Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P05231 (interleukin-6)
 23,907 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Tumor necrosis factor-alpha (TNF-alpha), a cytokine produced by astrocytes in vivo and in vitro, was tested for its effects on two malignant astrocytoma cell lines (A-172, U-87). Both lines were immunoreactive for glial fibrillary acidic protein, vimentin, Class I antigens, and interleukin-6. The lines differed in their expression of Class II and intercellular adhesion molecule-1 (ICAM-1) antigenic determinants: A-172 cells were negative for both Class II and ICAM-1 antigens, while U-87 cells were intensely positive for Class II and weakly positive for ICAM-1. When these astrocytoma cell lines were exposed to TNF-alpha, A-172 growth was stimulated while U-87 growth was inhibited. Furthermore, in U-87 cells, TNF-alpha enhanced both ICAM-1 and interleukin-1 beta (IL-1 beta) expression, and decreased immunoreactivity for transforming growth factor-beta (TGF-beta) protein. In contrast, in the presence of TNF-alpha, A-172 cells remained negative for IL-1 beta and TGF-beta, but showed an increased expression of ICAM-1. These results demonstrate that TNF-alpha can induce changes in growth rate, cytokine production, and surface antigen expression in malignant astrocytomas; however, the nature of these changes is dependent on the specific characteristics of these malignant astrocytomas. The resultant variability in the immunological microenvironment of these tumors may reflect differences in their growth potential.
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PMID:Differential effects of tumor necrosis factor-alpha on proliferation, cell surface antigen expression, and cytokine interactions in malignant gliomas. 809 40

Human neutrophil azurophilic granules contain an approximately 55-kDa protein, known as bactericidal/permeability-increasing protein (BPI), which possesses a high-affinity binding domain for the lipid A component of lipopolysaccharide (LPS). The in vivo LPS neutralizing activity of exogenous BPI was studied in a model of lethal Escherichia coli bacteremia. Five baboons were treated with BPI (5 mg/kg bolus injection followed by a 95 micrograms/kg/min BPI infusion over 4 hr), while four additional animals received a genetically engineered variant of BPI (NCY103). Five animals received a placebo treatment and served as controls. Both wild-type rhBPI and NCY103 significantly (P < 0.05) decreased blood levels of LPS throughout an 8-hr evaluation period following live bacterial challenge. Two hours following E. coli administration, LPS levels peaked in the controls, at 6.86 +/- 3.22 ng/ml, whereas LPS levels were 3.39 +/- 2.1 ng/ml in the BPI group and 2.04 +/- 1.18 ng/ml in the NCY103 group. Tumor necrosis factor-alpha (TNF-alpha) and interleukin-6 levels likewise were attenuated in the treatment groups, whereas circulating sTNFR I was significantly (P < 0.05) reduced only in the BPI group. Leukocytopenia and granulocytopenia were significantly (P < 0.02) lessened in the BPI group, by an average of 59% leukocytopenia and 65% granulocytopenia, respectively. This study supports the concept of E. coli LPS neutralization by BPI in vivo and demonstrates that a moderate (70%) reduction in peak LPS-LAL activity is sufficient to alter some hematologic and cytokine manifestations of bacteremia.
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PMID:The role of bactericidal/permeability-increasing protein in the treatment of primate bacteremia and septic shock. 819 14

The effects of intramuscular injections of minute amounts of polymyxin B were studied in 42 patients with endotoxemia. Plasma endotoxin was measured by means of an endotoxin-specific Endospecy test (Seikagaku Corp., Tokyo, Japan) after pretreatment of the plasma with a new perchloric acid method that we developed. The normal value of plasma endotoxin is less than 9.8 pg/mL. Polymyxin B was administered at a dose of 12,500 U every 6 hours. Plasma endotoxin rapidly decreased to the normal range in 40 of the 42 patients. Body temperature fell significantly. APACHE II scores were also significantly improved. Tumor necrosis factor-alpha and interleukin-6 (IL-6) decreased in survivors, while tending to persist in high values in patients who died. No side effects were observed in any of the patients. In conclusion, intramuscular injections of small doses of polymyxin B were useful in the treatment of endotoxemia.
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PMID:Clinical effects of intramuscular administration of a small dose of polymyxin B to patients with endotoxemia. 820 33

Peripheral vasodilation is a common feature of warm heart surgery and creates clinical concerns when pressor agents become necessary because of the potential for some of these drugs to adversely affect flow through newly engrafted arterial and venous bypass conduits. The possible role of a temperature-dependent production of cytokines in the pathogenesis of this vasodilation was investigated in a two-part study. In part I, lipopolysaccharide-activated peritoneal rabbit macrophages (5 x 10(6)/ml) were incubated at 30 degrees or 37 degrees C up to 9 hours and the concentration of tumor necrosis factor released in the supernatant was serially measured by a bioassay. Tumor necrosis factor production was found to increase over time for each of the two temperatures of incubation but was significantly higher throughout the observation period in normothermic experiments than in those done at 30 degrees C. Part II was a prospective clinical study involving 30 patients who underwent either cold (core temperature 28 degrees to 30 degrees C, n = 15) or warm (37 degrees C, n = 15) cardiopulmonary bypass and in whom serum levels of tumor necrosis factor alpha, interleukin-1 beta, and interleukin-6 were measured by enzyme-linked immunosorbent assays at 2, 4, 10, and 24 hours after bypass. Cytokine levels were found to be consistently higher in patients having normothermic bypass. Differences between the two groups were significant 2 hours after bypass for tumor necrosis factor alpha and interleukin-6 (p < 0.02 and p = 0.0001, respectively) and 4 and 10 hours after bypass for interleukin-1 beta (p < 0.01 and p < 0.04, respectively). The incidence of vasodilation necessitating vasopressor support was twofold higher in the normothermic group (six patients versus three in the hypothermic group). Taken as a whole, patients supported by pressor agents had significantly higher cytokine levels after bypass than those who did not require pressor therapy. Our results suggest that vasodilation occurring with warm heart operation is, at least partly, mediated by a temperature-dependent release of cytokines. Vasodilation might therefore be mitigated by simply allowing the core temperature to drift during bypass. Our recent clinical experience suggests that this "tepid" heart surgery (32 degrees to 34 degrees C) effectively blunts most of the vasodilatory response to strictly normothermic bypass without compromising maintenance of myocardial aerobiosis during arrest.
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PMID:A potential mechanism of vasodilation after warm heart surgery. The temperature-dependent release of cytokines. 828

Tumor necrosis factor can alter the cell cycle of tumor cells and protect hematopoietic stem cells from cell cycle-specific chemotherapy, but the ability of tumor necrosis factor to protect cancer cells from chemotherapy by manipulation of the cell cycle is unknown. Twenty-four-hour exposure of A549 human lung cancer cells to tumor necrosis factor shifted cells from S phase to G0/G1 phase as determined by analysis of isolated cell nuclei with an FACScan Cell Sorter. This effect was not seen in cells exposed to interleukin-1 or interleukin-6. Growth assays demonstrated that tumor necrosis factor slowed the doubling time of A549 cells, confirming that tumor necrosis factor caused G0/G1 arrest in these cells. Pretreatment with tumor necrosis factor rendered cells resistant to subsequent 1-hour exposure to doxorubicin, a chemotherapeutic agent active against S phase cells. Tumor necrosis factor did not protect cells against either cisplatin or mitomycin C, drugs not specific for S phase. Measurement of intracellular drug levels indicated that pretreatment with tumor necrosis factor did not affect doxorubicin uptake or efflux. These findings suggest that cells producing tumor necrosis factor within a tumor may render surrounding malignant cells resistant to cell cycle-specific chemotherapy, and this mechanism may explain failure of sequential immunotherapy-chemotherapy protocols.
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PMID:Tumor necrosis factor induces doxorubicin resistance to lung cancer cells in vitro. 828 17

Tumor necrosis factor (TNF) is considered to be a pivotal mediator of endotoxin-induced lethality. To assess the intermediate role of TNF in specific systemic inflammatory responses known to contribute to tissue injury in endotoxemia, eight healthy adult chimpanzees were intravenously injected with Escherichia coli endotoxin (4 ng/kg). In four of these animals the administration of endotoxin was followed immediately by a bolus intravenous injection of an anti-TNF monoclonal antibody (15 mg/kg). Treatment with anti-TNF completely prevented the endotoxin-induced increase in serum TNF activity, and profoundly reduced the appearance of interleukin-6 and -8 (both P < .05). Neutrophilia and lymphopenia were not affected by anti-TNF, whereas neutrophil degranulation, as measured by the plasma concentrations of elastase-alpha 1-antitrypsin complexes, was only slightly reduced (peak levels after endotoxin alone 31.0 +/- 3.4 ng/mL, versus 25.5 +/- 3.4 ng/mL after endotoxin with anti-TNF; P < .05). Anti-TNF did not influence endotoxin-induced activation of the coagulation system, as reflected by unchanged increases in the plasma concentrations of the prothrombin fragment F1 + 2 and thrombin-antithrombin III complexes. In contrast, anti-TNF strongly attenuated the activation of the fibrinolytic system, ie, peak plasma levels of plasmin-alpha 2-antiplasmin were 33.8 +/- 11.1 nmol/L after endotoxin alone and 17.0 +/- 2.9 nmol/L after endotoxin with anti-TNF (P < .05). These results suggest that TNF is not the common mediator of systemic inflammatory changes in low-grade endotoxemia. Moreover, the finding that in this mild model anti-TNF specifically inhibited fibrinolysis suggests that treatment with anti-TNF potentially may enhance the tendency towards microvascular thrombosis in sepsis.
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PMID:Differential effects of anti-tumor necrosis factor monoclonal antibodies on systemic inflammatory responses in experimental endotoxemia in chimpanzees. 828 42

Preliminary studies have demonstrated that some pituitary adenomas secrete immunoreactive interleukin-6 (irIL-6) when cultured in vitro. We have extended these studies by investigating 100 pituitary adenomas of different types measuring immunoreactive and bioactive IL-6. Tumors were cultured either as explants without fetal calf serum or as dispersed cells with 10% total calf serum. Fifty-three of the 100 (53%) pituitary cultures were found to release irIL-6 and in 44 adenomas examined, 32 (72.7%) secreted bioactive IL-6. In 61 explant cultures, 30 adenomas released IL-6, indicating autonomous secretion. The amount of IL-6 released by adenomas in cell culture was generally higher, although the incidence was similar to explant cultures. IrIL-6 was released by 7 of 14 prolactinomas, 15 of 27 somatotrophinomas, 5 of 7 corticotrophinomas (including 2 Nelson's adenomas), 1 of 1 thyrotrophinomas, 2 of 2 gonadotrophinomas, and 23 of 49 clinically non-functioning adenomas. Periadenomatous tissue removed from a patient with a corticotrophinoma was found to secrete IL-6 but in much lower concentration than from the adenoma tissue. Tumor necrosis factor-alpha and -gamma-interferon were not detected in the conditioned media. Four IL-6-secreting adenomas were examined by in situ hybridization for IL-6 messenger RNA, and three of these were positive with fluorescence present throughout the tissue examined. We have provided evidence that over half of pituitary adenomas secrete IL-6 which is bioactive and that IL-6 is synthesized within the tumor by the adenoma cells.
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PMID:Production of bioactive and immunoreactive interleukin-6 (IL-6) and expression of IL-6 messenger ribonucleic acid by human pituitary adenomas. 828 2

Peptide mediators, including tumor necrosis factor-alpha, interleukin 1 and interleukin-6, are associated with many chronic inflammatory diseases and septic shock. As such, considerable information has been collected by means of study of cytokine secretion from isolated cells or plasma cytokines during septic shock or inflammatory disorders. In this investigation, we used semiquantitative polymerase chain reaction analysis and a recently developed liver slice model to examine the characteristics of cytokine profiles that occur in the liver, the main organ involved in endotoxemia, after lipopolysaccharide challenge. Tumor necrosis factor-alpha, interleukin-1 alpha and interleukin-6 were rapidly secreted after in vivo LPS exposure or when added in vitro to rodent or human liver slice samples. This increase was associated with increased cytokine-specific mRNA transcripts. Kinetic analysis revealed that most tumor necrosis factor-alpha is released from the liver within 1 hr of lipopolysaccharide challenge, whereas interleukin-1 alpha and interleukin-6 continued to be produced for the entire culture period. Addition of monoclonal antibodies against tumor necrosis factor-alpha or interleukin-1 alpha to the culture partly inhibited interleukin-6 secretion, indicating that interleukin-1 alpha and tumor necrosis factor-alpha help mediate and sustain interleukin-6 synthesis. Depletion of hepatic sinusoidal macrophages (Kupffer cells) by a liposome-mediated macrophage "suicide" technique indicated that almost all of the secreted interleukin-1 alpha and tumor necrosis factor-alpha originate from these cells, whereas interleukin-6 secretion might also include other cell types. This study supports and extends previous findings and allows for a more rational approach to developing effective therapies against chronic inflammatory diseases and septic shock.
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PMID:Endotoxin-induced cytokine gene expression and excretion in the liver. 829 4

Tumor necrosis factor (TNF) has cytotoxic and gene-inductive activities on several cell types. Previous studies on L929 fibrosarcoma cells have revealed that the mitochondrial electron transport system plays a key role in inducing TNF cytotoxicity, presumably by the formation of reactive oxygen intermediates (ROI). Here we report that mitochondria-derived intermediates are not only cytotoxic but, in addition, function as signal transducers of TNF-induced gene expression. The activation of NF kappa B, which fulfills an important role in TNF-induced gene transcription, could be blocked by interference with the mitochondrial electron transport system. Furthermore, antimycin A, a mitochondrial inhibitor that increases the generation of ROI, potentiated TNF-triggered NF kappa B activation. The dual role of mitochondria-derived intermediates in cytotoxicity and immediate-early gene induction of TNF was further substantiated by isolating L929 subclones which lacked a functional respiratory chain. This depletion of the mitochondrial oxidative metabolism resulted in resistance towards TNF cytotoxicity, as well as in inhibition of NF kappa B activation and interleukin-6 gene induction by TNF. These findings suggest that mitochondria are the source of second messenger molecules and serve as common mediators of the TNF-cytotoxic and gene-regulatory signaling pathways.
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PMID:Depletion of the mitochondrial electron transport abrogates the cytotoxic and gene-inductive effects of TNF. 834 50

The aim of the present work is to investigate in vivo cytokine production during chemohyperthermia. 11 patients suffering from gastric adenocarcinoma (n = 6), ovarian adenocarcinoma (n = 4) or malignant mesothelioma (n = 1) were studied. Patients received 60 mg mitomycin or 100 mg cisplatin per square meter during 2 h in 6 liters of a heating solution (temperature 42 degrees C, flow rate 200 ml/min in a closed circuit) after previous surgical resection. Tumor necrosis factor-alpha (TNF-alpha) and interleukin-6 (IL-6) were measured at 0, 30, 45, 60 and 90 min, both in the blood stream and in the heating solution circulating intraperitoneally. We observed a slight increase in plasma IL-6 occurring as soon as 30 min, a dramatic rise in IL-6 in the heating solution. TNF-alpha values were only slightly augmented. In addition, the importance of various factors in the induction of IL-6 and TNF-alpha production during chemohyperthermia (temperature, mitomycin C, cisplatin) were studied using a whole blood ex vivo model.
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PMID:Cytokine production during intraperitoneal chemohyperthermia. 837 33


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