell adhesion events, probably contributing to its anti-inflammatory and anti-allergic activities.

Signaling Through the Murine T Cell Receptor Induces IL-17 Production in the Absence of Costimulation, IL-23 or Dendritic Cells

  • Liu, Xikui K.;Clements, James L.;Gaffen, Sarah L.
    • Molecules and Cells
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    • v.20 no.3
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    • pp.339-347
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    • 2005
  • IL-17 (IL-17A or CTLA-8) is the founding member of a novel family of inflammatory cytokines, and emerging evidence indicates that it plays a central role in inflammation and autoimmunity. IL-17 is made primarily, if not exclusively by T cells, but relatively little is known about how its expression is regulated. In the present study, we examined the requirements and mechanisms for IL-17 expression in primary mouse lymphocytes. Like many cytokines, IL-17 is induced rapidly in primary T cells after stimulation of the T cell receptor (TCR) through CD3 crossinking. Surprisingly, however, the pattern of regulation of IL-17 is different in mice than in humans, because "costimulation" of T cells through CD28 only mildly enhanced IL-17 expression, whereas levels of IL-2 were dramatically enhanced. Similarly, several other costimulatory molecules such as ICOS, 4-1BB and CD40L exerted only very weak enhancing effects on IL-17 production. In agreement with other reports, IL-23 enhanced CD3-induced IL-17 expression. However, IL-17 production can occur autonomously in T cells, as neither dendritic cells nor IL-23 were necessary for promoting short-term production of IL-17. Finally, to begin to characterize the TCR-mediated signaling pathway(s) required for IL-17 production, we showed that IL-17 expression is sensitive to cyclosporin-A and MAPK inhibitors, suggesting the involvement of the calcineurin/NFAT and MAPK signaling pathways.

Antigen Nonspecific Death of Immature Thymocytes by Corticosteroids and TNF (스테로이드와 TNF에 의한 항원 비특이적 미성숙 흉선세포 사멸)

  • Oh, Keunhee;Surh, Charles D;Cho, Jaejin;Lee, Dong-Sup
    • IMMUNE NETWORK
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    • v.4 no.2
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    • pp.81-87
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    • 2004
  • Background: In the thymus, developing thymocytes continually interact with thymic epithelial cell components. Self MHC restriction of mature T cells are imposed in the thymus through interaction of immature double positive thymocytes and thymic cortical epithelial cells. The site of negative selection, however, is a matter of debate. Through systemic injection of anti-TCR antibody or antigenic peptides, investigators suggested that most of the negative selection occurs in the thymic cortex. But the requirements for negative selection, i.e cellular counterparts and costimulatory molecules are more available in the medulla or cortico-medullary junction rather than in the thymic cortex. Methods: The direct and indirect pathways of thymocyte death after systemic anti-TCR antibody injection were separated through several experimental systems. B6 mice were either adrenalectomized or sham-adrenalectomized to evaluate the role of endogenous glucocorticoids from adrenal gland. Role of TNF were evaluated through using TNF receptor double knockout mice. Results: We found that without indirectly acting mediators such as $TNF-\alpha$ or corticosteroid, double positive thymocyte death were minimal by systemic injection of anti-TCR antibody in TNF receptor double knockout neonatal mice. Also by analyzing neonatal wild-type mice with adoptively transferred mature T cells, only peripheral activation of mature T cells could induce extensive double positive thymocyte death. Conclusion: Thus, systemically injected anti-TCR antibody mediated thymocyte death are mostly induced through indirect pathway.