Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: DrugBank:BIOD00017 (IFN-gamma)
 28,919 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Hyperthermia treatment has been shown to enhance the in vitro antiproliferative effects of IFN-alpha, IFN-beta, and IFN-gamma, with IFN-gamma being more strongly enhanced than IFN-alpha. The comparative effects of hyperthermia on the in vivo antitumor activities of IFN-alpha and IFN-gamma were evaluated in the murine system using both subcutaneous and intraperitoneal B16 melanoma tumor model systems. Heat-induced whole body hyperthermia, resulting in a 2 degree C rise in body temperature, was administered by incubating the mice for 8 hours in a dry incubator at 37.1 degrees C. Whole body hyperthermia was found to enhance the antitumor activity of IFN-alpha by approximately 1.0 fold and 1.2 fold for the subcutaneous and intraperitoneal tumor models, respectively. This represented an additive effect of hyperthermia and IFN-alpha. Hyperthermia was found to enhance the antitumor activity of IFN-gamma by approximately 2.9 fold and 2.2 fold for the subcutaneous and intraperitoneal tumor models, respectively. This represented a synergistic effect of hyperthermia and IFN-gamma. The results of this in vivo study confirm and extend the in vitro observation that hyperthermia more strongly enhances the antitumor action of IFN-gamma than IFN-alpha. These results may have clinical importance because they suggest that hyperthermia may be used in combination with IFN-gamma to provide a synergistically enhanced antitumor action.
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PMID:Effect of hyperthermia on the antitumor actions of interferons. 128 87

The effects of interferon (IFN) on the expression of ICAM-1 in human melanoma cell lines and the shedding of ICAM-1 into spent media were investigated using an indirect binding assay and a double determinant immunoassay (DDIA). While IFN increased the level of expression of ICAM-1 on melanoma cell lines, the susceptibility to IFN differed according to cell line. The enhancing effect of IFN-gamma was concentration-dependent, and it exceeded those of IFN-alpha and IFN-beta. Shedding of ICAM-1 into spent media was detected effectively, and the results agreed well with the expression of ICAM-1 on melanoma cells. Immunostaining of the surgically removed melanoma lesions was positively correlated with the thickness of the primary lesion. The expression of ICAM-1 in primary melanoma lesions was inversely correlated with the disease-free interval. The circulating ICAM-1 with stage 4 melanoma patients significantly exceeded that of stage 1-3 melanoma patients. These observations suggest that ICAM-1 in its soluble form may play an important role in host immunities and may be useful in evaluating the prognosis of patients with melanoma.
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PMID:Analysis of expression and soluble form of intercellular adhesion molecule-1 in malignant melanoma. 128 75

The effect of gamma-interferon (IFN-gamma) on the induction of interleukin-2 (IL-2) activated killer cell activity was studied: (I) in peripheral blood lymphocytes (LAK cells) from cancer patients and healthy donors, (II) in lymphocytes infiltrating solid tumors (TIL) from melanoma and breast cancer patients, and (III) in pleural effusion associated lymphocytes (EAL) from patients with lung adenocarcinoma. The coculture of LAK, TIL and pleural effusion mononuclear cells (MNC) with several doses of IFN-gamma (10, 50, 250, and 1250 U/ml) and a low dose of IL-2 (10 U/ml) for 5 days resulted in a synergistic effect on the cytotoxicity of these cells against several tumor cell lines. Furthermore there was a potentiation in the proliferation of MNC after a 5-day culture. The induction of lymphocyte cytotoxicity by a combination of IFN-gamma with low doses of IL-2 may be helpful in designing more effective cancer immunotherapeutic protocols with LAK, TIL or EAL.
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PMID:Gamma-interferon enhances the cytotoxic activity of interleukin-2-induced peripheral blood lymphocyte (LAK) cells, tumor infiltrating lymphocytes (TIL), and effusion associated lymphocytes. 128 41

Expression of the Ly-6A/E gene by transformed cells was investigated in 14 cell cultures of C57BL/6 and BALB/c mouse origin derived from spontaneous or chemically-induced non-hematopoietic tumours and from cells transformed by SV40 virus. Histologic types included carcinomas, sarcomas and a melanoma. Thirteen out of 14 cell cultures expressed membrane Ly-6A/E antigens; only the B16-A melanoma was negative, but it expressed Ly-6A/E after incubation with IFN-gamma. The effect of in vitro permanence was studied on early (< 10) and late (> 20) passages of B16-A melanoma and MN/MCA1 fibrosarcoma. Late passage B16-A cells were Ly-6A/E-negative and refractory to induction of Ly-6A/E (but not of H-2 antigens) by IFN-alpha, IFN-beta, or IFN-gamma; MN/MCA1 maintained a high expression of Ly-6A/E, but no increase was induced by IFNs. It was found that both early and late in vitro passages of MN/MCA1 actively produced IFN-alpha/beta. The analysis of cells of fibroblastic origin revealed a significant correlation between IFN release in the culture medium and Ly-6A/E levels. Culture of fibrosarcoma cells in the presence of an anti-IFN-alpha/beta serum reduced Ly-6A/E expression, thus indicating the existence of an autocrine loop.
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PMID:Ly-6A/E gene is widely expressed among transformed nonhematopoietic cells. Autocrine modulation by interferon. 129 72

The ability of interleukin-3 (IL-3) to induce antimicrobial and tumoricidal activity was evaluated. Macrophages infected with two intracellular protozoa, Leishmania amazonensis or Trypanosoma cruzi, were treated with cytokines. IL-3 induced a dose-dependent enhancement of microbistasis against leishmanias, and the activity of IL-3 (100 ng/ml) was comparable to that of gamma interferon (IFN-gamma) (1,000 U/ml). In addition, IL-3 in combination with either granulocyte-macrophage colony-stimulating factor (GM-CSF) or macrophage CSF (M-CSF) or with IFN-gamma reduced infection and lowered the required dose. IL-3 similarly activated macrophages to inhibit intracellular replication of T. cruzi. Furthermore, IL-3 induced antibody-independent tumoricidal activity against melanoma cells that was dose dependent and comparable to that of lipopolysaccharide and GM-CSF. The mechanisms by which IL-3 induced antimicrobial activity may involve at least the augmentation of oxidative capacity. IL-3, at concentrations of 0.5 ng/ml or greater, led to a significantly increased oxidative burst which paralleled the inhibition of protozoan replication. The enhancement of oxidative capacity by IL-3 (5 ng/ml or higher) was comparable to that of IFN-gamma. The induction of tumoricidal activity was associated with the production of tumor necrosis factor alpha (TNF-alpha), which in this system may feed back to enhance the macrophage inhibition of leishmanias, as demonstrated by neutralization of IL-3 activation by anti-TNF-alpha antibody. Thus, peripheral blood macrophages remain responsive to IL-3, as demonstrated by enhanced antimicrobial and tumoricidal activity. IL-3 may have potential clinical applications because of these properties and its effect on myelopoiesis.
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PMID:Interleukin-3 induces antimicrobial activity against Leishmania amazonensis and Trypanosoma cruzi and tumoricidal activity in human peripheral blood-derived macrophages. 131 23

The adherence of cells to microvascular endothelium is important in a number of processes, including inflammatory responses and metastasis. It has been demonstrated that in human models, cytokines such as TNF, IL-1, IFN-gamma increase the adhesiveness of endothelium for cells of the immune and inflammatory system by stimulating the expression of cell adhesion molecules on endothelial cell surfaces. We and others have shown similar cytokine-induced endothelial adhesiveness for tumor cells in murine and human models. In contrast to the effect of those modulators, transforming growth factor-beta (TGF-beta) has been shown to inhibit the binding of human neutrophils and T lymphocytes to human endothelium, although the mechanism of TGF-beta action remains unknown. Little is known about the effect of TGF-beta on tumor cell-endothelial interaction. In the present study, we demonstrate that TGF-beta inhibits basal and TNF-enhanced binding of murine P815 mastocytoma cells to murine microvascular endothelium (MME). The alterations in MME mediated by TGF-beta, also lead to the inhibition of adherence of murine splenocytes, thymocytes, and human lymphoblastoid cells but do not inhibit adherence of murine B16 melanoma cells. The effect of TGF-beta is transient and inhibition of the endothelial adhesive phenotype is strongest 12 to 24 h after addition of the factor to MME. The TGF-beta-mediated inhibition of P815 basal binding to endothelium is dependent on protein synthesis because cycloheximide reverses the TGF-beta effect. TGF-beta does not appear to activate classical signal transduction pathways. Inhibitors of G proteins do not abolish TGF-beta action, protein kinase C and protein kinase A activators elicit an effect opposite to that of the factor, TGF-beta does not increase intracellular cAMP levels, and finally calcium-mobilizing agents do not mimic, but rather inhibit the effect of TGF-beta. However, TGF-beta-mediated inhibition of both basal binding and TNF-enhanced P815 binding to MME is completely abolished in the presence of the protein phosphatase inhibitor okadaic acid which suggests that TGF-beta may elicit its effect by stimulating protein phosphatase activity.
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PMID:Inhibition of basal and tumor necrosis factor-enhanced binding of murine tumor cells to murine endothelium by transforming growth factor-beta 1. 131 61

The reactivity of four monoclonal antibodies (MAbs) directed against IFN-gamma inducible antigens with melanocytic cells was investigated in the course of local and systemic tumor progression of human malignant melanoma. Frozen sections of histologically defined melanocytic tissues at different stages of progression were stained with these MAbs using an indirect immunoperoxidase technique. The reactivity of MAbs Me15/B3 and Me15/F9, directed against two different epitopes of a 90-kDa molecule, was found to correlate with melanoma progression. Indeed, a significantly lower percentage of small than of advanced primary melanomas or metastases stained positively. A differential staining of nevocytic and dysplastic nevi was further observed for these two MAbs, which were also non-reactive with normal skin melanocytes. The reactivity of MAb Me14/D12, which identifies the intercellular adhesion molecule ICAM-1 and MAb Mel14/F12, directed against a 40-kDa molecule, was found to be independent of the Breslow thickness of primary melanomas. Both the latter MAbs stained a high proportion of nevocytic and dysplastic nevi. The co-expression of the surface molecules defined by MAbs Me14/D12, Me15/B3 and Me15/F9 in the course of melanoma progression was also analyzed. The frequency of this co-expression increased according to the Breslow thickness of primary melanomas. In addition, up to 100% of metastases, as opposed to 20% of dysplastic nevi, were found to be simultaneously stained by these three MAbs. It is therefore conceivable that high-risk melanocytic lesions might be identified by the use of a combination of MAbs directed against IFN-gamma regulated antigens.
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PMID:The differential reactivity of cells of the melanocytic lineage with four monoclonal antibodies against IFN-gamma inducible molecules. 134 19

Tumor cells often display alterations in their normal program of cellular differentiation. A promising approach for the treatment of cancer involves the induction of terminal differentiation and a loss of proliferative capacity in cancer cells. In human melanoma cells, the combination of mezerein (MEZ) and fibroblast interferon (IFN-beta), results in a rapid and irreversible suppression of cell growth with a concomitant increase in the synthesis of melanin. The induction of terminal differentiation is associated with alterations in the expression of several cellular genes, including fibronectin, ISG-15 and ISG-54, and changes in the expression of specific cell surface antigens, including intercellular adhesion molecule-1 (ICAM-1) and HLA Class I antigens. In the HO-1 human melanoma cell line, induction of terminal differentiation by MEZ plus IFN-beta results in an induction and/or increased expression of ICAM-1, HLA Class I antigens and HLA Class II antigens. IFN-beta and MEZ alone can modulate expression of these antigens to a lower extent than does the combination of compounds. Induction of terminal differentiation and the irreversible suppression of cell growth is not a prerequisite for antigenic modulation in HO-1 cells. This is indicated by the inability of immune interferon (IFN-gamma), a strong inducer of ICAM-1, HLA Class I antigens and HLA Class II antigens synthesis, or the combination of IFN-beta plus IFN-gamma which synergistically but reversibly suppresses HO-1 growth, to induce melanin synthesis or terminal differentiation in HO-1 cells.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Modulation of the antigenic phenotype of human melanoma cells by differentiation-inducing and growth-suppressing agents. 135 50

The passage of MHC class I heavy chains through the exocytic pathway is promoted by association with beta 2 microglobulin (beta 2m). In order to analyze the structural basis of this phenomenon, processing and cell surface expression of HLA class I molecules have been investigated in the beta 2m null human melanoma cell line FO-1 transfected with either the human or mouse beta 2m genes. These natural structural variants of beta 2m display 30% amino acid sequence divergence. In comparison with a human beta 2m transfectant of the FO-1 cell line (designated FO-1H), FO-1 cells transfected with the mouse beta 2m gene (FO-1C) express HLA class I molecules that are processed with grossly altered kinetics and are present on the cell surface at reduced levels. The suboptimal expression of HLA class I heavy chains encoded by FO-1C cells reflects a defect in heavy chain stability since cell surface expression of HLA class I antigens was increased following incubation at 30 degrees C. The increased cell surface expression paralleled accelerated processing of HLA class I heavy chains by FO-1C cells. In contrast, no induction in either cell surface expression or processing of HLA class I heavy chains was observed for the beta 2m-negative FO-1 parent cell line, which remained HLA class I antigen null when cultured at 30 degrees C, or the FO-1H human beta 2m transfectant, which expressed equivalent levels of HLA class I antigens on the cell surface at 37 degrees C and 30 degrees C. Further up-regulation of the temperature-sensitive induction of HLA class I antigen expression was accomplished by treatment of the FO-1C transfectant with interferon-gamma; this latter effect appears to be active at a posttranscriptional step for FO-1 cells since IFN-gamma was not as potent a transcriptional activator at 30 degrees C as it was at 37 degrees C. These results indicate that HLA class I heavy chains expressed by FO-1C cells are subject to temperature-sensitive and cytokine-inducible stabilization that increases their affinity for the structural variant of beta 2m and promotes exocytosis of the HLA class I heterodimer to the cell surface. Furthermore, beta 2m non-conformed MHC class I heavy chains undergo stabilization that is not associated with enhanced cell surface expression, indicating that the exocytosis of putative "empty" HLA class I antigens is a process dependent upon association with beta 2m.
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PMID:The role of beta-2 microglobulin in temperature-sensitive and interferon-gamma-induced exocytosis of HLA class I molecules. 141 16

The protein previously called "Mr approximately 50/pI approximately 6.9," which we observed to be induced by the immunoregulatory cytokine interferon (IFN)-gamma in human fibroblasts, was purified from a total cell lysate by preparative two-dimensional gel electrophoresis and identified by partial amino-terminal sequencing as leucine aminopeptidase (LAP), a 53-kDa cytosolic exopeptidase. Induction of LAP protein by IFN-gamma, confirmed by immunoblotting with an antiserum raised against bovine lens LAP, is a consequence of induction of LAP mRNA and occurs in all four human cell lines examined: HS153 fibroblasts, ACHN renal carcinoma, A549 lung carcinoma, and A375 melanoma. Induction of LAP mRNA is a secondary response to IFN-gamma, blocked by inhibition of protein synthesis with cycloheximide.
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PMID:Induction of leucine aminopeptidase by interferon-gamma. Identification by protein microsequencing after purification by preparative two-dimensional gel electrophoresis. 155 94


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