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)

The role of different protein kinases in the process of T cell activation has been studied using several inhibitors. The model we adopted was the activation of PBMC by monoclonal antibody OKT3. The results obtained confirm that PKC and PTK are involved. Thus, the inhibitors H-7, staurosporine, and genistein exerted a dose-dependent inhibition of CD2 up-regulation, CD25 expression, IL-2 production, and cellular proliferation. On the other hand, our data indicate that PKA is not involved since the inhibitor HA1004 was ineffective. W-7, an inhibitor of Ca(2+)-CaM protein kinases, inhibited OKT3-induced modulation of cell-surface markers and PBMC proliferation, whereas a slight increase in IL-2 release was detected at the highest dose used (20 microM). Using the MLCK inhibitor ML-9, we extended our studies to the myosin light chain kinase, which influences the organization of the cytoskeleton. ML-9-inhibited PBMC activation in terms of modulation of cell-surface markers and proliferation but stimulated IL-2 production. Similar results were obtained using the cytoskeleton disruptors demecolcine and cytochalasin B. Taken together the data described herein indicate that T cell activation is a complex event in which, aside from classical signal transduction-associated kinases PKC and PTK, at least two other kinases, Ca(2+)-CaM kinases and MLCK, seem to be involved, the latter probably through correct assembly of the cytoskeleton.
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PMID:Involvement of multiple protein kinases in CD3-mediated activation of human T lymphocytes. 790 41

The angiogenesis inhibitor AGM-1470 has recently been reported to inhibit collagen-induced arthritis in rats. To determine if the anti-arthritic effects of AGM-1470 might be due to T cell inhibition, we have studied its effects on T cell responses in vitro. Responses of human cells to tetanus toxoid (TT), and those of murine splenocytes to staphylococcal enterotoxin (SE), mitogens or a mls difference were inhibited by AGM-1470. Responses of human cells to SE, OKT3 and PHA were all partially inhibited on day 2 (d2) but not d3, and in fact were augmented on d6-8. The amount of IL-2 in SEA cultures was augmented on d4 and d5. There were no differences in the expression of CD3, CD4, CD8, CD25, CD45RA, CD45RO, LFA-1, VLA-4 or VLA-6 in inhibited cultures, except for slight decreases in CD25 and CD45RO in TT cultures. These results indicated that the angiogenesis inhibitor AGM-1470 also modulates human and murine lymphocyte function.
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PMID:Modulation of T lymphocyte function by the angiogenesis inhibitor AGM-1470. 827 96

The T cell activation pathway involves an increase in mitochondrial activity. This can be evaluated in individual cells using the fluorescent probe rhodamine 123 (Rh123) and flow cytometry. Peripheral blood mononuclear cells (PBMC) were stimulated with optimal concentrations of phytohaemagglutinin (PHA), superantigens (Sag) SEA and SEC2, and allogeneic cells. Activation kinetics were followed at days 1, 2, 4 and 7. In all activation conditions, Rh123 uptake was augmented with the CD25 expression, cell size, and DNA synthesis. Rh123 uptake reflected an increase in mitochondrial activity and mass, as assessed by experiments in which Rh123 was substituted for by the 10-nonyl acridine orange, which stains mitochondria in an energy-independent manner. The spectral characteristics of Rh123 allowed us to double stain cells with Rh123 and phycoerythrin-conjugated monoclonal antibodies. In PHA-activated cultures, CD4+ and CD8+ cells incorporated essentially the same amount of Rh123 at all time points, suggesting that the two subsets did not differ in their activation kinetics. Accordingly, after 1 week of culture, no significant modification in the CD4/CD8 ratio was observed. Sag-activated CD4+ cells incorporated a higher amount of Rh123 than did CD8+ cells and preferentially expanded after 1 week of culture as indicated by the increase in the CD4/CD8 ratio. The different behavior of the CD4 and CD8 subsets observed by dual color flow cytometry in the PHA and Sag models was confirmed using purified CD4+ and CD8+ cell preparations obtained by immunomagnetic sorting. CD4+ cells were also the preferential target in the allogeneic model, although the magnitude of the phenomenon was lower than in the Sag model. Present data indicate that Rh123 is a reliable marker for monitoring the mitochondrial compartment during T cell activation. The possibility of phenotyping Rh123-stained cells adds to the applicability of the probe.
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PMID:Rhodamine 123: a useful probe for monitoring T cell activation. 858 51

Germinal centers (GC) are well-defined areas in lymphoid organs were B cells proliferate and differentiate in response to T-cell-dependent antigens. The GC comprises B cells, follicular dendritic cells, tangible body macrophages, and a low number of CD4+ T cells. A large portion of these T cells expresses CD57. We have examined the ability of the CD4+ CD57+ GC T cells to become activated and to take part in B cell activation processes. These T cells coexpress CD45RO, CD69, CD28, and upon mitogenic stimulation CD25. The cell population was found neither to contain nor to be able to produce any specific mRNA for IL-2, IL-4, and IFN-gamma upon activation. Levels of mRNA encoding CD40 ligand was also undetectable under similar conditions. Furthermore, in contrast to ordinary CD4+ T cells, this population expressing CD57 was unable to induce B cells to Ig production in the presence of pokeweed mitogen or SEA unless IL-2 was added to the cultures. However, despite their apparent lack of function CD4+ CD57+ GC T cells were found to rescue GC B cells from cell death in vitro to the same extent as CD4+ CD57+ Th cells. The phenotypical and functional differences found between these Th cells and regular Th-cells suggest that they either represent a T cell subset with distinct properties within the GC yet to be determined or that they represent T cells, late in the immune response, having lost most of their original functions and capabilities.
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PMID:Immunoglobulin production induced by CD57+ GC-derived helper T cells in vitro requires addition of exogenous IL-2. 862 May 44

Working with the murine epidermal-derived dendritic cell (DC) line XS52, we have observed previously that antigen-specific interaction with T cells stimulates their "terminal maturation" into fully professional DC. In this study we examined the impact of dexamethasone (DEX) on this T cell-induced event. When added to cocultures of XS52 DC and the KLH-specific Th1 clone HDK-1 in the presence of antigen, DEX at relatively low concentrations (10(-9)-10(-7) M) prevented substantially or completely each of the changes that typify terminal maturation, including (a) secretion of relatively large amounts of IL-1beta, IL-6, and TNFalpha; (b) loss of CD115 (colony-stimulating factor-1 receptor) expression and proliferative responsiveness to colony-stimulating factor-1; and (c) elevated expression of CD86 (B7-2). XS52 cells also underwent terminal maturation upon exposure to lipopolysaccharide alone, and DEX also inhibited effectively each of the same changes, indicating that DC can serve as the direct target of DEX. By contrast, DEX inhibited XS52 DC-stimulated IL-2 secretion by HDK-1 T cells, but not other changes that accompany T cell activation, including the secretion of IFNgamma and TNFalpha and the elevated expression of CD25, CD28, and CD44. These results reveal a new immunosuppressive mechanism of glucocorticoid action, that is, direct inhibition of T cell-mediated terminal maturation by DC.
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PMID:A novel mechanism of glucocorticoid-induced immune suppression: the inhibiton of T cell-mediated terminal maturation of a murine dendritic cell line. 869 Jul 86

IL-2/LAK adoptive immunotherapy is one of new complementary treatments for advanced malignant tumors. This therapy has two main problems: high dose of IL-2 often causes serious side effects and it is difficult to gain enough amount of LAK cells. MPS is a new immunomodulator in cancer immunotherapy. The present study showed that, comparing with IL-2 10(6)U/L only, IL-2 2 x 10(5)U/L plus MPS 0.4mg/L was significantly more effective in activating both the growth of LAK cells and its cytotoxicity against HEP-2 cells. And the ratio of CD25 positive LAK cells cultured in this condition was also higher. This result suggests that MPS plays a role in creasing the membrane receptors of IL-2.
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PMID:[The effect of MPS on LAK cell growth and its cytotoxic activity against laryngeal cancer (HEP-2)]. 964 62

We have studied tissue expression of the cytokine receptors using a high sensitivity biotin-streptavidin system on cryostat sections. We used a panel of monoclonal antibodies from the 6th International Workshop on Human Leukocyte Differentiation Antigens, namely CD25 (IL-2R alpha), CD95 (FAS antigen), CD116 (GM CSFR), CD117 (SCFR), CD120 alpha (TNFR I), CD120b (TNFR II), CD121a (IL-1R I), CDw123 (IL-3R), CD124 (IL-4R), CD126 (IL-6R), CD127 (IL-7R), CDw128 (IL-8R), CD130 (gpl130), CD131 (IL-3R), CD132 (IL-2R gamma), CD134 (OC-40), CD135 (FLT3/FLK2). Examined tissues (lymph nodes and spleens) were obtained from 12 patients with folicular non-Hodgkin's lymphoma, periferal T non-Hodgkin's lymphoma, B lymphoma, myeloma, Hodgkin's disease, two cases of T cell rich B-lymphoma, autoimmune haemolytic anemia and two cases of rudimentary trombocytopenic purpura. Our results indicate that immunohistological technology using native tissues on cryostat sections, monoclonal antibodies and the visualisation with biotin-streptavidin is a particularly suitable supplementary staining procedure for detection of the cytokine receptors in tissues.
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PMID:[Immunohistochemical detection of cytokine receptors on cryostat tissue sections]. 1037 62

CD30+ large anaplastic lymphoid cells are seen in anaplastic large cell lymphoma (ALCL), and also in lymphomatoid papulosis (LyP) and other lymphoproliferative disorders. It can be difficult precisely to categorize these disorders with CD30+ cells. We report a case of primary cutaneous CD30+ ALCL with systemic metastases in whom the clinical disease subsequently evolved into LyP. The patient was initially administered cisplatin and etoposide and made a good response. Eighteen months later, recurrent, self-healing cutaneous small nodules appeared around the original tumour site without any systemic involvement. Histopathological examination of the recurrent lesions revealed infiltration with a mixture of cells that included neutrophils, eosinophils and CD30+ large anaplastic cells cytologically identical with those in the primary lesion. The anaplastic cells in both the primary and recurrent lesions were positive for monoclonal antibodies CD30, CD25 and a monoclonal antibody directed against the chimeric protein p80(NPM-ALK). These observations suggest the possibility that the ALCL and the subsequent LyP represent different clinical manifestations of proliferation of the same clone.
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PMID:CD30+ lymphoproliferative disorder: primary cutaneous anaplastic large cell lymphoma followed by lymphomatoid papulosis. 1145 20

This report describes an unusual extramedullary hematologic malignancy in an 18-month-old child who presented with a capillary leak syndrome that evolved into hyperleukocytosis with malignant cells. The circulating tumor cells did not express an antigen profile typical of any subtype of leukemia commonly observed in children. Tumor cells were CD3(-)/CD56(+); had germline TCR genes; and strongly expressed CD30, epithelial membrane antigen, and anaplastic lymphoma kinase (ALK) consistent with a null cell anaplastic large cell lymphoma (ALCL). The malignant cells contained a t(2;19)(p23;p13.1) that interrupted ALK and translocated it to the der(19). Reverse transcriptase-polymerase chain reaction and nucleotide sequence analysis revealed fusion of ALK to tropomyosin 4, an ALK fusion partner not described previously in hematologic malignancies. The clinical presentation and phenotypic features of this malignancy were not typical for ALCL because tumor cells expressed both myeloid (CD13, CD33, HLA-DR) and natural killer (NK) cell antigens. The neoplastic cells most resembled NK cells because in addition to being CD3(-)/CD56(+) with germline TCR genes, these cells were CD25(+)/CD122(+)/granzyme B(+) and possessed the functional properties of immature NK cells. The unusual clinical presentation, immunophenotype, and functional properties of these neoplastic cells suggest that this malignancy may be derived from the putative myeloid-NK precursor cell. Furthermore co-expression of NK and ALCL features supports the concept that a minority of null-ALCL may be derived from NK cells and expands the spectrum of phenotypes that can be seen in tumors produced by ALK fusion proteins. (Blood. 2001;98:1209-1216)
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PMID:Unusual childhood extramedullary hematologic malignancy with natural killer cell properties that contains tropomyosin 4--anaplastic lymphoma kinase gene fusion. 1149 72

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


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