Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P43026 (lipopolysaccharide)
 62,215 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A panel of human colonic adenocarcinoma cell lines was examined both for expression of mRNAs of the nitric oxide synthase (NOS) gene family and for evidence of enzymic activity based on citrulline and nitrite (NO2-) formation. Reverse transcription-polymerase chain reaction (RT-PCR), revealed that all lines (SW480, SW620, DLD-1 and WiDr) expressed mRNA for the Ca(2+)-dependent endothelial (e)NOS, while SW480 cells also expressed the Ca(2+)-dependent neuronal (n)NOS. The mRNA for the Ca(2+)-independent inducible (i)NOS was expressed both by cytokine-stimulated and by unstimulated SW480, SW620 and DLD-1 cells, but none was seen at any time in the WiDr cells. There was, however, little correlation between mRNA expression and enzymic activity based on citrulline and NO2- formation. Thus none of the cell lines exhibited measurable Ca(2+)-dependent NOS activity, while Ca(2+)-independent NOS activity was seen in all but the WiDr cells. Furthermore, DLD-1 cells generated citrulline with resultant NO2- formation only after stimulation with lipopolysaccharide (LPS) and/or cytokines, while SW480 and SW620 did so constitutively. Thus RT-PCR studies indicate that tumour cells of similar epithelial origin display a diverse pattern of NOS gene family expression, and parallel biochemical studies clearly indicate that such expression does not always result in measurable enzymic activity leading to the generation of NO.
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PMID:Human colon cancer cell lines show a diverse pattern of nitric oxide synthase gene expression and nitric oxide generation. 752 2

Intraportal inoculation of CC531 adenocarcinoma cells into syngeneic rats causes an increase of liver macrophage cell number but not of major histocompatibility complex class II antigen expression. On day 1 after inoculation of 10(5) CC531 cells, a fixed number of isolated liver macrophages lysed significantly more target cells in vitro than did control cells. This effect was still present after 4 weeks. A 10-fold higher initial tumor dose significantly suppressed the macrophage response during the first 2 weeks. In contrast to tumoricidal activity induced by lipopolysaccharide in vitro, the tumoricidal response following in vivo challenge with tumor cells appeared not closely related to the production of reactive nitrogen intermediates, as in the latter case it was not abrogated in the presence of nitric oxide synthase inhibitor. Furthermore, the liver macrophage population appeared not fully activated after tumor inoculation as lipopolysaccharide further increased tumoricidal activity in vitro. The observed numerical and functional response of liver macrophages to intraportally inoculated tumor cells points at an important role of these cells in aspecific immune reactivity aimed at the reduction of local tumor growth. Results suggest that mechanistic differences exist between macrophage tumoricidal activity induced by tumor cells as compared with lipopolysaccharide.
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PMID:Tumoricidal response of liver macrophages isolated from rats bearing liver metastases of colon adenocarcinoma. 753 89

The purpose of our study was to investigate the susceptibility of human glioblastoma multiforme (GBM) cells to lysis by human peripheral-blood monocytes following activation with biological response modifiers (BRM) and to lysis by various BRMs directly. Cytotoxic effects were determined using a monocyte-/BRM-mediated tumor cytotoxicity assay. Human peripheral-blood monocytes from healthy donors were activated in vitro by incubation for 24 h with different BRMs such as gamma- and beta-interferon (gamma, beta-IFN), lipopolysaccharide (LPS), muramyldipeptide (MDP) and tumor necrosis factor-alpha (TNF-alpha) in varying concentrations and combinations. Seven human GBM cell lines as well as an adenocarcinoma brain metastasis cell line and a malignant melanoma cell line served as target cells. Radiolabeled target cells were cocultivated with activated monocytes or with BRMs directly. Cytotoxicity was calculated after 72 h of cocultivation. High levels of cytotoxicity were mediated by monocytes activated with beta-IFN in six out of eight brain tumor cell lines and with TNF-alpha in five cell lines. The combination of two BRMs, in particular the combination of gamma-IFN + beta-IFN and gamma-IFN + TNF-alpha, was associated with an enhanced monocyte mediated lysis exceeding LPS control, whereas the combination of gamma-IFN + MDP was very effective against the metastasis cell line. Monocyte-mediated cytotoxicity against tumor target cells was up to ten fold higher than direct cytotoxicity of soluble BRMs. Our data indicate that BRM-stimulated peripheral-blood monocytes exert cytotoxic properties against human glioblastoma cells in vitro, which exceed those of BRMs alone up to ten fold. The higher tumoricidal activities observed after stimulation with combined BRMs suggest mutual promoting mechanisms of BRMs acting on the stimulation of lyctic activity in human peripheral blood monocytes.
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PMID:Activated monocytes kill malignant brain tumor cells in vitro. 780 82

Several functions of alveolar macrophages (AM) are modified by cigarette smoking. AM are the first line of defense in bronchoalveolar spaces and could be depressed in their cytotoxicity to tumor cells in smokers. An assay using A549 cells (human lung adenocarcinoma) as target cells was performed to assess cytostasis mediated by AM and their supernatants (SN) from healthy smokers (n = 8) and nonsmokers (n = 6). Contact-mediated cytostasis was decreased in AM of smokers (n = 8) relative to nonsmokers (n = 6) (22.9 +/- 5.7% versus 42.7 +/- 6.0% [+/- SEM], P < 0.04) and increased after lipopolysaccharide (LPS) stimulation in both groups (34.5 +/- 5.3% versus 46.8 +/- 5.2%, NS). Cytostasis induced by SN from nonstimulated AM was low in both groups and was still lower in smokers after LPS exposure (19.3 +/- 4.5% versus 34.5 +/- 4.8%, P < 0.04). Among cytotoxic factors produced by macrophages, interleukin (IL)-1 beta, IL-6, and tumor necrosis factor alpha (TNF alpha) may play an important role in cytostasis. Recombinant human (rH) IL-1 beta and rHTNF alpha had a moderate cytostatic activity, which was additive, whereas rHIL-6 had no significant activity on A549 cells. Bioactive IL-1 beta, IL-6, and TNF alpha were therefore measured in macrophage SN. Their levels tended to be lower in smokers than in nonsmokers and were much increased after LPS stimulation. Levels of the three cytokines were also found to correlate with each other; furthermore, a good correlation between cytokine levels in SN and cytostasis was observed.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Cytostatic activity of alveolar macrophages from smokers and nonsmokers: role of interleukin-1 beta, interleukin-6, and tumor necrosis factor-alpha. 794 92

Macrophages from mice bearing large D1-DMBA-3 mammary tumors have a decreased capacity to kill tumor targets. This effect is due to an impaired ability to produce nitric oxide (NO) in response to lipopolysaccharide (LPS) stimulation. Here we report that the DA-3 tumor cell line, derived from the in vivo adenocarcinoma D1-DMBA-3, produces a factor that inhibits both NO production/release and cytotoxicity of LPS-activated peritoneal exudate macrophages (PEM). However, other complex macrophage functions such as phagocytosis, superoxide production, mitochondrial dehydrogenase activity, and synthesis of proteins were not reduced by this factor. The NO inhibitor has been found to be lipid in nature. Lipid extracts from DA-3 cell culture supernatants were purified by repeated silica gel column chromatography. The active molecule was unambiguously characterized as phosphatidyl serine (PS) by fast atom bombardment tandem mass spectrometry. Preliminary results indicate a lack of induced NO synthase (iNOS) activity in the lysates of LPS-activated PEM pretreated with PS. The ubiquity of PS in the inner leaflet of biological membranes and its NO inhibitory property, suggest that this phospholipid may be one of the long elusive molecules responsible for regulating physiological levels of NO in the host and hence preventing cellular dysfunction and/or tissue damage. Furthermore, the possible overexpression and shedding of PS by DA-3 tumor cells may represent a novel mechanism to impair macrophage cytotoxicity, a host function that contributes to the protection against developing neoplasms.
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PMID:Isolation of a nitric oxide inhibitor from mammary tumor cells and its characterization as phosphatidyl serine. 806 42

Cytokines produced by intestinal epithelial cells may function as signals to neighbouring immune and inflammatory cells. We investigated production of the neutrophil and T-lymphocyte chemotactic cytokine interleukin-8 (IL-8) by intestinal epithelial cells using four colonic adenocarcinoma cell lines, T84, CaCo-2, HT29 and SW620, as a model system. These cell lines secreted substantial amounts of IL-8 if stimulated with IL-1 beta, tumour necrosis factor-alpha (TNF-alpha) or interferon-gamma (IFN-gamma), except CaCo-2 cells, which responded only to IL-1 beta. Bacterial lipopolysaccharide (LPS) was also an efficient stimulus of IL-8 release in SW620 and HT29 cells, whereas T84 and CaCo-2 cells were completely unresponsive to LPS, IL-8 secretion was greater at 4 hr after stimulation and was accompanied by induction of IL-8 messenger RNA. In T84 cells IFN-gamma and epidermal growth factor (EGF) stimulated IL-8 secretion synergistically with TNF-alpha, whereas in SW620 cells this synergism occurred only between IFN-gamma and TNF-alpha. IL-4, IL-10 and transforming growth factor-beta (TGF-beta), which can down-regulate IL-8 production in macrophages, had no effect on IL-8 generation by our cell lines. Adenocarcinoma cell culture supernatants also induced rapid transients of intracellular calcium in neutrophils. Depending on cell line and stimulus, supernatant bioactivity was completely or partially abrogated by neutralizing antibodies to IL-8, indicating that the cell lines investigated also generate other neutrophil-activating factors. IL-8 and possibly other chemokines generated by colonic adenocarcinomas may help to attract tumour-infiltrating leucocytes. Possibly, normal intestinal epithelial cells also have the potential to secrete this potent chemoattractant and thus might contribute to inflammatory responses of the intestinal mucosa, for example in inflammatory bowel disease.
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PMID:Colonic epithelial cell lines as a source of interleukin-8: stimulation by inflammatory cytokines and bacterial lipopolysaccharide. 783 10

Macrophage-mediated inhibition of mitochondrial respiration in EMT-6 murine mammary adenocarcinoma cells can be mimicked in vitro by treatment of the cells with interferon-gamma (IFN-gamma) in combination with tumor necrosis factor, interleukin-1, or lipopolysaccharide. Conditioned supernatants obtained from activated macrophages appear to contain interferon-gamma, suggesting that inhibition of mitochondrial respiration in tumor cells was caused by synergy of IFN-gamma with other cytokines. To further characterize monokines that cause inhibition of mitochondrial respiration in tumor cells, EA13.5 macrophage-like cells were isolated and selected for inhibition of mitochondrial respiration in EMT-6 tumor cells. After stimulation with IFN-gamma and lipopolysaccharide, the EA13.5 cells released into conditioned supernatants a cytotoxic mediator that induced nitric oxide synthesis and caused lesions in the electron transport chain of EMT-6 cells similar to the lesions caused by activated peritoneal macrophages. Enzyme-linked immunosorbent assay demonstrated that the conditioned supernatants produced by EA13.5 macrophage cells did not contain IFN-gamma. Treatment of the EA13.5 cell-conditioned supernatants with neutralizing antibody against IFN-gamma did not abrogate the inhibition of mitochondrial respiration in EMT-6 cells caused by these conditioned supernatants. This study demonstrated that unidentified macrophage cytotoxic mediators distinct from IFN-gamma are involved in the induction of nitric oxide synthesis and inhibition of mitochondrial respiration in tumor cells.
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PMID:Inhibition of tumor cell mitochondrial respiration by macrophage cytotoxic mediators distinct from interferon-gamma. 844 26

Recently we reported an antimetastatic activity of bacterial lipopolysaccharide (LPS) on a NK-cell-resistant murine fibrosarcoma (NFSa). Here we investigate and report the mechanistic significance of platelets in this activity. The number of circulating platelets was reduced to 63% of the control 3 days after an i.v. injection of 1.0 micrograms LPS, and then recovered to the level of control at day 10. Aggregation efficiency of platelets was impaired by LPS. The number of metastatic lung colonies after an i.v. injection of tumor cells was maximally reduced to 2.2% of the control at day 3 and increased in proportion to the recovery of platelet number. Neuraminidase (Ndase), which caused a non-immunological thrombocytopenia, also inhibited lung metastasis when injected prior to an i.v. tumor cell challenge. LPS and Ndase showed an identical pattern against five other syngeneic tumors; these agents inhibited lung metastases of the FSa fibrosarcoma and the SCC VII squamous cell carcinoma but failed to inhibit those of the NR-S1 squamous cell carcinoma, the MMCa#4 mammary adenocarcinoma and the NR-PG parotid gland tumor. All the three cells which were not responsive to any agents possessed a high aggregating activity of platelets while the other three tumors responsive to both agents did not show a detectable level of this activity. Platelet transfusion failed to modify the antimetastatic activity of LPS. These results suggest that platelets play an important role in the antimetastatic activity of LPS, though whether the role is principal or assistant remains to be seen.
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PMID:Significance of platelets in an antimetastatic activity of bacterial lipopolysaccharide. 847 98

Members of the Janus kinase (Jak) family of protein tyrosine kinases have recently been implicated in the proximal signal transduction events of cytokine receptors. Jak3, a newly discovered member of this family, is believed to be normally limited in its expression to cells of the lymphoid and myeloid lineages. Herein we show that Jak3 is expressed in primary human vascular cells, as well as other non-lymphoid and non-myeloid cell types. Reverse transcriptase-polymerase chain reaction and Northern blot analysis revealed that Jak3 mRNA was expressed at low levels in human umbilical vein endothelial cells (HUVEC), human aortic smooth muscle cells (HASMC), A549 (human lung carcinoma), and DLD-1 (human colon adenocarcinoma) cells. Higher basal levels of Jak3 mRNA were detected in HMEC-1 (human microvascular cell line) and HepG2 (human hepatocellular carcinoma) cells. Jak3 mRNA expression was induced in HUVEC, HMEC-1, and HASMC by treatment with interleukin-1beta, tumor necrosis factor-alpha, interferon-gamma, and lipopolysaccharide. Jak3 protein was detectable at low levels in untreated HMEC-1, and these levels increased significantly with cytokine treatment. Furthermore, Jak3 protein was phosphorylated upon treatment of these cells with interleukin-4. This work shows that Jak3 is expressed or inducible in human vascular endothelial, vascular smooth muscle, and other non-lymphoid and non-myeloid cells, suggesting a broader role for Jak3 in the cytokine signal transduction of these cells.
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PMID:Expression of Janus kinase 3 in human endothelial and other non-lymphoid and non-myeloid cells. 866 78

Ukrain is a semisynthetic compound consisting of alkaloids from Chelidonium majus L. conjugated to thiophosphoric acid, with immunomodulatory and therapeutic properties in cancer patients. The present in vitro studies demonstrate that Ukrain is an effective biological response modifier augmenting, by up to 48-fold, the lytic activity of splenic lymphocytes obtained from alloimmunized mice. The lytic activities of interleukin-2 (IL-2) treated spleen cells and peritoneal exudate lymphocytes were also significantly increased by the addition of Ukrain to the cell mediated lysis (CML) assay medium. The highest Ukrain-induced enhancement of splenic lymphocytolytic activity in vitro was found to occur at day 18 after alloimmunization was dose-dependent and specific for the immunizing P815 tumour cells. Since Ukrain was present only during the CML assays, its mode of action is thought to be via direct activation of the effector cells' lytic mechanism(s). The effect of Ukrain on the growth of Balb/c syngenic mammary adenocarcinoma was also evaluated. Intravenous, but not subcutaneous or intraperitoneal, administration of this drug was found to be effective in delaying tumour growth in an actual therapeutic protocol initiated five days after tumour implantation. No deleterious side-effects were observed using these in vivo treatment modalities. The role of macrophages in the observed retardation of tumour development was investigated, using peritoneal exudate macrophages (PEM) in cytotoxicity assays. Previous studies showed that PEM of mammary tumour-bearing mice lose their capacity to kill a variety of tumour target cells including the in vitro cultured homologous tumour cells (DA-3). Pretreatment of PEM from normal mice with 2.5 microM Ukrain for 24 h, followed by stimulation with either IFN-gamma or with lipopolysaccharide (LPS) plus IFN-gamma enhanced their cytotoxic activity. Treatment of PEM from tumour-bearing mice with 2.5 microM Ukrain and LPS results in a reversal of their defective cytotoxic response against DA-3 target cells. Furthermore, Ukrain alone, in the absence of a secondary signal, induced the activation of tumouricidal function of PEM from tumour-bearing, but not from normal, mice. These data indicate that Ukrain's in vivo effects against the development of mammary tumours may be due, at least in part, to its ability to restore macrophage cytolytic function.
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PMID:Modulation of immune effector cell cytolytic activity and tumour growth inhibition in vivo by Ukrain (NSC 631570). 889 12


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