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 human hepatoma cell line, PLC/PRF/5, which is persistently infected with hepatitis B virus (HBV), has integrated HBV-DNA, secretes HBV surface antigen (HBsAg), and does not grow readily in congenitally athymic (nu/nu) mice. The present investigation was undertaken to ascertain whether the low tumorigenicity of this cell line was governed by a host immune response and/or was related to expression of HBsAg. Subcutaneous injection of 4-5 X 10(6) cells into BALB/c nude mice produced localized encapsulated tumors with morphologic features of primary hepatocellular carcinoma in 25% of the animals within 29-40 d. No tumor growth was observed at lower cell inocula. In contrast, SK-HEP-1, an HBV-negative human hepatoma cell line, produced tumors at 1-5 X 10(6) cells inocula in 66% of the animals. Immunosuppression of mice with antilymphocyte serum (ALS) or irradiation increased tumor incidence in mice inoculated with 1 X 10(6) PLC/PRF/5 cells to almost 100% and produced local invasiveness. Immunosuppression also reduced the latency, i.e., time to tumor appearance, and increased mean tumor weight. These results suggest that tumorigenicity was limited by the host immune response. The nature of the response was delineated by treating nude mice challenged with tumor cells with sheep anti-mouse interferon globulin (anti-IFN). When 2 X 10(6) cells were injected, tumor growth occurred in 75% of anti-IFN-treated mice, whereas controls injected with the same number of cells, but not receiving anti-IFN, failed to develop tumors. The tumors in the anti-IFN-treated mice were highly invasive and the latency period until tumor appearance was reduced to 3-5 d. An inverse correlation was found between susceptibility of the hepatoma cells to natural killer (NK) activity in vitro and resistance to tumor growth in vivo. In vitro cytotoxicity for PLC/PRF/5 cells was eliminated by anti-NK 1.1 and complement, establishing the effector cell as an NK cell. NK cell activity 14 d after inoculation of mice with PLC/PRF/5 cells was augmented against PLC/PRF/5 target cells but not against SK-HEP-1 cells. Treatment of mice with ALS, irradiation, or anti-IFN abolished NK activity against PLC/PRF/5 cells. Co-cultivation of nude mouse spleen cells with PLC/PRF/5 but not with HBsAg or SK-HEP-1 cells induced secretion of murine IFNalpha. These results suggest that the IFN/NK cell system may play a role in limiting tumorigenicity and invasiveness of HBV-infected human hepatocellular carcinoma cells by a mechanism similar to that found for other cells persistently infected with viruses.
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PMID:Role in nude mice of interferon and natural killer cells in inhibiting the tumorigenicity of human hepatocellular carcinoma cells infected with hepatitis B virus. 619 49

Autoantibodies against non organ-specific may be induced by IFN treatment in HCV liver chronic disease. In order to assess this issue and its clinical significance, 44 patients with chronic hepatitis C (anti HCV and RNA-HCV +) treated with IFN were evaluated. In 13 patients (29.5%) the following autoantibodies were detected during the treatment: AAML (5), AAN (9), ALK-M (4). Only in the A-LKM + patients there was a slight increase in aminotransferases with a reappearance of the viremia. Moreover 2 of these patients showed a flare of their liver disease without systemic findings. During the follow up (28) months one of the patients normalized the aminotransferases with clearance of serum HCV RNA. There were no statistical differences in the sustained response rate between patients with (2/13) or without (4/31) autoantibodies. The development of AAN, AAML and ALKM at low titer during IFN treatment in CH-C is without clinical relevance. However, ALKM detection is occasionally associated with the "breakthrough" phenomenon with HCV eradication, suggesting an immuno-modulatory activity of IFN.
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PMID:[Prevalence and clinical significance of autoantibodies in chronic hepatitis C treated with interferon alfa]. 757 7

The array of cytokines produced by T cells in effector sites is a primary means by which these cells mediate host defense. It is well recognized that cloned T cells are heterogeneous with regard to cytokine synthesis and, thus, in their ability to mediate specific immune responses, but the extent to which the patterns of cytokine secretion observed in cloned cells reflect actual populations of memory/effector T cells existing in vivo is largely unknown. Here, we report our findings using a multiparameter flow cytometric assay that allows simultaneous determination of an individual T-cell's ability to produce multiple cytokines and its phenotype after only short (4 to 8 hours) in vitro incubation with an activating stimulus and the secretion inhibitor Brefeldin A. This assay shows a rapid accumulation of interleukin-2 (IL-2), IL-4, and gamma-interferon (gamma-IFN) in the cytoplasm of CD4+ cells after stimulation with either accessory cell-independent (phorbol 12-myristate 13-acetate [PMA] + ionomycin [I]) or accessory cell-dependent (staphylococcal enterotoxins [SE] A and B) T-cell-activating stimuli. Further analysis showed that production of gamma-IFN and IL-4 is predominantly, if not exclusively, restricted to the CD45ROhigh memory/effector T-cell subset, whereas IL-2 may be produced by both the CD45ROhigh and CD45ROlow subsets. Simultaneous determination of IL-2 and gamma-IFN production among CD45ROhigh/CD4+ T cells showed distinct subsets that produce each of these cytokines alone (an average of 30% for IL-2 alone, 8% for gamma-IFN alone), both (16%), or neither (46%). Similar analyses with the small IL-4-producing memory/effector T-cell subset (only 4.3% of total CD4+/CD45ROhigh T cells) showed that an average of 51% of these IL-4-producing cells also synthesize average of 51% of these IL-4-producing cells also synthesize IL-2, 23% synthesize only IL-4, 16% synthesize all three cytokines, and 9.6% synthesize IL-4 and gamma-IFN. These patterns of cytokine synthesis were found to be similar with both PMA + I and SEA/SEB stimulation and were observed in both peripheral blood memory/effector CD4+ T cells and in T cells of similar phenotype obtained from cutaneous delayed-type hypersensitivity sites. Taken together, these data strongly support the in vivo existence of human memory/effector T-cell subsets with "preprogrammed" cytokine synthesis potential, although they suggest that these subsets may be more complex than originally proposed in the TH1/TH2 hypothesis.
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PMID:Direct demonstration of cytokine synthesis heterogeneity among human memory/effector T cells by flow cytometry. 763 49

The cytokine profile of human peripheral blood mononuclear cells (PBMC) stimulated by staphylococcal enterotoxin (SE) A and B was examined. Production of tumor necrosis factor (TNF alpha), interleukin (IL)-1, IL-6, IL-2, and gamma interferon (IFN-gamma) was observed. In contrast, Th2 cytokines IL-4 and IL-10 were absent from SEA- or SEB-stimulated PBMC. Moreover, adding IL-10 to SE-stimulated PBMC inhibited the production of IL-1, IL-6, TNF alpha, and IFN gamma by 50 to 80% but had less effect (8-30%) on T cell proliferation. IL-4 was less effective than IL-10 in inhibiting cytokine production and enhanced T cell proliferation by SEA or SEB. The anti-inflammatory agent, dexamethasone, was the most potent agent in controlling the SE-mediated effects as evidenced by inhibited T cell proliferation (55%) and reduced levels of IL-1, IL-6, and IFN gamma (60% to 100%) and TNF alpha (50%). Reducing levels of toxic mediators such as TNF alpha, IL-1, IL-6, and IFN gamma by dexamethasone in SE-induced T cell responses may be a useful therapeutic strategy to circumvent SE toxicity and pathogenesis.
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PMID:Differential inhibitory effects of interleukin-10, interleukin-4, and dexamethasone on staphylococcal enterotoxin-induced cytokine production and T cell activation. 788 17

The effects of a short period of in vivo systemic rh-IFN-alpha/2b treatment on epidermal-growth-factor(EGFR)-, estrogen(ER)- and progesterone(PR)-receptor content in 11 primary human cervical tumors was investigated by the radioreceptorial technique. EGFR levels were found to be significantly higher in cervical tumors after rh-IFN-alpha/2b treatment with respect to basal levels. In 2 cases, immunohistochemical and cytofluorimetric analysis showed that rh-IFN-alpha/2b treatment induces an increase in EGFR immunoreactivity and in the fraction of EGFR-positive cells. No difference in ER and PR levels in cervical tumors before and after rh-IFN-alpha/2b treatment was observed. Our results suggest that rh-IFN-alpha/2b up-regulates EGFR in primary human cervical tumors in vivo.
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PMID:Effect of recombinant human interferon-alpha/2b on epidermal-growth-factor-, estrogen- and progesterone-receptor expression in primary cervical cancer. 792 66

We previously demonstrated that the gene tyk2 rescues the phenotype of a human mutant cell line unresponsive to alpha (IFN) and partially responsive to IFN-beta. Here, we describe functional complementation of the mutant cells with the corresponding cDNA. To characterize the putative non-receptor protein tyrosine kinase encoded by the gene tyk2 and begin to understand its functioning, we have raised polyclonal antibodies against a segment of the protein. Using these, we have identified tyk2 as a 134-kDa protein which is rapidly and transiently phosphorylated on tyrosine in response to IFN-alpha/beta and possesses an inducible kinase activity when tested in vitro. IFN-gamma has no effect on the phosphorylation state of the protein. In agreement with previous genetic evidence, these results assign a role to tyk2 in the IFN-alpha/beta signalling pathway and not in the IFN-gamma pathway. Fractionation of cell lysates have helped to localize the bulk of the protein in the cytoplasm, with a minor fraction associated with the cell membrane. Both protein pools undergo activation upon short-term IFN treatment of intact cells. Through the study of the effect of pervanadate on the phosphorylation level and the activity of tyk2, we conclude that activation of tyk2 by IFN-alpha does not require an intermediate regulatory tyrosine phosphatase.
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PMID:Activation of the protein tyrosine kinase tyk2 by interferon alpha/beta. 805 12

Treatment of HER2/neu-overexpressing target cells with interferon gamma (IFN gamma) (200-2000 U/ml for 3 days) markedly enhances their sensitivity to lymphokine-activated killer (LAK) cell lysis. Increased sensitivity is associated with an up-regulation of intercellular adhesion molecule ICAM-1 determinants and a down-regulation of HER2/neu expression. In the present study, we show that exposure to another cytokine, tumor necrosis factor alpha (200 U/ml for 3 days), also decreased HER2/neu expression but had no effect on LAK cell lysis and ICAM-1 expression. This suggests that down-regulation of oncogene expression is not sufficient by itself to induce an enhanced sensitivity to LAK cell lysis. IFN-induced enhanced lysis was associated with an increased binding between effectors and targets, and antibodies to ICAM-1 as well as its counter-receptor LFA-1, blocked the increased binding and lysis. Treatment with IFN gamma still significantly enhanced lysis even when concanavalin A was added to the assay to induce maximal binding, indicating that a post-binding effect also participated in enhanced cytotoxicity. These post-binding alterations, were also sensitive to blocking with anti-ICAM-1 and anti-LFA-1 antibodies. Treatment with IFN also sensitized targets to lysis by T cells in the presence of lectin but had no effect on the relative resistance of HER2+ cells to lysis mediated by perforin or TNF. Together these data demonstrate the importance of ICAM-1 determinants in binding and post-binding events in the IFN-induced increased lysis of HER2/neu+ targets.
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PMID:Interferon-gamma-induced increased sensitivity of HER2/neu-overexpressing tumor cells to lymphokine-activated killer cell lysis: importance of ICAM-1 in binding and post-binding events. 810 95

It is well known that interferon-gamma (IFN-gamma; type II) potentiates various responses of human tumor necrosis factor (TNF) in a wide variety of cells and that this potentiation is accompanied by the up-regulation of TNF receptor synthesis. In the present studies we examined the regulation of TNF receptors by type I and type II IFNs in a hepatocellular carcinoma cell line, HEP G2. Exposure of these cells to IFN-gamma led to a decrease in TNF receptor number (4029 vs. 2719 sites/cell) without any change in the receptor affinity (0.96 nM vs. 1.1 nM). The effect was time and dose-dependent. Like IFN-gamma, IFN-alpha and IFN-beta (type I) down-modulated the TNF receptors on these cells. The effect of IFNs on the TNF receptors was inhibited by staurosporin, a protein kinase C (PK-C) inhibitor. Furthermore, by the use of receptor-specific antibodies, we found that the IFN-dependent decrease was primarily due to the p60 form of the TNF receptor. Our results presented are the first to demonstrate that IFNs can also down-modulate TNF receptors in certain cells and that this effect is mediated through PK-C.
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PMID:Both type I and type II interferons down-regulate human tumor necrosis factor receptors in human hepatocellular carcinoma cell line Hep G2. Role of protein kinase C. 827 22

Interferons have been postulated to inhibit cell growth by modulating the cellular response to growth factors. We now demonstrate that interferon increases tyrosine phosphorylation of EGFR in the human breast carcinoma cell line MDA 468, in the presence of EGF. The kinase activity of EGFR was elevated about two-fold when cells were cultured in the presence of IFN. Antiphosphotyrosine immunoblotting revealed that phosphorylation was increased two-fold on tyrosine residues in EGFR. These results suggest that IFN affects EGF signal transduction, and that such changes may play a role in growth inhibition induced by IFN in MDA 468 cells.
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PMID:Interferon-enhancement of tyrosine phosphorylation of epidermal growth factor receptors in human breast carcinoma cells. 831 88

Epidermal growth factor is a potential mitogen for many different human tumours. Its effect is mediated via a bispecific receptor (EGFR), the expression of which correlates well with invasive disease. We investigated the modulation of EGFR by cytokines produced following bacillus Calmette Guerin (BCG)-immunotherapy. Our data demonstrate the IFN gamma, TNF alpha and IL-1 alpha can decrease the expression of EGFR on some bladder tumour cell lines. IFN gamma reduced EGFR expression on two of eight cell lines (RT4, SD). However, IL-1 and TNF did not share this activity. When cells were treated with a combination of all three cytokines, EGFR was decreased on three cell lines (RT4, RT112, SD) and furthermore, the change in the receptor expression was even more marked. Treatment with phorbol ester (thereby activating protein kinase C) resulted in rapid disappearance of the receptor from the cell surface. Interestingly, the decrease of EGFR expression did not require protein synthesis. Although the cytokines studied could down modulate EGFR, this only occurred on three out of eight cell lines; therefore, it is unlikely that the suppression of proliferative activity caused by cytokine-induced decrease of EGFR expression is central to the antitumour action of BCG therapy, but in a proportion of tumours this mechanism may be involved.
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PMID:Cytokine modulation of epidermal growth factor receptor expression on bladder cancer cells is not a major contributor to the antitumour activity of cytokines. 856 66


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