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)

Endotoxin (lipopolysaccharide, LPS) has the property of inducing tolerance to its own biological effects. This phenomenon has been extensively studied in animal models but only few studies exist on the regulation in humans. Here we describe experiments designed to determine the cytokine regulation and cellular changes in humans during induction of LPS tolerance after repeated LPS injections. Intravenous administration of purified LPS Salmonella abortus equi to cancer patients induces high amounts of circulating tumor necrosis factor-alpha (TNF-alpha), interleukin-6 (IL-6), interleukin-8 (IL-8), granulocyte colony-stimulating factor (G-CSF), and macrophage colony-stimulating factor (M-CSF). Repeated injections of LPS at daily intervals resulted in a marked downregulation of the cytokine response and in the case of TNF-alpha, IL-8, G-CSF, and M-CSF the cytokine response was reduced to baseline levels. In contrast, significant increases in serum IL-6 were detected up to day 5 of repeated LPS injections. Hematological changes included transient decreases in WBCs affecting granulocytes, monocytes, and lymphocytes, followed by a marked granulocytosis. The drop in WBCs remained unaltered throughout the 5 day course of repeated LPS injections whereas the granulocyte overshoot recovery diminished gradually. When PBMCs of the cancer patients were restimulated ex vivo a marked enhancement of the capacity to produce TNF-alpha, IL-113, and IL-6 occurred, which is in contrast to the decreasing TNF-alpha serum levels obtained in vivo. In parallel, a shift in monocyte subpopulations from CD14+/CD16- to CD14+/CD16+ cells was observed. The data provide evidence that different mechanisms are implicated in the cytokine downregulation following repeated LPS injections to cancer patients. Furthermore, PBMCs from LPS tolerant patients do not demonstrate a reduction in their capacity to produce cytokines.
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PMID:Endotoxin tolerance: regulation of cytokine production and cellular changes in response to endotoxin application in cancer patients. 128 77

Cells of the macrophage lineage are considered to be of special importance in the defense of the host against tumor development and spread. Immunotherapeutic strategies to stimulate macrophage (MAC) tumor cytotoxicity make use of activating compounds such as gamma-interferon which are given systemically. However, there are several lines of evidence that in malignant disease the generation of cytotoxic effector MACs is impaired. Both defective cell maturation and loss of responsiveness to activation are described. Here, a first clinical phase I trial of adoptive immunotherapy in cancer patients using autologous MACs generated in vitro from blood monocytes (MOs) is reported. Mononuclear cells were isolated by cytapheresis and density centrifugation and cultured in hydrophobic Teflon bags for 7 days with 2% autologous serum and recombinant human gamma-interferon being present for the last 18 h. Cytotoxic MO-derived MACs were then purified by countercurrent elutriation and reinfused into the patient. A total of 72 therapies have been performed with patients being treated i.v. (n = 8) and i.p. (n = 7). In vitro generated MACs proved to be mature as judged by the expression of maturation-associated surface molecules (MAX antigens, CD16, CD51, CD71), were cytotoxic to U937 tumor cells, and were efficient secretory cells. Cell dose escalation was performed in the first patients beginning with 10(8) MACs to finally infuse the total number of cells recovered from one single cycle of isolation and culture. MAC yield varied from 1 to 17 x 10(8) representing 13-79% of MOs initially seeded. Adoptive MAc transfer was well tolerated. Side effects observed were low-grade fever (less than 38.5 degrees C), induction of the coagulation cascade, and abdominal discomfort after i.p. application. The procoagulant activity of MAC autografts was cell dose dependent and demonstrated by detection of circulating fibrin monomers and thrombin-antithrombin complexes. Biological responses observed included elevated serum neopterin levels and the appearance of interleukin-6 in sera and ascitic fluids. Indication of a possible therapeutic effect was only observed in i.p.-treated patients and consisted of disappearance of malignant ascites in 2 of 7 patients.
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PMID:Adoptive transfer of tumor cytotoxic macrophages generated in vitro from circulating blood monocytes: a new approach to cancer immunotherapy. 170 43

The role of endogenously mediated fever and exogenous hyperthermia as modulators of immune functions remains poorly understood. It is known that fever is mediated by several cytokines, including interleukin-1 alpha and interleukin-1 beta (IL-1 alpha and IL-1 beta), interleukin-6 (IL-6), tumour necrosis factor-alpha (TNF-alpha) and the interferons. The present communication examines the effect of exogenous hyperthermia on the detection of these cytokines and shows the suppressive effect of elevated temperature (39 degrees) on the amount of IL-1 beta, IL-6 and IFN-gamma (P less than 0.001) but not on IL-1 alpha and TNF-alpha concentrations. It is suggested that a negative feedback mechanism exists between temperature and the production of some of the molecules involved in the mediation of fever. It is known that hyperthermia increases the proliferative response of lymphocytes. We found a twofold increase in [3H]thymidine incorporation at 39 degrees compared to 37 degrees. The distribution of cells expressing CD3, CD4, CD8, CD14, CD16, CD19 and CD25 markers was the same at 37 degrees and 39 degrees.
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PMID:Effects of in vitro hyperthermia on the proliferative response of blood mononuclear cell subsets, and detection of interleukins 1 and 6, tumour necrosis factor-alpha and interferon-gamma. 190 20

Staining with CD14 and CD16 monoclonal antibodies will identify two monocyte subpopulations in human blood: a major population of regular monocytes, which strongly expresses the CD14 antigen (CD14++), and a minor population with weak expression of CD14 and expression of the CD16 antigen (CD14+/CD16+ cells). As shown herein, the latter cells account for 45 +/- 22 cells/microL and 9% +/- 5% of the monocytes in healthy control donors (n = 35). In septicemia patients, the CD14+/CD16+ cells can become a major population, with more than 50% of all monocytes in 3 of 18 patients and with more than 500 cells in 4 of 18 cases. There was no correlation of CD14+/CD16+ cells to any clinical parameter except for CD14+/CD16+ percentage and body temperature (P = .013). The CD14++ regular monocytes showed a substantial decrease in CD14 antigen density in 9 of 11 patients. Three-color immunofluorescence shows that the CD14+/CD16+ monocytes in septicemia patients when compared with the CD14++ monocytes exhibit a higher level of class II antigen and a lower level of CD11b and CD33 antigens, consistent with a more mature nature of the CD14+/CD16+ cells. Levels of interleukin-6 (IL-6) were increased in septicemia patients; 3 of 5 patients with high numbers of CD14+/CD16+ cells (> 200/microL) had high levels of IL-6 (> 250/U/mL). These data suggest that septicemia may lead to substantial changes in blood monocyte composition and this may be related to elevated levels of cytokines such as IL-6.
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PMID:The novel subset of CD14+/CD16+ blood monocytes is expanded in sepsis patients. 769 40

CD16, a low affinity receptor for IgG, was found on cultured human glomerular mesangial cells (GMC) by Western blot analysis, cell ELISA and in situ hybridization. To characterize the molecule in more detail, reverse polymerase chain reaction was performed and the PCR products were analyzed. From sequence analysis and from hybridization experiments with oligonucleotides specific for either the transmembrane form or the glycosylphosphatidylinositol anchored form it was found that GMC-CD16 was similar to NK-CD16. This indicates that GMC express the transmembrane form of CD16. Comparison between nonstimulated GMC and GMC stimulated by aggregated gammaglobulin revealed no qualitative or quantitative difference in the expression of CD16. Incubation of GMC with aggregated gammaglobulin or with monoclonal antibodies to CD16 was followed by a time and dose dependent release of interleukin-6, suggesting that signals were transmitted by CD16. The occupancy of CD16 by immune complexes that may be deposited in various forms of glomerulonephritis might contribute to the perpetuation of inflammatory processes in the kidney.
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PMID:Human glomerular mesangial cells express CD16 and may be stimulated via this receptor. 770 21

Allogeneic blood transfusions have been associated with impaired outcome in surgical patients. This effect may be mediated by leukocytes. Animal experiments have shown that at least some of the effect can be modified by removal of leukocytes from transfused blood. Therefore, we compared the effects of autologous + leukocyte-depleted against standard allogeneic red blood cell transfusion on postoperative immunosuppression in 24 men undergoing coronary artery bypass surgery. In the autologous + leukocyte-depleted red blood cell transfusion group, patients received 800 +/- 200 mL (mean +/- SD) autologous blood and 2.2 +/- 2.0 units (mean +/- SD) of leukocyte-depleted saline-adenine-glucose-mannitol (SAGM) red blood cells. In the standard red blood cell transfusion group, patients were transfused with 5.5 +/- 1.4 units (mean +/- SD) of SAGM red blood cells. Leukocyte and differential counts; percentages of lymphocyte subpopulations (CD3-, CD4-, CD8-, CD16-, CD20-, CD25-, and B5-positive lymphocytes) and monocytes (CD14); phytohemagglutinin-, concanavalin A-, and pokeweed mitogen-induced and unstimulated proliferation of separated lymphocytes; unstimulated and pokeweed mitogen-stimulated production of IgG, IgM, or IgA; and serum interleukin-6, interleukin-1 beta, and serum C-reactive protein concentrations were measured preoperatively and on postoperative Days 1, 7, and 21. Significant changes were seen in these variables, but there were no differences between the groups. Three of the 12 patients in the allogeneic leukocyte-containing red blood transfusion group became human lymphocyte antigen (HLA) alloimmunized. No infections or other complications occurred in any patients. We conclude that HLA alloimmunization was the only effect that could be modified by use of autologous blood.
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PMID:Blood transfusion with autologous and leukocyte-depleted or standard allogeneic red blood cells and the immune response to open heart surgery. 794 71

Altered polymorphonuclear leukocyte (PMN) function is thought to contribute to organ dysfunction during the systemic inflammatory response syndrome (SIRS). To test this hypothesis, we evaluated whole blood PMN function adherent to fibronectin or laminin in patients with mild or severe acute pancreatitis as a paradigm for sirs. Whole-blood PMN intracellular H2O2 production, expression of CD32w (Fc gamma R II), CD16 (Fc gamma R III), and phagocytosis were performed using dichlorofluorescein diacetate, fluorescein isothiocyanate-labeled anti-CD32w, CD16, and serum-opsonized fluorescent microspheres. Group I (n x 7) represents normal control individuals; group II (n x 11) represents patients with mild acute pancreatitis. Group III (n x 15) represents critically ill patients with severe acute pancreatitis. Adherence of PMN from groups I and II to matrix proteins resulted in a 5% to 20% increase in each PMN function assayed whereas adherence of PMN from group III to matrix proteins resulted in 50% to 75% increases in each PMN function assayed. Pertussis toxin, pentoxifylline, and dibutyryl cyclic adenosine monophosphate (cAMP) each reduced group I-II H2O2 production and phagocytosis. Pentoxifylline and dibutyryl cAMP but not pertussis toxin reduced group III H2O2 production. Both intracellular H2O2 and phagocytosis assays from group III but not groups I-II showed exaggerated upregulation when exposed to NaF (4 mmol/L). Anti-interleukin-6 reduced the increase in intracellular H2O2 production in group III patients and significantly altered the exaggerated oxidative response to NaF. Longitudinal studies of group III whole-blood PMN showed persistent upregulation of intracellular H2O2 production in those patients whose hospital courses were complicated by multiple system organ failure. These results demonstrate abnormal whole blood PMN function during the systemic inflammatory response syndrome in the presence of fibronectin, or laminin and that this is mediated in part via a pertussis toxin insensitive altered guanosine triphosphate-binding protein.
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PMID:Polymorphonuclear leukocyte dysregulation during the systemic inflammatory response syndrome. 811 41

Immunoglobulin is known to be an immunomodulator. It can induce protein mediators from mononuclear cells, particularly monocytes in vitro. Intravenous immunoglobulin (IVIg) has been used as a therapy in several clinical situations. In this study, the influence of IVIg infusion on the plasma levels of two protein mediators, interferon-gamma (IFN-gamma) and interleukin-6 (IL-6), was assessed in patients with secondary generalized epilepsy. Compared to preinfusion levels, plasma interferon-gamma was increased in 18 of 18 patients 20 min after the 6- to 8-hr infusion of IVIg. Plasma interferon-gamma levels reached their peak at various times from 20 min to 3 days post IVIg infusion, dependent upon the individual patient. Plasma IL-6 levels also increased after IVIg infusion. Generally, IL-6 reached its peak level after IFN-gamma. No activated T cells or B cells were observed as determined by the expression of surface CD25, CD23, and HLA-DR 20 min following the infusion when the IFN-gamma and IL-6 levels were assessed. The expression of the high-affinity receptor for IgG, CD64, on monocytes was significantly enhanced after IVIg infusion, while the low-affinity receptor for IgG, CD32, was only slightly increased. Cytoplasmic staining of PBMC indicates that both CD16-positive and CD16-negative cells may contribute to the increase seen in plasma IFN-gamma. These data raise the possibility that the therapeutic effects of intravenous immunoglobulin may be related, at least in part, to the immunomodulatory activity as demonstrated by the changes in plasma levels of IFN-gamma and IL-6.
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PMID:Intravenous immunoglobulin induces interferon-gamma and interleukin-6 in vivo. 824 76

The expression of Fc receptors for IgG (Fc gamma R) and IgA (Fc alpha R) and of various other antigens on the human monocytic cell line U937 and peripheral blood monocytes, under stimulation with human recombinant tumour necrosis factor-alpha (TNF-alpha) and other cytokines, was investigated by flow cytometry. TNF-alpha, as well as interferon-gamma (IFN-gamma) or interleukin-6 (IL-6) had a significant up-regulating effect on U937 expression of Fc gamma RI/CD64. Furthermore, the action of TNF-alpha was augmented by IL-6, and more evidently by IFN-gamma. IFN-alpha alone had only a marginal effect, but was able to increase the TNF-alpha-driven Fc gamma RI expression. In contrast to U937 cells, TNF-alpha did not enhance significantly Fc gamma RI expression on human monocytes. Interestingly, on both U937 cells and monocytes, Fc alpha R was augmented markedly by TNF-alpha. Furthermore, TNF-alpha induced the expression of HLA-DR and HLA-DP antigens on monocytes and U937 cells. The expression of Fc gamma RII/CD32, FC gamma RIII/CD16, CD14, complement receptor type 1 (CR1/CD35), CR4 (CD11c/CD18), and MHC class-I antigens, was not influenced significantly by TNF-alpha. The results of this study show that TNF-alpha may act on human mononuclear phagocytes, alone or in combination with other cytokines, by modulating the expression of various cell-surface antigens.
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PMID:Influence of tumour necrosis factor-alpha on the expression of Fc IgG and IgA receptors, and other markers by cultured human blood monocytes and U937 cells. 829 57

Earlier studies on propofol have shown increased percentages of T helper cells after minor surgery. In this study, the effects of propofol infusion anaesthesia on the immune response were compared with those of combined isoflurane anaesthesia in 30 patients (median age 47 years, ASA 1-2) undergoing major surgery. The total dose of propofol in the propofol infusion group of 15 women was 860 mg (range 540-1520 mg) and the median end-expiratory isoflurane concentration in the combined isoflurane group of 15 women was 0.6% (range 0.5-0.8). The following were measured; leucocyte and differential counts; percentages of lymphocyte subpopulations (CD3, CD4, CD8, CD19, CD16 and HLA-DR+CD3); phytohaemagglutinin-, concanavalin A-, and pokeweed mitogen-induced and unstimulated lymphocyte proliferation; plasma interleukin-6; serum group II phospholipase A2, C-reactive protein and cortisol concentrations. Measurements were made pre-operatively, at the end of the operation and on the first and fifth postoperative days. No statistically significant overall differences were observed in the immune response between the groups. The serum cortisol response was weaker in the propofol group than in the isoflurane group (p < 0.05). Time-related changes were seen within the groups.
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PMID:The influence of anaesthetic technique upon the immune response to hysterectomy. A comparison of propofol infusion and isoflurane. 854 87


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