Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0027819 (neuroblastoma)
 27,800 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Gamma-interferon (IFN-gamma) increases class I major histocompatibility complex (MHC) expression in human neuroblastoma cell lines. These cells are of interest because of the initial paucity of MHC expression, a paucity that is also seen in neural tumors and normal brain. The aim of this study was to define further the class I molecules, and to begin to analyze the genetic basis of the regulation. Northern blot analysis with cDNA probes for HLA and beta 2-microglobulin (beta 2-m) RNAs shows that both are present in reduced quantities (relative to a B-cell control) in control neuroblastoma cells. The levels of both RNAs are increased following IFN-gamma. This behavior parallels that of the corresponding polypeptides. Further monoclonal antibody analysis of the class I proteins from IFN-treated cells shows that both HLA-A and HLA-B are present. For two cell lines, expression of appropriate polymorphic specificities is also shown to be increased. We conclude that IFN-gamma can cause increased expression of appropriate HLA-A,B,C specificities on cells of neuronal origin. This raises the question of whether these molecules can serve predicted immunological functions.
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PMID:Interferon-mediated induction of class I MHC products in human neuronal cell lines: analysis of HLA and beta 2-m RNA, and HLA-A and HLA-B proteins and polymorphic specificities. 309 12

IFN-gamma is known to induce expression of Ia antigens on a variety of cell types. In the present study, this activity of IFN-gamma has been analyzed with a panel of 36 melanoma cell lines, normal melanocytes, and 97 cell lines representing a range of other differentiation lineages. 55% of the melanoma cell lines express Ia antigens in a constitutive manner without IFN-gamma induction. Of the 16 Ia-melanoma lines, 13 could be induced to express Ia antigens by IFN-gamma, whereas three were noninducible. Melanocytes, which do not normally express Ia antigens, are converted to Ia expression by IFN-gamma. Ia antigens expressed constitutively or after IFN-gamma induction were identified with antibodies detecting monomorphic and allomorphic products of DR and DC loci. IFN-gamma appeared to be unique in its ability to induce Ia expression on melanoma and melanocytes; 14 other agents (including IFN-alpha and IFN-beta) known to influence growth or differentiation did not have Ia-inducing activity. Equally striking is the restriction of antigenic changes following IFN-gamma induction to HLA-associated products; of the 38 systems of cell surface antigens examined, only HLA-A,B,C, beta 2m, and Ia antigens were affected. A variety of other Ia- cell types were shown to be Ia-inducible by IFN-gamma; these included established lines of breast, colon, pancreas, bladder, kidney, ovary, and brain cancers, and cultures of normal fibroblasts, kidney epithelia, and epidermal keratinocytes. In contrast, three tumor types, teratocarcinoma, choriocarcinoma, and neuroblastoma, were not inducible for Ia expression, even though IFN-gamma could induce expression of HLA-A,B,C products. The broad representation of Ia antigens on most somatic cell types expressed either constitutively or after IFN-gamma can be viewed in an immunological context (antigen presentation/immune regulatory signals) or could indicate that Ia products have functions other than those related to immune reactions.
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PMID:Surface antigens of melanoma and melanocytes. Specificity of induction of Ia antigens by human gamma-interferon. 620 1

The human neuroblastoma cell line T98G is sensitive to the antiproliferative activity of both alpha- and gamma-interferons (IFNs). Specific binding of a homogeneous 125I-IFN-alpha 2 probe to high-affinity membrane receptors (apparent Kd = 6.2 X 10(-10) M) can be decreased by pretreatment of these cells with human IFN-gamma (HuIFN-gamma, derived by recombinant DNA techniques). The regulation of HuIFN-alpha 2 binding by such pretreatment is reflected by subsequent inhibition of both the antiviral and antiproliferative activities of HuIFN-alpha 2 on T98G cells. Thus, binding of HuIFN-gamma to its distinct cell-surface receptor can modify expression of the separate IFN-alpha receptor, presumably through an indirect effect on the apparent Kd of the IFN-alpha 2 receptor-ligand interaction.
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PMID:Modulation of human interferon-alpha receptor expression by human interferon-gamma. 633 99

Expansion of the natural killer (NK) subset of lymphocytes represents a rare leukemia phenotype with variations in clinical presentation, morphology, surface phenotype, and effector function. This paper reports on a 5-year-old male patient who had an unusual presentation of an NK cell leukemia that was initially diagnosed as neuroblastoma. A bone marrow (BM) aspirate showed clumps of undifferentiated cells with the following phenotype: CD56bright+, CD33dim+, CD45-, CD2-, CD19-, CD16-, and CD57-. Cytochemistry was noncontributory. The patient, having failed to respond to conventional neuroblastoma chemotherapy, was subsequently diagnosed as having NK cell leukemia based on functional in vitro assays. The patient responded to acute lymphoblastic leukemia (ALL) chemotherapy but relapsed 4 weeks into treatment and eventually died 25 weeks after initial presentation. The cell surface phenotype observed is consistent with a rare NK cell subset, the biology of which has not been well defined. Freshly isolated BM cells killed K562 cells in a conventional 51Cr-release assay. Both interleukin-2 (IL-2) and interferon-alpha (IFN-alpha) induced LAK activity against the Daudi cell line. IL-2 induced proliferation of the leukemic cells. TNF-alpha, IFN-gamma, IL-6, IL-1ra, and TGF-beta levels were assessed and found to be concentrated in BM, in contrast to plasma samples. TNF-alpha was present at a high concentration in BM (150.9 pg/ml), probably a reflection of the associated disease pathology of severe bone pain and pyrexia. In summary, this paper details clinical and laboratory investigations of a leukemia of a rare NK cell subset.
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PMID:Recognition of unusual presentation of natural killer cell leukemia. 757 92

We showed earlier that interferon-gamma is a powerful inducer of differentiation of human neuroblastoma (NB) cells. Although 2',5' oligo-adenylate synthetase (2,5 OAS) may play a role in mediating the anti-proliferative and/or differentiative effects of interferons (IFNs), direct evidence is lacking. We have investigated gene and protein expression of the 4 different 2,5 OAS isoforms and their cumulative enzymatic activity in a previously characterized IFN-gamma-sensitive human NB cell line, LAN-5. Analysis of total and poly(A)+ RNA by Northern blot and RT-PCR indicated that expression of the mRNA coding for the 40-, 46-and 69-kDa isoforms was induced in a time- and dose-dependent manner, reaching a maximum after a 36-hr treatment with 1000 IU/ml of IFN-gamma. In the absence of treatment, only the mRNA for the 69-kDa isoform was detectable by RT-PCR. Inhibition of transcription with actinomycin D showed that 2,5 OAS mRNA was quite stable, with a half-life of about 4 hr. With respect to the protein content, no 2,5 OAS isoform was present in proliferating LAN-5 cells; following IFN-gamma treatment, the 100-, 69-and 46-kDa isoforms became detectable. Accordingly, 2,5 OAS enzymatic activity, virtually undetectable in untreated LAN-5 cells, increased up to 132 pmol oligoadenylate/micrograms protein/hr after 48 hr of treatment, then slowly decreased, remaining detectable up to 96 hr. However, the 2,5 OAS proteins required an exogenous activation by synthetic dsRNA to exert enzymatic activity. It is therefore conceivable that they do not play a biological role in NB cell functions. Moreover, an increase in 2,5 OAS enzymatic activity was also observed in NB cells resistant to the differentiation-promoting activity of IFN-gamma, further suggesting that 2,5 OAS induction was not sufficient to trigger IFN-gamma-dependent neuronal maturation. Furthermore, other differentiation-inducing agents, such as retinoic acid and cytosine arabinoside, or complete proliferative arrest produced by serum deprivation, failed to enhance 2,5 OAS activity, thus indicating that the 2,5 OAS system is not directly involved in mediating other differentiative pathways of NB cells.
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PMID:Induction of 2.5 OAS gene expression and activity is not sufficient for IFN-gamma-induced neuroblastoma cell differentiation. 762

Intercellular adhesion molecule-1 (ICAM-1) is an important cell surface adhesion receptor of the immune system. Its cell surface expression on a wide variety of cells, including cancer cells, is regulated by various proinflammatory cytokines. In the present study, we investigated the role of calcium (Ca2+) and calmodulin (CaM) in the retinoic acid and gamma-interferon (IFN-gamma) signaling in the human neuroblastoma cell line SK-N-SH for up-regulating ICAM-1 expression. A 24-h incubation in the presence of Ca(2+)-mobilizing agents (A23187 and thapsigargin) resulted in the induction of ICAM-1 expression. Both Ca(2+)-mobilizing agents stimulated ICAM-1 expression additively to IFN-gamma but not to retinoic acid, suggesting that IFN-gamma does not use Ca2+ to stimulate ICAM-1, whereas retinoic acid might use it in part. As a second messenger, Ca2+ can be coupled with calmodulin. Using calmodulin inhibitors (W7 and calmidazolium), we found that retinoic acid-stimulated, A23187-stimulated, and thapsigargin-stimulated but not FIN-gamma-stimulated ICAM-1 were inhibited. Calmodulin signaling elicited by retinoic acid was an early event occurring within the first h of retinoic acid treatment, providing evidence that they may both be coupled to regulate gene expression. Using a novel CaM kinase II inhibitor, KN-62, we demonstrated that retinoic acid stimulated ICAM-1 expression in a CaM kinase II-dependent fashion. The mechanisms whereby CaM kinase II mediates retinoic acid activity on ICAM-1 expression remain to be elucidated.
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PMID:Retinoic acid-stimulated intercellular adhesion molecule-1 expression on SK-N-SH cells: calcium/calmodulin-dependent pathway. 791 11

Expression of cytokine genes, TNF-alpha, TNF-beta and IFN-gamma, in human astroglial cell lines and in fresh brain specimens was studied by PCR. mRNA transcripts of TNF-alpha could be detected in three out of five astrocytomas and neuroblastoma cell lines, and after stimulation with IL-1 beta/IFN-gamma or LPS/IFN-gamma all these cell lines expressed TNF-alpha genes. TNF-beta genes could not be detected in these cell lines. We were able to detect expression of IFN-gamma genes within two astrocytoma cell lines, which interestingly did not show TNF-alpha activity. In addition to the cultured cells, we also examined gene expression of these cytokines within four human malignant astrocytoma specimens, two peritumoral brain and two autopsied normal brains. The results show that tumour and surrounding reactive lesions express TNF-alpha genes (four of six) but not normal brains. The concentration of these cytokines in the supernatant of cultured cells was measured quantitatively by TNF-alpha, -beta or IFN-gamma ELISA. The combined stimulation of these neuroglial cell lines with IL-1 beta and LPS or IFN-gamma, revealed a high level of TNF-alpha activity. This was especially evident with a neuroblastoma cell line. The concentration of TNF-alpha in the supernatant of the IMR32 neuroblastoma cell line increased markedly upon stimulation with IL-1 beta in both a time- and dose-dependent fashion in the presence of LPS or IFN-gamma. Next, we examined expression of IL-1 beta and IFN-gamma genes in the brain specimens. The result shows that four in six tumour and peritumoral regions expressed IFN-gamma genes and one specimen showed IL-beta gene by PCR. From these experiments it is suspected that neuroglial cell-derived TNF-alpha induced by IL-1 beta of IFN-gamma may participate in local immune reactions of the brain in an autocrine and paracrine fashion.
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PMID:Expression of tumour necrosis factor-alpha, -beta and interferon-gamma genes within human neuroglial tumour cells and brain specimens. 803

Intercellular adhesion molecule 1 (ICAM-1) is a major adhesion receptor of the immune system. Its cell surface expression on a wide variety of cells including cancer cells regulated by various proinflammatory cytokines. Incubation of the human glioma cell line HS 683 and the neuroblastoma cell line SK-N-SH with 12-phorbol 13-myristic acid (PMA), retinoic acid, or gamma-interferon (IFN-gamma) strongly stimulates ICAM-1 expression. In the present study, we investigated the role of the protein kinase C (PKC)-mediated signal transduction pathway in this process. We found that IFN-gamma, but not retinoic acid, was able to induce activation and translocation of PKC after 60 min in a dose-dependent fashion, contrasting with the very rapid activation and translocation induced by PMA which occurred at 15 min. The PKC inhibitors 1-(5-isoquinolinesulfonyl)-2-methyl-piperazine dihydrochloride and staurosporine, as well as depletion of PKC by a 24-h treatment with 100 nM PMA, decreased the PMA-mediated stimulation but not the retinoic acid- or the IFN-gamma-mediated stimulation of ICAM-1 expression. On the contrary, they rather stimulated ICAM-1 expression. Furthermore, this stimulation was additive with retinoic acid and IFN-gamma. A 24-h incubation in the presence of retinoic acid or IFN-gamma strongly inhibited activation and translocation of PKC by PMA. These results suggest that although PMA-induced ICAM-1 expression is PKC dependent on HS 683 and SK-N-SH cells, the stimulation of ICAM-1 expression by retinoic acid and by IFN-gamma may be due to PKC inactivation at longer time points (24 h), as mimicked by 1-(5-isoquinolinesulfonyl)-2-methylpiperazine dihydrochloride, staurosporine, or PKC depletion by high doses of PMA.
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PMID:Transduction of retinoic acid and gamma-interferon signal for intercellular adhesion molecule-1 expression on human tumor cell lines: evidence for the late-acting involvement of protein kinase C inactivation. 809 32

Both IFN-alpha/beta and IFN-gamma have recently been demonstrated to induce a rapid but transient activation of phospholipase A2 (PLA2) in BALB/c 3T3 fibroblasts and a human neuroblastoma cell line. We report that IFN-gamma induces the synthesis and prolonged activation of cytosolic phospholipase A2 (cPLA2) in a human bronchial epithelial cell line (BEAS 2B). Treatment of the cells with IFN-gamma (300 U/ml) increased the release of [3H]arachidonic acid (AA) from prelabeled cells with a maximal effect at 12 h after stimulation. The increased [3H]AA release was inhibited by the PLA2 inhibitor p-bromophenacyl bromide (10(-5) M). Calcium ionophore A23187 (10(-5) M) further increased the [3H]AA release from the IFN-gamma-treated cells. Subcellular enzyme activity assay revealed that IFN-gamma increased PLA2 activity in both the cytosol and membrane fractions with a translocation of the cPLA2 to cell membranes in a Ca(2+)-free cell lysing buffer. Treatment with IFN-gamma also induced the release of 15-HETE, an arachidonic acid metabolite. Immunoblot showed that IFN-gamma induced the synthesis of cPLA2 protein. Nuclear run-on assay demonstrated that IFN-gamma initiated cPLA2 gene transcription within 15 min, and this effect was sustained at 4 h and returned to near control level at 12 h. The cPLA2 mRNA level was assayed by reverse transcription and PCR. IFN-gamma was found to increase the cPLA2 mRNA after 2-24 h treatment. Furthermore, the IFN-gamma induced cPLA2 mRNA increase was blocked by inhibitors of protein kinase C and calcium/calmodulin-dependent protein kinases, suggesting the involvement of these protein kinases in IFN-gamma-induced gene expression of cPLA2. This study shows that IFN-gamma induces the synthesis and prolonged activation of cPLA2.
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PMID:Interferon-gamma induces the synthesis and activation of cytosolic phospholipase A2. 811 94

Three human neuroblastoma cell lines were examined to determine the effect of recombinant gamma-interferon (IFN-gamma) treatment on the expression of trk proto-oncogene. Increased levels of trk proto-oncogene mRNA were observed in two neuroblastoma cell lines (KP-N-RT and KP-N-SI(FA)) after IFN-gamma treatment. The levels of trk mRNA increased with growth inhibition and morphological change in a time- and dose-dependent manner. The decreased level of N-myc mRNA after IFN-gamma treatment in KP-N-RT was inversely correlated with trk mRNA. Our results suggest that IFN-gamma can modulate the signal transduction of nerve growth factor in human neuroblastoma cells.
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PMID:Increased expression of trk proto-oncogene by gamma-interferon in human neuroblastoma cell lines. 814 93


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