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Query: UNIPROT:P05231 (interleukin-6)
 23,907 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In the present study we evaluated the antitumor effects of recombinant human interleukin-6 (rhIL-6), expressed in Chinese hamster ovary cells, in a murine primary tumor model. We showed that treatment with rhIL-6 substantially inhibited the implantation and growth rates of CT-26 adenocarcinoma tumor cells in the rectal submucosa of syngeneic mice. This effect was achieved by injecting rhIL-6 for 7 consecutive days starting 1 day prior to tumor inoculation. No obvious antitumor effect was noted when rhIL-6 injections started 5 days after tumor inoculation. Analysis of the mechanisms by which rhIL-6 exerts its antitumor effects did not reveal a direct antitumor effect on CT-26 tumor cells or the up-regulation of major histocompatibility complex antigens on these cells. However, infiltration of lymphocytes at the tumor site was observed. Increase of carcinoembryonic antigen by IL-6 was clearly seen in human HT-29 colon carcinoma cells. The possible application of these results for adjuvant immunotherapy of selected colorectal patients and prevention of reimplantation of tumor cells disseminated during surgery is discussed.
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PMID:Inhibition of CT-26 murine adenocarcinoma growth in the rectum of mice treated with recombinant human interleukin-6. 806 98

Resident glial cells and invading inflammatory cells are responsible for cytokine production within the brain. Astrocytes are known to secrete a variety of cytokines upon stimulation with cytokines themselves, protein kinase C activators, bacterial or viral constituents. Astrocytes also have surface receptors for a wide number of neurotransmitters and neuropeptides and some of these substances affect astrocyte immune functions, such as major histocompatibility complex (MHC) class II antigen expression. To elucidate the activity of neuromediators on cytokine secretion by glial cells, we studied the secretion of interleukin-6 (IL-6) by cultured rat astrocytes after incubation with various neurotransmitters and neuropeptides. Norepinephrine (NE) and the beta-adrenergic agonist isoproterenol (IPT) induced IL-6 secretion in a dose-dependent fashion. NE effect was predominantly mediated by beta 2-adrenergic receptors with a minor contribution of alpha 1-adrenergic receptors. The induction of IL-6 release by dibutyryl-cAMP indicated that IL-6 secretion secondary to beta 2-adrenergic receptor activation probably occurs through cAMP signalling pathways. Vasoactive intestinal peptide (VIP) was the sole neuropeptide able to induce IL-6 secretion. NE and VIP promoted IL-6 mRNA synthesis and both substances synergized with interleukin-1 beta (IL-1 beta) and tumor necrosis factor alpha (TNF alpha) in inducing IL-6 release. Our findings provide further evidence that neurons modulate astrocyte cytokine production and thereby regulate central nervous system immune functions.
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PMID:Norepinephrine and vasoactive intestinal peptide induce IL-6 secretion by astrocytes: synergism with IL-1 beta and TNF alpha. 837 50

Astrocytes contribute to the immunocompetence of the central nervous system (CNS) via their expression of class II major histocompatibility complex (MHC) antigens and the production of inflammatory cytokines such as interleukin-1 beta (IL-1 beta), tumor necrosis factor alpha (TNF-alpha) and interleukin-6 (IL-6). Of these cytokines, IL-6 is of particular interest because one of its many immune and inflammatory actions is the promotion of immunoglobulin synthesis, and it is thought that IL-6 expression within the brain exacerbates autoimmune diseases of the CNS, which are marked by local immunoglobulin production. Several stimuli induce astrocyte IL-6 expression, including such inducible endogenous factors as IL-1 beta and TNF-alpha. We have investigated the possibility that a constitutively present endogenous factor, the neurotransmitter norepinephrine (NE), can induce astrocyte IL-6 production. We report that NE induces both IL-6 mRNA and protein in primary neonatal rat astrocytes, with optimal induction at 10 microM. IL-6 protein induction by NE is comparable to that seen with IL-1 beta or TNF-alpha, and NE synergizes with these cytokines for a ten-fold enhanced effect. In contrast to astrocytes, microglia are relatively unresponsive to NE, IL-1 beta and TNF-alpha for IL-6 production. Experiments with the beta-adrenergic receptor agonist isoproterenol, and alpha and beta-adrenergic receptor antagonists (propranolol, phentolamine, atenolol, and yohimbine) indicate that beta 2 and alpha 1-adrenergic receptors are involved in NE induction of astrocyte IL-6 expression.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Interleukin-6 production by astrocytes: induction by the neurotransmitter norepinephrine. 839 17

In the present study we evaluate the antitumor efficacy of a glycosylated molecule of interleukin-6 (IL-6), which was cloned and expressed in Chinese hamster ovary cells. When tested with two syngeneic murine tumors, the MC38 adenocarcinoma and the MCA106 fibrosarcoma, recombinant IL-6 (rIL-6) significantly reduced the number of day-3 established MC38 lung metastases, but had no effect on MCA106 lung metastases. A similar effect of rIL-6 was seen on day-3 MC38 liver metastases. The antitumor activity mediated by rIL-6 was achieved at doses of the cytokine ranging from 6 micrograms to 150 micrograms/day. There was no correlation between the responsiveness to rIL-6 of these two tumors and their susceptibility, in vitro, to a direct cytostatic effect of the cytokine or the increase in the expression of major histocompatibility complex (MHC) antigens after exposure to rIL-6. However, a correlation was seen between the antitumor response to rIL-6 and the initial number of tumor cells expressing MHC antigens. The possible role of MHC antigens expressed on tumor cells, the generation of MHC-restricted cytotoxic cells and the responsiveness to IL-6 are discussed.
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PMID:Antitumor effects of recombinant interleukin-6 expressed in eukaryotic cells. 842 7

In order to investigate activation of the innate immune system in murine toxoplasmosis, T- and B-cell-deficient SCID mice and their co-isogenic immunocompetent C.B-17 counterparts were orally infected with a low-virulent strain of Toxoplasma gondii (DX strain). SCID mice developed a fatal necrotizing toxoplasmosis, whereas CD4+ and CD8+ T cells contributing to inflammatory infiltrates conferred resistance to immunocompetent mice. Significant amounts of interferon-gamma (IFN-gamma) were detectable in SCID mice. The most likely source for this cytokine is activated natural killer (NK) cells. In comparison to immunocompetent mice IFN-gamma levels were reduced in cerebrospinal fluid (CSF) and serum of SCID mice at days 7 and 14 of disease. Similar amounts of tumour necrosis factor (TNF) were detected in both strains of mice. In addition, immunohistochemistry showed major histocompatibility complex (MHC) class II antigen expression on SCID and C.B-17 microglial cells and macrophages demonstrating activation of these cells in both strains. However, the up-regulation of MHC class II antigen on microglia was less pronounced in SCID mice, presumably due to reduced levels of IFN-gamma. Interleukin-6 (IL-6) levels in CSF and serum were elevated in both strains and correlated with systemic and intracerebral disease activity. In conclusion, our results demonstrate activation of macrophages and NK cells as the predominant defence mechanisms of the comprised SCID immune system during toxoplasma infection. This implies a major role for the innate immune system during early stages of toxoplasmosis although T cells are necessary to control the infection efficiently.
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PMID:Expression of major histocompatibility complex class II antigens and levels of interferon-gamma, tumour necrosis factor, and interleukin-6 in cerebrospinal fluid and serum in Toxoplasma gondii-infected SCID and immunocompetent C.B-17 mice. 847 25

Multinucleated giant cell formation (MNGC) occurs in central nervous system AIDS. The mechanism of fusion of microglia in these cases is unknown. We investigated the ability of lymphokines to induce fusion and found that interleukin-3 (IL-3), interleukin-4 (IL-4), gamma interferon (gamma-IFN), and granulocyte-macrophage colony stimulating factor (GM-CSF) induced MNGC formation in cultures of rat microglia in vitro. The diacylglycerol analogue phorbol myristate acetate (PMA) also induced MNGC. Interleukin-1 (IL-1), interleukin-6 (IL-6), and tumor necrosis factor alpha (TNF alpha) failed to induce fusion. Preincubation of the IL-3 treated cultures with anti-IL-3, anti-leukocyte function associated antigen-1 (LFA-1) alpha-chain (CD11a), and anti-intercellular adhesion molecule-1 (ICAM-1) inhibited cell fusion. Antibody to polymorphic Class II major histocompatibility complex (MHC) determinants also inhibited MNGCs. Cell surface LFA-1 was predominantly observed on MNGC, suggesting that LFA-1 expression is involved in microglia fusion. We thus propose that MNGC formation of microglia result from the effects of T cell-derived cytokines probably through the induction of cell surface adhesion molecules.
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PMID:Lymphokine induction of rat microglia multinucleated giant cell formation. 850 64

Murine retinal glia are normally negative for major histocompatibility complex (MHC) Class II antigens and express low levels of MHC Class I and intercellular adhesion molecule-1 (ICAM-1) as detected by avidin-biotin-peroxidase immunohistochemistry. These surface molecules associated with immune function were either induced (Class II) or upregulated (Class I and ICAM-1) on cultured retinal glial cells in a dose- and time-dependent manner following exposure to recombinant interferon-gamma (rIFN-gamma). MHC Class I and II expression by passaged and primary cells was maximal (> 90% positive) after incubation with 100 U/m1 of rIFN-gamma for 48 h. ICAM-1 expression by primary and passaged cells tripled between 48 and 72 h after exposure to 25 or 50 U/m1 of rIFN-gamma. By 72 h after exposure to 100 U/m1 of rIFN-gamma, 62% of the retinal glia were positive for ICAM-1, whereas under normal culture conditions these molecules were detected on < 3% of the retinal glia. Bacterial lipopolysaccharide (LPS), a known stimulator of central nervous system (CNS) astrocytes, increased ICAM-1 expression only 3-fold to 9% of cells staining positively, but neither MHC Class I nor Class II expression was altered from baseline levels. Surface expression of ICAM-1, MHC Class I, and MHC Class II was unaffected by exposure to either rTNF-alpha (1000 U/m1) or rIL-6 (100 U/m1) for 24 h. Under normal culture conditions, intracellular interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-alpha) were detected immunohistochemically. Exposure to either rIFN-gamma or LPS induced more intense staining which correlated with increased secreted levels of both cytokines in culture supernatants. Levels of secreted TNF-alpha increased 6-fold after stimulation with LPS for 24 h, while secreted IL-6 increased over 9-fold. These results support the hypothesis that retinal glia may participate in intraretinal immune processes following stimulation during inflammatory and infections processes via either cell surface-or soluble mediator-dependent mechanisms or a combination of both.
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PMID:Modulation of immune-associated surface markers and cytokine production by murine retinal glial cells. 859 92

During the induction phase of contact sensitization and other cutaneous immune responses a proportion of epidermal Langerhans cells (LC) is induced to leave the skin and migrate via afferent lymphatics to lymph nodes draining the site of exposure. The cells that accumulate in draining nodes have acquired the characteristics of immunostimulatory dendritic cells and effectively present antigen to responsive T lymphocytes. In the present study we have questioned whether LC in the epidermis and the lymph node dendritic cells into which they develop express interleukin-6 (IL-6), a cytokine that has been shown to serve as an important costimulator of T lymphocyte activation. In situ immunocytochemical analyses using a biotin-streptavidin staining technique revealed that dendritic cells resident in the epidermis of untreated mice constitutively express this cytokine. Keratinocytes expressed detectable IL-6 only following local exposure to the contact allergen oxazolone. Such treatment also appeared to enhance the expression by epidermal dendritic cells of this cytokine. Analyses of unfractionated and LC-enriched and -depleted populations of epidermal cells revealed a close correlation between major histocompatibility complex (MHC) class II (Ia) antigen expression and staining for IL-6, implicating LC as the sole or major source of this cytokine in unstimulated epidermis. Finally, compared with tissue isolated from mice treated with vehicle alone, draining lymph nodes prepared from animals 18 hr following sensitization with oxazolone displayed a substantial increase in both the frequency of dendritic cells and the number of IL-6+ cells within the paracortex. These data demonstrate that resident epidermal LC and the dendritic cells into which they develop are important sources of IL-6. Their constitutive and inducible expression of this cytokine will facilitate the induction of cutaneous immune responses.
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PMID:Constitutive and inducible expression of interleukin-6 by Langerhans cells and lymph node dendritic cells. 867 3

Reovirus serotype 1, strain Lang (T1/L), a well characterized enteric virus, elicits humoral and cellular immune responses in mice. Although orally and intradermally induced infections generate comparable reovirus-specific serum antibody titers, little is known about the effects of the route of infection on the systemic immunoglobulin G (IgG) response. To assess whether the route of exposure affects virus-specific humoral immunity, we infected various strains of mice with reovirus T1/L by the oral or intradermal routes. At day 10 following infection, virus-specific serum antibody titers and IgG subclasses were determined by enzyme-linked immunosorbent assay. Serum IgG2a and IgG2b antibodies were detected in all mouse strains independent of the route of infection. Mice of the H-2d haplotype that received an intradermal infection also had high levels of reovirus-specific serum IgG1. This dichotomy of responses was not associated with differences in the types of cytokine produced by draining peripheral lymph nodes. However, peripheral lymph node lymphocytes from C3H mice produced significantly higher levels of gamma interferon than did BALB/c, C57BL/6, and B10.D2 mice. Additionally, peripheral lymph node lymphocytes from all strains of mice produced only low levels of interleukin-5, with no detectable level of interleukin-4 or interleukin-6. Analysis of specific antibody at inductive sites of the immune response showed that orally infected Peyer's patches produced predominantly IgA and intradermally infected peripheral lymph nodes produced predominantly IgG2a. Western blot (immunoblot) analysis showed that virus-specific IgA, IgG1, and IgG2a reacted with reovirus structural proteins. These data suggest that the route of infection affects the isotype and IgG subclasses, but not the antigen specificity, of the local antibody response. In addition, virus-specific IgG1 generated following an intradermally induced infection is linked to the H-2d major histocompatibility complex haplotype.
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PMID:Effects of the route of infection on immunoglobulin G subclasses and specificity of the reovirus-specific humoral immune response. 870 19

Studies of hamster-human and mouse-human somatic fibroblast hybrids and transfected mouse fibroblasts have demonstrated that signaling through the human interferon-gamma receptor (hu-IFN-gammaR) requires the formation of a complex consisting of ligand (IFN-gamma), a ligand binding receptor chain (IFN-gammaR1), and a signal transducing receptor chain (IFN-gammaR2). To date, the ability of this receptor complex to transduce the full repertoire of biological signals has been difficult to assess due to the limited number of activities that IFN-gamma can exert on fibroblasts. The current report assesses the ability of hu-IFN-gammaR chains to transduce signals in the absence of background human gene products by expressing hu-IFN-gammaR2 in a transformed macrophage cell line (F10/96) derived from a hu-IFN-gammaR1 transgenic mouse. Our results indicate that F10/96 clones expressing both human receptor proteins bind hu-IFN-gamma with an affinity comparable to that of human cells. Binding of either human or mouse IFN-gamma to its respective receptor elicits classic IFN-gamma responses such as up-regulation of major histocompatibility complex antigens, enhanced expression of IRF-1, and increased production of NO2- radicals, interleukin-6, tumor necrosis factor-alpha, and granulocyte macrophage-colony stimulating factor. However, hu-IFN-gamma could not fully protect the clones from cytopathic effects of encephalomyocarditis virus and vesicular stomatitis virus while mo-IFN-gamma could. These results demonstrate that while co-expression of hu-IFN-gammaR1 and hu-IFN-gammaR2 is necessary and sufficient for most IFN-gamma-induced responses, it is not sufficient to confer a generalized antiviral state. These findings further suggest that additional species-specific accessory factor(s) are necessary for full signaling potential through the IFN-gamma receptor complex. The nature and potential role of such factors in IFN-gammaR signaling is discussed.
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PMID:Mouse macrophages carrying both subunits of the human interferon-gamma (IFN-gamma) receptor respond to human IFN-gamma but do not acquire full protection against viral cytopathic effect. 895 96


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