Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:2.7.10.1 (ERK)
 95,504 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

T lymphocytes require two signals for activation. Recognition of antigen/MHC complexes by the T cell receptor delivers the first signal, while a second signal, delivered by the cell surface receptors CD80 and/or CD86 binding to the T cell surface molecule CD28, has been shown to be effective for the initiation of effective T cell responses. While some of the cytoplasmic effector molecules involved in T cell receptor signaling is known, little is known regarding those involved in the co-stimulation of T cells by CD28. Using the T cell leukemic cell line Jurkat as a model for T cell activation, we demonstrate that cross-linking CD28 using monoclonal antibodies causes tyrosine phosphorylation and activation of MAP kinase/ERK. This activation was rapid, peaking at approximately 5 minutes post CD28 cross-linking, and transient. Activation of MAP kinase/ERK occurred 3 fold less efficiently in a Jurkat line lacking functional p56lck (JCAM.1), and was almost undetectable in a line lacking CD45 (J45.01). These results suggest that CD28 cross-linking can activate intracellular signaling pathways via several different tyrosine kinases. Thus CD28 signaling can activate src family kinases lck and fyn, as well as the Tec family kinase emt/itk. Activation of any one or a combination of these tyrosine kinases may be sufficient for the activation of MAPK following CD28 cross-linking. Activation of MAPK has been shown to cause activation of AP-1 and other transcription factors via serine and/or threonine phosphorylation.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Activation of extracellular signal-regulated protein kinase (ERK/MAP kinase) following CD28 cross-linking: activation in cells lacking p56lck. 852 74

This study compares the ability of LFA-3 (CD58) and B7-1 (CD80) ligands to provide costimulatory signals for superantigen (SAg)-stimulated CD8+ and CD4+ T cells. We show that B7-1 and LFA-3 costimulation activate CD8+ T cells to proliferation, cytokine production (IL-2, TNF, and IFN-gamma), and cytotoxicity. A long-lasting proliferative response was observed after combined DR/B7-1/LFA-3 costimulation. Detailed analysis of SEA-activated CD8+ T cells revealed that maximal production of IFN-gamma was seen in LFA-3-costimulated cells, while production of IL-2 was mainly induced after B7-1 costimulation. A fivefold increase in the IFN-gamma production was observed when activated CD8+ T cells were costimulated with Chinese hamster ovary (CHO)-DR/LFA-3 cells compared with the secretion induced by CHO-DR/B7-1. In contrast, SEA-treated CD4+ T cells costimulated with B7-1 or LFA-3 gave rise to a similar production of IFN-gamma, suggesting a preferential function for the CD2/LFA-3 pathway in the regulation of IFN-gamma in CD8+ T cells. Moreover, the generation of CTL was supported similarly by B7-1 and LFA-3 costimulation, but not by CHO-DR cells. We conclude that ligation of the CD28 and CD2 receptors mediate distinct effect on CD8+ and CD4+ T cell effector functions.
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PMID:The role of B7-1 and LFA-3 in costimulation of CD8+ T cells. 899 78

OX40 ligand (OX40L), a member of the TNF family, was shown to be capable of signaling both the cells on which it is expressed and those expressing OX40, its cognate receptor. Here we show that OX40L is expressed on dendritic cells (DC), the most efficient APC to prime naive T cells. The expression and the functional activity of OX40L were examined by means of mAbs used to stain or cross-link OX40L on 1) freshly isolated human blood DC (bDC) and 2) monocyte-derived DC at different stages of differentiation. These were derived from monocytes cultured either with IL-4 and granulocyte-macrophage CSF (IL-4-Mo-DC) or with IL-4 and granulocyte-macrophage CSF plus TNF-alpha. Both types of Mo-DC expressed OX40L after stimulation through CD40; ligation of OX40L on activated IL-4-Mo-DC enhanced by 4- to 35-fold their cytokine production (TNF-alpha, IL-12 p40, IL-1 beta, and IL-6) and increased CD80, CD86, CD54, and CD40 expression. Stimulation of activated IL-4-Mo-DC through OX40L strikingly enhanced their maturation as evidenced by CD83 up-regulation, CD115 (CSF-1R) down-regulation, and typical morphologic changes. OX40L was constitutively expressed on a subset of bDC, and its ligation slightly enhanced CD40L-stimulated IL-12 production. OX40L was down-regulated after overnight culture and spontaneously reexpressed on a subset of mature bDC (CD83high, CD33high, CD11chigh, CD5+). Thus, the expression of OX40L on DC suggests a physiologic role of this molecule during T cell priming by virtue of its ability to costimulate both T cell and DC activation and differentiation.
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PMID:Expression and function of OX40 ligand on human dendritic cells. 937 71

Dendritic cells (DC), the most potent antigen-presenting cells found to date, can be generated from the adherent fraction of peripheral blood mononuclear cells (PBMC) by culture with granulocyte-macrophage colony-stimulating factor (GM-CSF) and IL-4. When interferon gamma (IFN-gamma) was added to the culture medium, the expression of CD1a, CD4 and CD80 markers were significantly reduced, while that of HLA-A, B, C, MHC II (MHC-DR), CD11a and CD54 were increased. T cell proliferation analysis showed that the DC derived from monocytes cultured with GM-CSF, IL-4 and IFN-gamma only induced weak responses in both activated and naive allogenic CD4(+) and CD8(+) T cells when compared to the reaction elicited by DC cultured without IFN-gamma. Furthermore, the DC derived from cultures with IFN-gamma, loaded with an immunogenic peptide derived from the HER2/neu protein [HER2 (9466)], only induced low levels of TNF release and weak proliferative responses in a specific cytotoxic CD8(+) T lymphocyte clone. Therefore, our results indicate that IFN-gamma negatively influences the differentiation and function of monocyte-derived DC by affecting the expression of surface molecules involved in their antigen-presenting function. This supports the general hypothesis that there exists a feedback immune regulatory mechanism between T cells and monocytes/DC.
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PMID:Interferon gamma impairs the ability of monocyte-derived dendritic cells to present tumour-specific and allo-specific antigens and reduces their expression of CD1A, CD80 AND CD4. 981 27

The escape of malignant cells from the immune response against the tumor may result from a defective differentiation or function of professional antigen-presenting cells (APC), ie, dendritic cells (DC). To test this hypothesis, the effect of human renal cell carcinoma cell lines (RCC) on the development of DC from CD34(+) progenitors was investigated in vitro. RCC cell lines were found to release soluble factors that inhibit the differentiation of CD34(+) cells into DC and trigger their commitment towards monocytic cells (CD14(+)CD64(+)CD1a-CD86(-)CD80(-)HLA-D Rlow) with a potent phagocytic capacity but lacking APC function. RCC CM were found to act on the two distinct subpopulations emerging in the culture at day 6 ([CD14(+)CD1a-] and [CD14(-)CD1a+]) by inhibiting the differentiation into DC of [CD14(+)CD1a-] precursors and blocking the acquisition of APC function of the [CD14(-)CD1a+] derived DC. Interleukin-6 (IL-6) and macrophage colony-stimulating factor (M-CSF) were found to be responsible for this phenomenon: antibodies against IL-6 and M-CSF abrogated the inhibitory effects of RCC CM; and recombinant IL-6 and/or M-CSF inhibited the differentiation of DC similarly to RCC CM. The inhibition of DC differentiation by RCC CM was preceeded by an induction of M-CSF receptor (M-CSFR; CD115) and a loss of granulocyte-macrophage colony-stimulating factor receptor (GM-CSFR; CD116) expression at the surface of CD34(+) cells, two phenomenon reversed by anti-IL-6/IL-6R and anti-M-CSF antibodies, respectively. Finally, a panel of tumor cell lines producing IL-6 and M-CSF induced similar effects. Taken together, the results suggest that the inhibition of DC development could represent a frequent mechanism by which tumor cells will escape immune recognition.
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PMID:Inhibition of the differentiation of dendritic cells from CD34(+) progenitors by tumor cells: role of interleukin-6 and macrophage colony-stimulating factor. 984 45

We studied how the interaction between human dendritic cells (DC) and Toxoplasma gondii influences the generation of cell-mediated immunity against the parasite. We demonstrate that viable, but not killed, tachyzoites of T. gondii altered the phenotype of immature DC. DC infected with viable parasites up-regulated the expression of CD40, CD80, CD86, and HLA-DR and down-regulated expression of CD115. These changes are indicative of DC activation induced by T. gondii. Viable and killed tachyzoites had contrasting effects on cytokine production. DC infected with viable T. gondii rather than DC that phagocytosed killed parasites induced secretion of high amounts of IFN-gamma by T cells from T. gondii-seronegative donors. IFN-gamma production in response to DC infected with viable parasites required CD28 and CD40 ligand (CD40L) signaling. In addition, this IFN-gamma response was dependent in part on IL-12 secretion. Production of IL-12 p70 occurred after interaction between T cells and DC infected with viable T. gondii, but not after incubation of T cells with DC plus killed tachyzoites. IL-12 synthesis was inhibited by blockade of CD40L signaling. IL-12-independent IFN-gamma production required CD80/CD86-CD28 interaction and, to a lesser extent, CD40-CD40L signaling. Taken together, T. gondii-induced activation of human DC is associated with T cell production of IFN-gamma through CD40-CD40L-dependent release of IL-12 and through CD80/CD86-CD28 and CD40-CD40L signaling that mediate IFN-gamma secretion even in the absence of bioactive IL-12.
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PMID:Human dendritic cells discriminate between viable and killed Toxoplasma gondii tachyzoites: dendritic cell activation after infection with viable parasites results in CD28 and CD40 ligand signaling that controls IL-12-dependent and -independent T cell production of IFN-gamma. 1090 56

In the present study, we show that endothelial-like cells (ELCs) can develop from human CD14-positive mononuclear cells (CD14 cells) in the presence of angiogenic growth factors. The CD14 cells became loosely adherent within 24 h of culture and subsequently underwent a distinct process of morphological transformation to caudated or oval cells with eccentric nuclei. After 1 week in culture the cells showed a clear expression of endothelial cell markers, including von Willebrand factor (vWF), CD144 (VE-cadherin), CD105 (endoglin), acetylated low-density lipoprotein (AC-LDL)-receptor, CD36 (thrombospondin receptor), FLT-1, which is vascular endothelial cell growth factor (VEGF) receptor-1, and, to a weaker extent, KDR (VEGF receptor-2). Furthermore, in these cells structures resembling Weibel-Palade bodies at different storage stages were identified by electron microscopy, and upon culturing on three-dimensional fibrin gels the cells build network-like structures. In addition, cell proliferation and vWF expression was stimulated by VEGF, and the endothelial cell adhesion molecules CD54 (ICAM-1), and CD106 (VCAM-1) became transiently inducible by tumor necrosis factor-alpha (TNF-alpha). In contrast, the dendritic markers CD1a, and CD83 were not expressed to any significant extent. The expression of CD68, CD80 (B7-1), CD86 (B7-2), HLA-DR and CD36 may also suggest that ELCs might be related to macrophages, sinus lining or microvascular endothelial cells. Taken together, our observations indicate that ELCs can differentiate from cells of the monocytic lineage, suggesting a closer relationship between the monocyte/macrophage- and the endothelial cell systems than previously supposed.
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PMID:Endothelial-like cells derived from human CD14 positive monocytes. 1092 8

In cultures, and in tissues as well, Hodgkin's and Reed-Sternberg (H-RS) cells and anaplastic large cell lymphoma (ALCL) cells are known to express a variety of cytokines, including IL-1, -5, -6, -8, -9, TNF-alpha, GM-CSF, M-CSF, TGF-beta, CD70, CD80, and CD86. Various numbers of H-RS/ALCL cells may express cytokine receptors (R), such as CD30, CD40, IL-2R (CD25/CD122), IL-6R (CD126), IL-7R (CD127), TNF-R (CD120), TGF-beta-R (CD 105/endoglin), M-CSF-R (CD115), and SCF-R (CD117/c-kit receptor). All of these cytokines and cytokine receptors are implicated in the growth regulation of H-RS/ALCL cells, the histopathologic alterations in tissues, and the clinical manifestations in patients with Hodgkin's disease (HD) or ALCL. Many of these cytokines or cytokine receptors also play an important role in the pathogenesis of other types of lymphomas. In this review, we describe the cytokine or cytokine-receptor expression that is diacritic for H-RS/ALCL cells. The identification of such unique cytokine-cytokine receptor interactions is likely to explain the biologic property that distinguishes HD/ALCL from other types of lymphomas. These interactions include those of CD30L-CD30, CD40L-CD40, CD70-CD27, CD80/CD86- CD28, SCF-CD117, IL-9-IL-9R, and IL-7-IL-7R. The H-RS/ALCL cells express IL-9 and two cytokine receptors, CD30 and CD117, which are observed infrequently in NHLs. Although IL-7 expression is not restricted to H-RS/ALCL cells, the expression of IL-7 in conjunction with IL-9 and/or CD117 may be regarded as unique for HD/ALCL because of an unusual combination and a synergistic activity among these cytokines. The expression of CD70 and CD80/CD86 (as cytokines) may exert a unique effect in HD because of intimate contact between H-RS cells and CD27/CD28-positive T cells. The expression of these costimulators (CD70 and CD80/CD86) and other adhesion/constimulator molecules such as CD54 and CD58, along with the secretion of soluble cytokines such as IL-1, IL-6, IL-7, or TNFs by H-RS/ALCL cells, could result in the profound T-cell proliferation often seen in lymph nodes involved by HD and some ALCL. On the other hand, the expression of CD30L and CD40L by surrounding T cells may affect the proliferation of H-RS/ALCL cells. The cytokine-cytokine receptor interaction between H-RS cells and T cells via direct cell-cell contact is bidirectional, a situation not commonly seen in NHLs. Copyright 1995 S. Karger AG, Basel
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PMID:Hodgkin's Disease and Anaplastic Large Cell Lymphoma Revisited. 1. unique cytokine and cytokine receptor profile distinguished from that of non-hodgkin's lymphomas. 1172 67

We report the immunological characterization of three colon carcinoma cell lines, COLO 205, SW620 and SW403, which we selected to combine with cytokine-secreting fibroblasts for the development of an allogeneic tumour cell vaccine. The cell lines expressed HLA-A2 as well as shared tumour-associated antigens (TAAs) representative of colon carcinomas: CEA, Ep-CAM, MUC1, HER2/neu and MAGE antigens. They did not secrete high levels of the immunosuppressive factors TGF-beta, IL-10 or prostaglandins. The lines presented TAAs in a manner recognized by immune effector cells, which was demonstrated by the lysis of SW620 by HLA-A2-restricted anti-p53 cytotoxic T lymphocytes (CTL). COLO 205 and SW620 were genetically modified to express the co-stimulatory molecule CD80 (B7.1), which increased the ability of the cells to stimulate CTL in vitro. CTL clones derived from HLA-A2+ peripheral blood mononuclear cells stimulated with the CD80-expressing lines lysed the stimulator cell and an HLA-A2+ colon cancer cell line, but did not lyse an isogeneic fibroblast line or an HLA-A2- colon cancer cell line. CTL clones derived from colon carcinoma patients immunized with an allogeneic vaccine containing these lines demonstrated killing of autologous tumour cells, the vaccine cell lines and other HLA-A2+ colon cancer cell lines, but not fibroblasts isogeneic to certain of the target cell lines. Our studies demonstrate that these colon carcinoma cell lines express shared TAAs that can induce CTLs which recognize and lyse other colon carcinoma cells, and support the continued clinical evaluation of the CD80 gene modified allogeneic colon cell/cytokine-secreting fibroblast carcinoma vaccine.
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PMID:Antigenic and immunologic characterization of an allogeneic colon carcinoma vaccine. 1210 28

The ability of acute myeloid leukaemia (AML) cells to acquire dendritic cell (DC)-like characteristics in vitro with a rapid culture method based either on the phorbol ester PMA or calcium ionophores has been studied in comparison to conventional AML-DC cultures with the cytokines granulocyte-macrophage colony-stimulating factor (GM-CSF), tumour necrosis factor-alpha (TNF-alpha), interleukin-3 (IL-3), SCF, FLT3-L and IL-4. In all AML patients, antigen-presenting cells (APC) could be generated from leukaemic cells in 2 days by incubation with PMA or calcium ionophore (A23187 or ionomycin) in the presence as well as in the absence of IL-4. In 30 out of 36 patients APC could be generated after 2 weeks of culture in cytokine-enriched medium. AML-APC cultured with PMA or calcium ionophores immunophenotypically and functionally were at a more mature stage than those cultured in cytokine-enriched medium. The most mature APC were generated by calcium ionophore A23187 plus IL-4, as evidenced by the higher expression of CD40, CD80, CD86 and HLA-DR. Autologous T cell mediated cytotoxicity towards AML blast cells in vitro was observed in 2 cases tested. The persistence of cytogenetic abnormalities confirmed the leukaemic origin of the AML-APC. The generation of AML-APC was possible from freshly isolated as well as cryopreserved material. Our data show that generation of sufficient AML-APC by A23187 plus IL-4 is feasible, for vaccination purposes, in approximately 70% of AML specimens, offering a time-saving and cost-effective approach in preparing anti-leukaemia vaccines.
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PMID:Rapid generation of antigen-presenting cells from leukaemic blasts in acute myeloid leukaemia. 1253 36


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