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)

PTH-related protein (PTHrP), the peptide that is responsible for most cases of hypercalcemia of malignancy, is also produced under normal circumstances by a variety of tissues. Its role and regulation at these sites are not well understood. Recently, we have shown that PTHrP is induced in the spleen during the host response to endotoxin (LPS) and that tumor necrosis factor (TNF) is a major mediator of this effect. Given the large body of in vitro evidence suggesting that PTHrP can be produced by lymphocytes and act in an autocrine loop to alter their function, studies were undertaken to determine whether lymphocytes were the cells responsible for PTHrP production in the spleen. Both constitutive and LPS-induced PTHrP messenger RNA (mRNA) levels were the same in mice lacking mature T cells (nude mice) and in mice lacking natural killer (NK) cells (due to pretreatment with antibody against NK 1.1) compared to levels in normal mice, suggesting that neither mature T cells nor NK cells were the splenic source of PTHrP. Even scid mice that lack functioning T and B cells responded to TNF with the induction of splenic PTHrP mRNA levels comparable to those in control mice. Localization of PTHrP mRNA in subfractions of rat spleens after in vivo treatment with LPS confirmed the results of the murine studies; PTHrP mRNA was barely detectable in the lymphocyte-rich single cell fraction of the spleen. In contrast, the stromal fraction of the spleen was enriched with PTHrP mRNA both in the basal state and in response to LPS. A similar pattern of distribution was seen for interleukin-6; LPS only increased mRNA levels of this TNF-inducible cytokine in the splenic stroma. In addition, mRNA for the PTH/PTHrP receptor, which decreased in response to LPS, colocalized with PTHrP mRNA in the stromal fraction of the spleen. Immunohistochemical studies identified PTHrP in two populations of splenic cells: 1) smooth muscle cells located in the splenic capsule and trabeculae and 2) a subpopulation of stromal cells located in the red pulp of the spleen, primarily in a subcapsular distribution. Consistent with the localization of PTHrP mRNA, lymphocytes in the white pulp of the spleen did not stain for PTHrP.
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PMID:Endotoxin induces parathyroid hormone-related protein gene expression in splenic stromal and smooth muscle cells, not in splenic lymphocytes. 762 77

The route of nutrient provision has been reported to influence some aspects of the host inflammatory response in both patient populations and normal subjects. The tumor necrosis factor receptor system is a complex regulatory mechanism that modulates the bioavailability of tumor necrosis factor (TNF). We sought to determine whether maintenance on total parenteral nutrition (TPN) can alter host response to endotoxin challenge, specifically as it relates to the TNF receptor system. Seventeen healthy men were randomized to receive either TPN (n = 8) or a defined formula enteral diet (ENT, n = 9) prior to intravenous infusion of endotoxin (Lot EC-5, 20 U/kg). The subjects that received 1 week of antecedent TPN exhibited an increased heart rate and temperature and decreased mean arterial pressure post-LPS compared to those subjects maintained on enteral nutritional support. The TPN subjects also exhibited comparatively higher TNF and interleukin-6 levels in response to endotoxin. Monocyte TNF receptor levels decreased in both groups post-LPS, but TPN subjects exhibited consistently greater expression of this functional membrane-associated TNF receptor. After LPS, soluble tumor necrosis factor receptor II (sTNFr II, p75) peaked three times higher in TPN subjects than in ENT subjects. Conversely, sTNFr I (p55) was higher in the enterally fed group. From these studies it appears that antecedent TPN not only influences clinical manifestations of endotoxin but also modulates the regulation of all associated TNF receptors and shedding of soluble receptors.
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PMID:Parenteral nutrition alters monocyte TNF receptor activity. 763 Jan 32

The effects of Porphyromonas gingivalis lipopolysaccharide (P-LPS) and Escherichia coli lipopolysaccharide (E-LPS) on the gene expression and production of inflammatory cytokines of human periodontal ligament fibroblasts (HPLF) were examined by a Northern (RNA blot) assay and enzyme-linked immunosorbent assay, respectively. mRNAs for interleukin-6 (IL-6), IL-8, and transforming growth factor beta (TGF-beta) were detected in HPLF cells, but IL-1 alpha, IL-1 beta, tumor necrosis factor alpha, transforming growth factor alpha, and granulocyte-macrophage colony-stimulating factor were not detected by reverse transcription-PCR. The expression of TGF-beta mRNA was not influenced by either LPS. P-LPS (1 to 10 micrograms/ml) and E-LPS (100 micrograms/ml) markedly stimulated the expression of IL-6 and IL-8 mRNAs compared with the control. The synthesis of IL-6 and IL-8 was also stimulated by 10 and 100 micrograms of both LPSs per ml, but IL-8 synthesis was not stimulated with E-LPS at 1 microgram/ml. Secretion of IL-6 and IL-8 into the culture medium was detected at 6 and 3 h, respectively, after exposure to P-LPS (10 micrograms/ml). These findings suggested that P. gingivalis leads to periodontal tissue destruction and alveolar bone resorption through IL-6 and IL-8 released from HPLF cells stimulated with its LPS.
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PMID:Inflammatory cytokine gene expression in human periodontal ligament fibroblasts stimulated with bacterial lipopolysaccharides. 764 93

alpha 2-Macroglobulin receptor/low density lipoprotein receptor-related protein (alpha 2M-R/LRP) is a broad specificity receptor that may function in lipoprotein metabolism, proteinase regulation, and growth factor regulation. In this study, we demonstrated that alpha 2M-R/LRP expression in macrophages can be markedly decreased by LPS and by IFN-gamma. Regulation of alpha 2M-R/LRP in RAW 264.7 cells was demonstrated at the mRNA, antigen, and receptor-function levels. In receptor-function studies, the decrease in alpha 2M-R/LRP expression was detected as a 90% decrease in the Bmax or maximum receptor binding capacity for activated alpha 2M after treatment with LPS or IFN-gamma. Western blot analysis of whole cell lysates demonstrated significant loss of alpha 2M-R/LRP heavy-chain. Northern blot analysis of poly(A)+ RNA revealed a marked decrease in alpha 2M-R/LRP mRNA after treatment with LPS (79% decrease) or IFN-gamma (70% decrease). Other cytokines, including tumor necrosis factor-alpha, transforming growth factor-beta-1, and interleukin-6 did not regulate alpha 2M-R/LRP. The ability of LPS and IFN-gamma to regulate alpha 2M-R/LRP was confirmed in experiments with primary cultures of murine bone marrow macrophages. These studies demonstrate that macrophage alpha 2M-R/LRP is subject to significant downregulation by physiologically significant cytokines and signaling macromolecules.
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PMID:Regulation of macrophage alpha 2-macroglobulin receptor/low density lipoprotein receptor-related protein by lipopolysaccharide and interferon-gamma. 768 Jun 64

The control of metallothionein (MT) synthesis was investigated in freshly prepared rat hepatocytes in experiments of short-term duration. Viability and metabolic function were maintained in incubations of 6-h duration. MT synthesis was measurable in hepatocytes from fed rats at Zn concentrations down to 1 microM. Zn and dexamethasone induced concentration-dependent increases in the synthesis of MT with maximal increases above the 5-h control of 3.2- and 2.5-fold, respectively. Zn induction of MT was first measurable at 2 h and was inhibited by actinomycin C. Although initial (0 h) MT concentrations in hepatocytes from fasted rats were double those from fed rats, after 6-h incubation in the presence of 50 microM Zn, the fasted rat hepatocytes showed only half the MT concentrations of the fed rat hepatocytes. Glucagon and interleukin-6 (IL-6) were less effective inducers and increased MT synthesis by 28 and 17%, respectively. IL-6 (100 U/mL) was found to have an additive effect on MT synthesis above that of Zn alone (1-50 microM) or Zn plus dexamethasone (1 microM). A supernatant from LPS-stimulated macrophages increased MT synthesis by 40%. The basal MT synthesis was not increased by either tumor necrosis factor-alpha (TNF-alpha) or interleukin-1 (IL-1). All incubations were carried out in the presence of RPMI 1640 medium with Hepes (20 mM), bicarbonate (24 mM), and fatty acid-free albumin (FAFA; 0.5% w/v). MT synthesis was also seen using Krebs bicarbonate buffer with glucose (10 mM), Hepes (20 mM), and FAFA (0.5% w/v), and although the level of MT synthesis was less than in RPMI, the increases in concentrations of MT at 5 h were 225, 139, 36 and 20% for Zn, dexamethasone, glucagon, and control, respectively. It is concluded that MT synthesis occurs in freshly prepared hepatocytes and that these cells are responsive to some of the established inducers of MT. This system enables the study of MT synthesis in individual rats in various metabolic and pathological states.
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PMID:Metallothionein induction in freshly isolated rat hepatocytes. 768 80

The hypothesis was tested that alcohol may modulate alveolar macrophage cytokine receptors, thus interfering in lung immune defense mechanisms. Male rats were treated with alcohol either acutely (7 hr continuous intravenous alcohol infusion at a rate of 30 mg/100 g body weight/hr after a priming dose of 175 mg/100 g body weight) or chronically (feeding an alcohol-containing liquid diet for 12-14 weeks). Three hr before killing, the rats received an intravenous injection of Gram-negative bacterial lipopolysaccharide (LPS; Escherichia coli, O26:B6, 100 micrograms/100 g body weight). After anesthesia with sodium pentobarbital, the trachea was cannulated, and the lungs excised and lavaged to obtain alveolar macrophages. The recovered cells were used to measure the binding of recombinant human [125I]tumor necrosis factor-alpha (TNF-alpha) and [125I]interleukin-6 (IL-6). Kd and Bmax were determined at 4 degrees C, thus reflecting only the cell-surface binding sites and their affinity. Two binding sites were detected for both cytokines: high-affinity (Kd1 in the range of 20-110 pM), low-capacity (Bmax1 in the range of 1-13 fmol/10(6) cells), and low-affinity (Kd2 in the range of 0.6-1.3 nM), high-capacity (Bmax2 in the range of 34-100 fmol/10(6) cells). Acute alcohol treatment significantly decreased Bmax1 (39%) and Bmax2 (79%) for TNF-alpha, whereas chronic alcohol feeding abrogated the Bmax1 (Bmax1 = 0), without affecting Bmax2. In the acute group, LPS had an effect similar to that of alcohol. Alcohol administration did not modify the LPS effects. The following changes were monitored for IL-6 binding. Acute alcohol treatment markedly reduced (86%) Bmax2.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Expression of tumor necrosis factor-alpha and interleukin-6 cell-surface receptors of the alveolar macrophage in alcohol-treated rats. 769 40

The B9 assay is known to be a specific and sensitive assay for the estimation of interleukin-6 activity. This assay was found to be compromised by lipopolysaccharide in concentrations > or = 40 ng lipopolysaccharide per ml. The lipopolysaccharide stimulates proliferation of the B9 cell line in a dose-dependent manner both when measuring the proliferation by thymidine incorporation and when using the MTT assay. However the LPS dose-response curve is different compared to the dose-response curve for IL-6. A sample containing 100 ng LPS/ml but no IL-6 would be estimated erroneously to contain 12 pg IL-6. The interference of lipopolysaccharide is totally abolished by the addition of polymyxin B to the samples but the addition has no effect on the IL-6 induced proliferation.
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PMID:Lipopolysaccharide in concentrations above 40 ng/ml stimulates proliferation of the IL-6-dependent B9 cell line. 771 31

Although lymphocyte-derived cytokines are known to augment macrophage cytokine production in vitro, their effect on macrophage tumor necrosis factor-alpha (TNF-alpha) and interleukin-6 (IL-6) secretion during gram-negative bacterial sepsis has not been characterized. The purpose of this study was to examine the effect of lymphocyte-derived cytokines on macrophage TNF-alpha and IL-6 secretion during gram-negative bacterial peritonitis. To examine this problem, uninfected and infected mice were studied. Mice were infected with Escherichia coli O111:B4 and two subgroups were examined consisting of those pretreated iv 1 hr prior to bacterial challenge with either (1) saline or (2) anti-E. coli O111:B4 LPS mAb 2A3, the latter administered to abrogate the effects of LPS in vivo. Thus, three groups of mice were studied in relation to pretreatment and infectious challenges: (1) saline/saline (control); (2) saline/E. coli (saline); and (3) mAb 2A3/E. coli (mAb 2A3). Nonadherent splenocytes (> 95% lymphocytes by histologic staining criteria) harvested 16 hr later from mice in each group were incubated in culture ex vivo for 3 hr to obtain supernatants containing lymphocyte-derived cytokines. These supernatants containing lymphocyte-derived cytokines then were incubated in vitro with naive splenic macrophages with or without E. coli O111:B4 LPS. Macrophage TNF-alpha and IL-6 levels were determined using L929 and B9 bioassays.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Lymphocyte-derived cytokines augment macrophage tumor necrosis factor-alpha and interleukin-6 secretion during experimental gram-negative bacterial sepsis. 779 54

Macrophages represent the primary line of host defences in the peritoneal cavity. In order to study the metabolic activity and maturation stage of human resident peritoneal macrophages (PM phi). peritoneal fluid (PF) was taken by Douglas puncture from healthy hyperstimulated infertile women undergoing oocyte retrieval for in vitro fertilization. Peritoneal fluid and macrophage culture fluids were studied for different inflammatory mediators such as interleukin-1 (IL-1), tumour necrosis factor (TNF) and interleukin-6 (IL-6). The level of macrophage colony-stimulating factor (M-CSF), which represents a macrophage proliferation and differentiation factor, was determined in the PF and in the serum. Furthermore, the macrophage phenotypic profile was analysed, in particular the expression of sex steroid hormone receptors. IL-1. IL-6 and TNF were detectable in the PF and in the culture supernatants of PM phi whether stimulated or not by IFN-gamma and LPS. The mean level of M-CSF in the PF was 6.37 +/- 2.02 ng/ml as measured by RIA; this level did not correlate with the concentration of PM phi. The mean PF-M-CSF level was 1.4-fold higher than in the sera as measured by a EIA. Oestrogen and progesterone receptors could not be demonstrated on the PM phi analysed, so that a direct relationship between the ovarian steroid concentration in these women and the function of PM phi was unlikely. As compared to peripheral blood monocytes (Mo). PM phi showed a phenotypic profile, with some more mature features, e.g. increased expression of CD14, CD68, FcRII, FcRIII, CR3, CR4 and MHC class II determinants. These results indicate that resident PM phi have acquired in vivo a certain differentiation and/or activation state under micro-environmental factors where cytokines secreted by the M phi themselves or by other cells such as the mesothelium may play important roles.
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PMID:Human resident peritoneal macrophages: phenotype and biology. 781 96

Bacillus anthracis exotoxins mediate most of the symptomatology of severe anthrax. In addition to a clinical syndrome reminiscent of septic shock, which may be mediated by cytokines produced by macrophages stimulated with lethal toxin, infected patients show profound edema at sites of infection. Edema is mediated by edema toxin (ET), which comprises of a binding molecule, protective antigen, and an active moiety, edema factor, which possesses intrinsic adenylyl cyclase activity. Intracellular cyclic AMP (cAMP) regulates the production of several cytokines that modulate edema formation and play important roles in host defense against invading bacteria. To determine whether ET enhanced the accumulation of cAMP in monocytes and thereby influenced cytokine production, we cultured human monocytes with endotoxin (lipopolysaccharide [LPS]) and dilutions of ET and determined the levels of interleukin-6 (IL-6) and tumor necrosis factor alpha (TNF-alpha) in culture supernatant fluids. We further estimated cytokine-specific mRNA accumulation in monocytes by reverse transcription PCR and examined intracellular cAMP concentrations following treatment with ET. ET and LPS each induced monocytes to secrete comparable amounts of IL-6. ET did not inhibit and in most experiments modestly enhanced LPS-induced IL-6 production. In contrast to this stimulatory effect on IL-6 production, ET induced little or no TNF-alpha production. Moreover, ET profoundly inhibited LPS-induced TNF-alpha synthesis. These regulatory phenomena were also observed at the mRNA level in association with dose-related enhancement of intracellular cAMP in ET-treated monocytes. Monocytes treated with dibutyryl cAMP, an active analog of cAMP, produced cytokines in a pattern identical to that of cells treated with ET. The disruption of cytokine networks as a consequence of unregulated, ET-induced cAMP accumulation in human monocytes may impair cellular antimicrobial responses and contribute to clinical signs and symptoms.
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PMID:Anthrax edema toxin differentially regulates lipopolysaccharide-induced monocyte production of tumor necrosis factor alpha and interleukin-6 by increasing intracellular cyclic AMP. 792 6


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