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)

Chronic airway inflammation is an important feature of cystic fibrosis (CF), markedly influencing morbidity and mortality. We wanted to assess the contribution of the respiratory epithelium in the mediation of local inflammatory events, and, more particularly, its regulating role through cytokine secretion. We have studied the regulation of interleukin-6 and 8 (IL-6 and IL-8) production by the SV40 transformed airway epithelial cell line JME/CF15 (homozygous for the deletion of Phe 508). We show that unstimulated JME/CF15 cells secrete IL-6 and IL-8. Neutrophil chemotactic activity (NCA) is detected in supernatants. The secretion of IL-6 and IL-8 is increased following stimulation of the JME/CF15 cells by IL-1 beta and neutrophil elastase. Lipopolysaccharide and granulocyte macrophage colony stimulating factor (GM-CSF) have no effect on secretion of IL-6 or IL-8. Neutrophil elastase inactivates recombinant human IL-6 at 37 degrees C in vitro, but has no effect at 4 degrees C, suggesting a proteolytic effect of elastase on IL-6. IL-8 activity remains preserved, even after prolonged exposure to elastase. Our data suggest that the airway epithelium may play an active role in the mediation of neutrophil chemotaxis. Local production of IL-8 in response to elastase and IL-1 beta, together with the inactivation of the anti-inflammatory protein IL-6, may result in a significant upregulation of airway inflammation in cystic fibrosis.
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PMID:Regulation of cytokine secretion by cystic fibrosis airway epithelial cells. 811 34

The influence of OK-432, a streptococcal preparation, on human polymorphonuclear leukocytes (PMN) was examined. OK-432 increased O2- generation was also observed when PMN were cultured with 10(-2)KE/ml OK-432 for 1 h and then stimulated with phorbol myristate acetate or formyl-metionyl-leucil-phenylalanine (FMLP). In addition, PMN O2- generation was promoted by culture supernatants of peripheral blood mononuclear cells (PBMC) incubated with 10(-3) or 10(-2) KE/ml OK-432. Furthermore, OK-432 (10(-3)-10(-2) KE/ml) enhanced the chemiluminescence of FMLP- and PMA-stimulated PMN. However, nitroblue tetrazolium reduction and myeloperoxidase activity were only minimally enhanced. Not only the candidacidal activity of PMN but also antibody-dependent cell-mediated cytotoxicity against Candida and Raji cells were enhanced in correspondence with the increased generation of reactive oxygen species. Culture of PMN or PBMC for 24 h with OK-432 resulted in a concentration-dependent increase in the substantial production of interleukin-1 beta, interleukin-6 and tumor necrosis factor-alpha. OK-432 also enhanced granulocyte-macrophage colony stimulating factor and gamma-interferon generation by leukocytes in a dose-dependent manner. Our research indicates that OK-432 enhances PMN function directly as well as via the promotion of cytokine production, and suggests that these effects of OK-432 could be beneficial in immunosuppressed patients.
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PMID:Enhancement of polymorphonuclear leukocyte (PMN) function by OK-432. 815 May 58

It has been shown previously that opioids induce antinociceptive effects at peripheral sites in the presence of inflammatory processes. Besides being elicited by local injection of opioids, such effects can also be obtained by activation of intrinsic opioid mechanisms, e.g. following stress. In the present study the possible role of cytokines in this mechanism was investigated. Unilateral inflammation of the hindpaw of rats was induced by local injection of Freund's complete adjuvant. Intraplantar injection of tumor necrosis factor alpha (TNF alpha) or interleukin-6 induced a dose-dependent increase in the threshold in the paw pressure test in the inflamed but not in the non-inflamed paw. This increase was prevented by local injection of naloxone and the mu-opioid receptor specific antagonist CTOP (D-Phe-Cys-Tyr-D-Trp-Arg-Thr-Pen-Thr-NH2) as well as by 3-E7, an universal opioid peptide antibody. In rats pretreated with cyclosporin A to suppress the immune system, the antinociceptive effect of TNF alpha was completely inhibited. In concert with previous studies these data indicate that the tested cytokines release opioid peptides (e.g. beta-endorphin and/or enkephalins) from immune cells of the inflamed tissue which act on opioid receptors present on sensory nerve terminals, resulting in antinociception.
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PMID:Peripheral mechanisms of opioid antinociception in inflammation: involvement of cytokines. 828 87

Aggregation studies have become a useful criterion for analyzing leukocyte motility and activation in vitro. The T-cell-derived lymphokine human leukocyte inhibitory factor (LIF) is a modulator of many important polymorphonuclear (PMN) functions in addition to aggregation such as chemotaxis, lysosomal degranulation, phagocytosis, bactericidal killing, augmented antibody-dependent cellular cytotoxicity (ADCC), induction of neutrophil Fc-gamma, complement type-1 and FMLP receptors, and production of superoxide and H2O2. Our investigations focused on the ability of LIF to modulate the aggregation of macrophages (MO) induced by calcium ionophore A23187. The ionophore A23187 directly induced potent aggregation of macrophages, which was markedly enhanced when the cells were pretreated with LIF. However, the addition of LIF in the absence of other costimuli did not directly induce MO aggregation. LIF was shown to enhance PMN aggregation induced by N-formyl-Met-Leu-Phe (FMLP), but did not augment the aggregation of FMLP-stimulated macrophages, indicating a cellular specificity of aggregation-inducing costimuli following LIF priming. Additional cytokines examined for possibly inducing MO aggregation were interleukin-1 (IL-1), tumor necrosis factor-alpha (TNF), and interleukin-6 (IL-6); all proved to be incapable of inducing aggregation directly, nor did they enhance the effect of A23187 ionophore on macrophage aggregation. Additionally, we found that LIF can directly stimulate MO to activate specific pathways of the arachidonic acid cascade, inducing the synthesis and release of thromboxanes and leukotriene B4. LIF did not augment the potent ability of A23187 to induce increased production of LTB4 or TxA2 by human MO. These new results coupled with our previously published data indicate that LIF can enhance the activation of both MO and PMN leukocytes when exposed to either A23187 or FMLP, respectively. Moreover, these data suggest that LIF can contribute directly to monocyte-macrophage leukocyte activation, in addition to PMN activation, during inflammatory responses, resulting in greater cell aggregation, activation, and specific proinflammatory arachidonic acid product release.
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PMID:Leukocyte inhibitory factor (LIF) potentiates human macrophage aggregation and activation responses to calcium ionophore A23187 and directly induces leukotriene B4 and thromboxane A2 release. 829 72

Constitutive up-regulation of interleukin-6 (IL-6) gene expression is observed in many neoplastic cell lines. The contribution of mutations in p53 to the up-regulation of the IL-6 promoter was evaluated in transient transfection experiments. In HeLa cells, wild-type (wt) human or murine p53 preferentially repressed the IL-6 promoter. The p53 mutants Val-135 and Phe-132 up-regulated IL-6 promoter activity in these cells at both 32.5 and 37 degrees C. The temperature-sensitive Val-135 mutant was not only not inhibitory or "wt-like" at the lower temperature, but had gained a transcriptional activator phenotype which was temperature-independent in HeLa cells. The functional DNA target for transcriptional modulation of the IL-6 promoter by p53 species included the multiple cytokine- and second messenger-response element (-173 to -145); point mutations in the transcription factor C/EBP beta-binding site within the second messenger-response element largely blocked the ability of p53 mutants Val-135 and Phe-132 to up-regulate this promoter. The up-regulation of IL-6 promoter constructs by co-transfection into HeLa cells of a C/EBP beta constitutive expression vector was blocked in a dominant negative manner by wt p53. In contrast, the p53 mutants Val-135 and Phe-132 further enhanced C/EBP beta-mediated up-regulation of IL-6 promoter constructs. The modulation of C/EBP beta function by p53 species provides a basis for the involvement of p53 not only in the regulation of cytokine synthesis but also in the altered responsiveness of tumor cells to cytokines.
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PMID:Modulation of the human interleukin-6 promoter (IL-6) and transcription factor C/EBP beta (NF-IL6) activity by p53 species. 832 85

The release of free radicals and pro-inflammatory cytokines such as nitric oxide (NO) and tumor necrosis factor alpha (TNF alpha) is commonly observed in adult respiratory distress syndrome (ARDS) following infection or exposure to microbial products. The aim of this study was to scrutinize the involvement of NO in ARDS in a mouse model determined by the sequential exposure to lipopolysaccharide (LPS) and formyl-norleucyl-phenylalanine (FNLP). Nitrite measurements in bronchoalveolar lavage fluids (BALF) and sera demonstrated that exposure to microbial products elicits large amounts of NO in LPS/FNLP-challenged mice. This release was significantly inhibited by infusion with the inducible NO synthase antagonist, aminoguanidine (AG). Our results show that LPS/FNLP exposure induces lung damage as demonstrated by protein and lactate dehydrogenase (LDH) increases in BALF. Liver damage was also detected in LPS/FNLP-challenged mice with increases in serum ornithine-carbamoyltransferase (OCT) levels. LPS/FNLP infusion led to elevated levels of the cytokines interleukin-6 (IL-6) and tumor necrosis factor alpha (TNF alpha) in the sera. LPS/FNLP also led to neutrophil adhesion in the lung vasculature, as seen by increased levels of myeloperoxydase. Interestingly, inhibition of NO release in challenged mice led to an important increase in markers of tissue damage in the lungs and livers, but a decrease in neutrophil recruitment. Infusion of AG in LPS/FNLP-challenged mice led to a much increased level of sera TNF alpha. These data suggest that after exposure to microbial products, NO generated as a result of activation of the inducible NO synthase blocks the full expression of tissue damage in the lungs.
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PMID:The involvement of nitric oxide in a mouse model of adult respiratory distress syndrome. 854 74

To understand the structure-function relationship in the human interleukin-6 (IL-6) system, comparative studies were performed on the basis of NMR data obtained using the wild-type IL-6 and six mutants. In each of the six mutants, either Leu152, Leu159, Leu166, Leu168, Leu175, or Leu182, which exist in the C-terminal receptor-binding region, was substituted with Val. The resonance assignments of Val, Ile, Leu, and Phe residues were made by using specific double-labeling and site-specific mutagenesis strategies. On the basis of chemical shift and NOE data collected for six IL-6 mutants and those for the wild-type IL-6, we analyzed the structural changes induced by the substitution of each of the six Leu residues. The NMR data showed that substitution of Leu182 with Val (L182V) induced no structural change in IL-6, suggesting that Leu182 is located on the surface of the IL-6 molecule. A significant decrease in receptor-binding activity was observed in the L182V mutant. It was concluded that the side chain of Leu182 is directly involved in receptor binding. Substitution of Leu175 with Val (L175V) was shown to induce a significant structural change in IL-6. The NMR data are discussed on the basis of the location of four helix elements and an up-up-down-down helix topology of the predicted structure of IL-6 [Bazan, J.F. (1991) Neuron 7, 197-208]. It is possible that helix D bent more sharply toward helix B in the L175V mutant than in the wild-type IL-6 to maintain a closely packed and solvent-inaccessible core formed in the mutated region. It is suggested that the kink of helix D is related to the decrease in receptor-binding activity in the L175V mutant. On the basis of the observed NOE network, the folding topology of IL-6 was analyzed. A comparison of the folding topology of IL-6 with that of human granulocyte colony-stimulating factor determined by X-ray crystallography [Hill, C. P., Osslund, T. D., & Eisenberg, D. (1993) Proc. Natl. Acad. Sci. U.S.A. 90, 5167-5171] indicated that IL-6 has a significant similarity of folding topology to that of human granulocyte colony-stimulating factor.
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PMID:Folding topologies of human interleukin-6 and its mutants as studied by NMR spectroscopy. 855 85

Interleukin-6 (IL-6) induces tyrosine phosphorylation and activation of the latent transcription factor Stat3 in HepG2 cells. Mutation of Stat3 tyrosine 705 to phenylalanine (Y705F) inhibits IL-6-induced tyrosine phosphorylation of this Stat3 mutant in transfected HepG2 cells. In cotransfections of HepG2 cells, the Stat3 mutant Y705F causes a reduction of the tyrosine phosphorylation of wild type Stat3-FLAG. Moreover, Y705F inhibits the action of endogenous Stat3 in cotransfected cells, reducing IL-6 induction of a Stat3-responsive reporter construct. Y705F therefore acts as a dominant negative mutation of Stat3.
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PMID:Dominant negative stat3 mutant inhibits interleukin-6-induced Jak-STAT signal transduction. 862 74

The pleiotropic cytokine interleukin-6 (IL-6) has been predicted to be a protein with four antiparallel alpha-helices. On target cells, IL-6 interacts with a specific ligand binding receptor subunit (IL-6R), and this complex associates with the signal-transducing subunit gp130. Human IL-6 acts on human and murine cells, whereas murine IL-6 is only active on murine cells. The construction of chimeric human/murine IL-6 proteins has allowed us to define a region (residues 77-95, region 2c) within the human IL-6 protein that is important for IL-6R binding and a region (residues 50-55, region 2a2) that is important for IL-6R dependent gp130 interaction. Guided by sequence alignment and molecular modeling, we have constructed several IL-6 variants with point mutations in these regions and have tested them for receptor binding and signal initiation. Within region 2c, phenylalanine 78 was involved in receptor binding, whereas lysine 54 within region 2a2 participated in gp130 activation. Furthermore, some IL-6 variants with lysine 54 replacements could be used to construct muteins that retained receptor binding but failed to activate gp130. Such IL-6 muteins were efficient IL-6 receptor antagonists.
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PMID:Identification of single amino acid residues of human IL-6 involved in receptor binding and signal initiation. 887 26

Interleukin-6 (IL-6) inhibitors are good potential therapeutic agents in human patients, and anti-IL-6 antibodies are among the best candidates. Here, we have successfully humanized mouse monoclonal antibody SK2, which specifically binds to IL-6 and strongly inhibits IL-6 functions. Since this antibody possesses N-linked carbohydrates on Asn-30 of VH region, which seems to be very close to an antigen-binding site, influence of these carbohydrates on antigen-binding was investigated. A biosensor study showed that the mouse SK2 Fab and its deglycosylated fragments had almost equal Kd (Kon/Koff), 26.8 nM (1.05 x 10(6)/2.81 x 10(-2)) and 24.7 nM (1.28 x 10(6)/3.15 x 10(-2)), respectively. Furthermore, a mutant chimeric SK2 antibody, in which the N-glycosylation site was removed from the VH region, showed a Kd of 11 nM, almost similar to that of the original chimeric SK2 antibody, determined by Scatchard analysis with 125I-IL-6. These data indicate the carbohydrates of mouse SK2 VH region do not significantly influence antigen-binding activity. In the next step, two versions of each humanized SK2 VL and VH regions were carefully designed based on the amino acid sequences of human REI and DAW, respectively. Only one alteration, Tyr to Phe, was made at position 71 in the two light chains, according to the canonical residue for LI. A N-glycosylation site was introduced on the two heavy chains, by changing Ser to Asn at position 30. All four combinations of humanized light and heavy chains could bind to IL-6 as well as the chimeric SK2 antibody. The light chain first version, however, could not efficiently inhibit IL-6 binding to its receptor, indicating the importance of the LI loop conformation for the inhibitory activity of SK2 antibody. In contrast, both versions of the heavy chains were comparable, in yielding good humanized SK2 antibodies, suggesting that the glycosylation of the SK2 VH region has no influence in recreating a functional antigen-binding site in this humanization.
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PMID:Humanization of an anti-human IL-6 mouse monoclonal antibody glycosylated in its heavy chain variable region. 914 Jul 29


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