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)

We investigated the regulation of IL6 biological activity, de novo synthesis, and mRNA levels in adult vascular endothelial cells (EC) by bacterial endotoxin or inflammatory cytokines. Cells incubated without stimulus released scant IL6 activity. IFN gamma, IL2, or PDGF did not augment IL6 release from EC. LPS, lipid A, and TNF increased IL6 release modestly (5 to 20-fold), while recombinant IL1s (rIL1s) stimulated this process 100 to 400-fold. Differential release of IL6 from EC treated with LPS or rIL1 continued for at least 144 hr. Exposure to LPS or rIL1 caused EC to synthesize IL6 de novo. EC secreted the newly synthesized IL6 into the supernatant, rather than retaining it within or bound to cells. EC accumulated IL6 mRNA after 3 hr of exposure to rIL1. However, we could only detect IL6 message in cells incubated with LPS under "superinduction" conditions with cycloheximide, consistent with lower levels of IL6 biological activity in response to LPS compared to IL1 stimulation. We propose that local production of IL6 by vascular EC, which comprise the barrier between tissues and the blood, may influence regional immune and inflammatory responses.
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PMID:Adult human vascular endothelial cells express the IL6 gene differentially in response to LPS or IL1. 278 20

There is now good evidence that anti-thyroid drugs such as methimazole have immunomodulatory effects which may be important in the treatment of patients with Graves' disease, but the immunological mechanisms by which these agents act are not clear. This study has examined the effect of methimazole on four important soluble mediators of the immune response, interleukin-1 (IL-1), interleukin-2 (IL-2), gamma-interferon (gamma-IFN) and B-cell differentiation factor (BCDF). When peripheral blood mononuclear cells from normal subjects were stimulated with mitogens (phytohaemagglutinin, concanavalin A or pokeweed mitogen) in the presence of 10-100 mumol/l methimazole, there was an increase in IL-2 activity in the culture supernatants. This effect was apparent between 24 and 60 h: enhanced proliferation of T-cells was also seen in methimazole-supplemented cultures. There was no effect of the drug on IL-2 receptor expression or on IL-1 and gamma-IFN production. BCDF was increased by methimazole in one of three experiments with pokeweed mitogen but not in three experiments with concanavalin A. These results suggest that the enhancement of mitogen-stimulated T-cell proliferation in vitro with methimazole is due to an increase in the IL-2 available to the T-cells in these cultures. Thus the in-vivo immunological effects of these drugs are likely to be complex since they may have at least two, possibly related, actions on the intrathyroidal lymphoid infiltrate, namely inhibiting oxygen radical generation and increasing IL-2 levels.
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PMID:Effect of the anti-thyroid drug methimazole on interleukin-1 and interleukin-2 levels in vitro. 309 61

Interleukin-6 (IL-6/BSF-2/IFN beta 2) is a multifunctional cytokine that regulates the growth and differentiation of various tissues, and is known particularly for its role in the immune response and acute phase reactions. A complementary DNA encoding the human IL-6 receptor (IL-6-R) has now been isolated. The IL-6-R consists of 468 amino acids, including a signal peptide of approximately 19 amino acids and a domain of approximately 90 amino acids that is similar to a domain in the immunoglobulin (Ig) superfamily. The cytoplasmic domain of approximately 82 amino acids lacks a tyrosine/kinase domain, unlike other growth factor receptors.
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PMID:Cloning and expression of the human interleukin-6 (BSF-2/IFN beta 2) receptor. 313 46

The induction of antibody secretion by B cells requires T-cell-derived factors1-5. Such factors have been described1,2,6-12 but the precise relationship among these various factors is not clear, and it has been difficult to demonstrate that these factors act directly on the B cell and do not exert their effect via T cells or macrophages. In this report we describe the direct induction of IgM synthesis and secretion in cloned lines of long-term tissue culture adapted neoplastic B cells (BCL1) by T-cell supernatants from phorbol-12-myristate 13-acetate (PMA)-induced EL-4 cells or concanavalin A (Con A)-induced 7.1.1a cells5,9. We have termed this activity BCDFmu (B-cell differentiation factor for IgM). The supernatants containing BCDFmu induce activated and neoplastic B cells to secrete IgM5 and the factor responsible is distinct from BCGF13, interleukin-2 (IL-2)5, the classical T-cell replacing factor (TRF) described by Schimpl and Wecker5, and immune interferon (IFN gamma)5.
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PMID:Lymphokine-induced IgM secretion by clones of neoplastic B cells. 660 74

Recent research indicates that the proopiomelanocortin derivative alpha-melanocyte stimulating hormone (alpha-MSH) is a significant modulator of host reactions including fever and inflammation. Although the precise mechanism of action is still unknown, cytokine antagonism is believed to be responsible for at least a part of its anti-inflammatory/antipyretic influence: alpha-MSH antagonizes pyrogenic and proinflammatory effects of cytokines such as interleukin-1 (IL-1), interleukin-6 (IL-6), tumor necrosis factor (TNF), and interferon gamma (IFN gamma). Although it is clear that the peptide can act within the brain to inhibit fever and peripheral inflammation, an anti-inflammatory effect on a peripheral target was evidenced in animals with transection of the spinal cord. Recent data show that alpha-MSH is significant also in human disorders such as AIDS, rheumatoid arthritis, and myocardial infarction. This molecule is believed to be a key factor in neuroimmunomodulation and it may be useful as a therapeutic agent in control of inflammatory reactions.
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PMID:The neuropeptide alpha-melanocyte-stimulating hormone: a key component of neuroimmunomodulation. 748 26

Castleman's disease (CD) is a lymphoproliferative disorder characterized by enlarged hyperplastic lymph nodes. CD may be localized or multifocal, and is often associated with signs and symptoms of generalized inflammation. The systemic manifestations of CD have been previously attributed to an overproduction of interleukin-6 (IL-6) by the tumor, although there is evidence that IL-6 is not responsible for all of the symptoms. We describe a 9-year-old boy who developed Castleman's disease with systemic findings of hypochromic microcytic anemia, growth arrest, inflammation, and hyperimmunoglobulinemia. Following surgical resection, all of the symptoms and laboratory abnormalities resolved. Using reverse transcriptase polymerase chain reaction (RT-PCR) analysis of the tumor, we found elevated levels of IL-6 mRNA as expected, but also elevated levels of tumor necrosis factor beta (TNF-beta) and gamma interferon (gamma-IFN) mRNA. Because these cytokines are mediators of immune regulation and inflammation, we propose that TNF-beta and gamma-IFN also play an important role in the pathophysiology of Castleman's disease.
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PMID:Elevated levels of tumor necrosis factor-beta, gamma-interferon, and IL-6 mRNA in Castleman's disease. 749 11

Rapid transcriptional induction of genes in response to gamma interferon (IFN-gamma) is mediated by the IFN-gamma activation site (GAS) and its cognate protein, the IFN-gamma activation factor (GAF). We describe a GAS-associated, differentiation-induced factor (DIF) as a potential molecular link between the activities of IFN-gamma and of growth and differentiation factors. DIF DNA binding was activated by colony-stimulating factor 1 in murine macrophages and also during tetradecanoyl phorbol acetate-induced differentiation or IFN-gamma treatment in myeloid U937 cells. IFN-gamma activation of DIF decreased significantly upon monocytic differentiation. DIF binding to DNA was inhibited by antiphosphotyrosine antibodies and could be induced by treatment of U937 cells with vanadate. Unlike GAF, DIF-DNA complexes did not contain the 91-kDa protein (p91) from ISGF-3. DIF bound with high affinity to GAS from the promoters of the IFP 53/tryptophanyl-tRNA synthetase and Fc gamma RI genes, intermediate affinity to the Ly6A/E GAS, and low affinity to the guanylate-binding protein GAS. DIF may belong to a family of cytokine- or growth factor-induced factors binding with variable affinities to GAS-related elements: the interleukin-6-responsive acute-phase response factor associated with GAS from different IFN-inducible promoters but with a different preference of binding compared with DIF. The sis-inducible element of the c-fos promoter bound GAF but not DIF. However, the sis-inducible element could be changed by point mutation to compete for GAF and DIF binding. Our data show DIF to be a novel DNA-binding protein which is activated in response to differentiating signals. Moreover, they suggest that a family of cytokine- or growth factor-regulated proteins integrates and coordinates the responses to cytokines and to growth and differentiation factors by binding to GAS-related elements.
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PMID:A factor induced by differentiation signals in cells of the macrophage lineage binds to the gamma interferon activation site. 750 5

Recently it has been shown that IFN-alpha inhibits expression of GM-CSF in adherent cells of human long-term bone marrow cultures (LTBMC) stimulated with interleukin-1 (IL-1), tumour necrosis factor-alpha (TNF-alpha) or endotoxin. The murine bone marrow stromal cell line +/+(-1).LDA11 was used to further define regulatory mechanisms of IFN-alpha inhibition on GM-CSF expression. This cell line originated from a murine Dexter type culture and exhibits a preadipocytic phenotype. As in human LTBMC, we could demonstrate a inhibitory effect of IFN-alpha co-incubation on GM-CSF activity in serum-free supernatants of +/+(-1).LDA11 stromal cell cultures stimulated with IL-1 or TNF-alpha or the combination of IL-1 plus TNF-alpha. IFN-alpha inhibitory effect on GM-CSF expression was shown to be dose dependent with minimal response at 10 U/ml and maximal inhibition at a dose of 500 U/ml. Northern blot analysis confirmed these data at the mRNA level. Reprobing of Northern blots for interleukin-6 (IL-6) mRNA showed increased expression after IFN-alpha incubation, demonstrating specific and differential regulatory effects of IFN-alpha on cytokine production in bone marrow stromal cells. Inhibition of GM-CSF mRNA by IFN-alpha was time dependent, starting at about 90-120 min post-treatment. Cycloheximide (CHX) incubation abolished the inhibitory effect of IFN-alpha on GM-CSF expression, suggesting the requirement of a labile protein. Reporter gene studies were used in order to evaluate the effect of IFN-alpha incubation on GM-CSF mRNA transcription in stromal cells. For this purpose, GM-CSF promoter fragments were subcloned into a luciferase expression vector. Neither constitutive nor TNF-alpha stimulated GM-CSF transcription was inhibited by IFN-alpha coincubation. On the other hand, actinomycin-D chase experiments revealed a reduced GM-CSF mRNA stability after IFN-alpha incubation. The induction of a RNAase, possibly a 2-5A-dependent RNAase, by IFN-alpha may be a possible cause for the increased GM-CSF mRNA decay. These results show a regulatory role for IFN-alpha in the bone marrow microenvironment possibly involved in the myelosuppressive effect of IFN-alpha therapy or viral infections.
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PMID:Interferon-alpha (IFN-alpha) inhibits granulocyte-macrophage colony-stimulating factor (GM-CSF) expression at the post-transcriptional level in murine bone marrow stromal cells. 757 56

Both hyper- and hypothyroidism have been reported during prolonged recombinant human interferon-alpha (rhIFN alpha) therapy. To assess the short term effects of IFN alpha therapy on thyroid hormone metabolism, we measured thyroid hormone concentrations in eight healthy volunteers for 24 h after sc administration of rhIFN alpha and, on another occasion, after sc administration of saline (control study). There were no effects of rhIFN alpha on plasma T4 and free T4 or on thyroid hormone binding index. However, rhIFN alpha induced a significant decrease in the plasma concentrations of TSH (P < 0.03) and T3 (P < 0.02) compared with those in the control study, associated with an increase in rT3 concentrations (P < 0.02). IFN alpha induced a moderate increase in interleukin-6 (IL-6) concentrations (P < 0.02 vs. control study), whereas IL-1 and tumor necrosis factor concentrations remained below the detection limit in all subjects. It is concluded that IFN alpha administration induces major changes in thyroid hormone metabolism, possibly mediated in part by IL-6. The acute effects of rhIFN alpha mimic the euthyroid sick syndrome and appear to be different from the effects of chronic rhIFN alpha treatment on thyroid hormone metabolism.
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PMID:Acute effects of interferon-alpha administration on thyroid hormone metabolism in healthy men. 759 16

To evaluate the role of cytokines in the sick euthyroid syndrome, we tried to establish an animal model of non-thyroidal illness in mice by the administration of a sub-lethal dose of bacterial endotoxin (lipopolysaccharide; LPS) which induces a variety of cytokines, including tumour necrosis factor (TNF alpha), interleukin-1 (IL-1 alpha), interleukin-6 (IL-6) and interferon-gamma (IFN gamma). When compared with pair-fed controls, a single dose of LPS resulted in (a) systemic illness, (b) induction of TNF alpha and IL-6 and (c) a decrease of liver 5'-deiodinase mRNA from 4 h onwards followed by a decrease of serum tri-iodothyronine (T3) and thyroxine (T4) at 8 h and of serum free T3 (fT3) and free T4 (fT4) at 24 h; serum TSH remained unchanged. We then studied whether a single dose or a combination of IL-1 alpha, TNF alpha, IL-6 or IFN gamma could induce the sick euthyroid syndrome in mice, again using pair-fed controls. None of the cytokines except IL-1 alpha caused systemic illness, and IL-1 alpha was the only cytokine that decreased liver 5'-deiodinase mRNA transiently. IL-1 alpha, TNF alpha or IL-6 did not decrease serum T3, T4 and TSH, but administration of IFN gamma decreased serum T4, T3 and fT3 in a dose-dependent manner without changes in serum TSH. Administration of all four cytokines together had no synergistic effects; observed changes were of a smaller magnitude than after LPS. The following conclusions were reached.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:The role of cytokines in the lipopolysaccharide-induced sick euthyroid syndrome in mice. 759 43


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