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)

Autoimmune thyroiditis is characterized by lymphocytic accumulation within the thyroid which may be the result, in part, of immunomodulatory cytokine secretion by thyrocytes. We have tested human thyroid cell cultures (n = 9) for interleukin-6 (IL-6) release using two bioassays. IL-6 was detected in all culture supernatants under basal conditions and was increased by gamma-interferon, tumour necrosis factor and TSH in a dose-dependent manner. The bioactivity was confirmed as IL-6 by immunoblotting experiments and could not be accounted for by contamination of the thyroid cell cultures with fibroblasts, lymphocytes or monocytes. Circulating IL-6 levels were not raised in patients with Graves' hyperthyroidism. Exogenous recombinant IL-6 reduced cyclic AMP production in response to TSH when added to thyroid cell cultures. Since IL-6 plays a major role in B cell differentiation and T cell activation, release of IL-6 by thyrocytes may increase the intrathyroidal autoimmune response in Graves' disease and Hashimoto's thyroditis. Our results also suggest that IL-6 may modulate thyroid cell function.
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PMID:Regulation of interleukin-6 release by human thyrocytes. 217 56

Human B-cell differentiation factor (BCDF) was purified to homogeneity by sequential filtration and chromatography of culture supernatants from TCL-Na1 cells on an AcA34 gel column and then on a Mono P column with fast protein liquid chromatography and reversed-phase HPLC. A 5300-fold enrichment in specific activity of BCDF with about 25% recovery was attained. The homogeneity of purified BCDF was evidenced by the following: (i) the specific activity was 1.7 X 10(7) units/mg of protein, (ii) only two bands, Mr 19,000 and 21,000, were identified by NaDodSO4/PAGE under reduced as well as nonreduced conditions, and (iii) BCDF activity was recovered from the gel after NaDodSO4/PAGE in the fractions corresponding to protein bands of Mr 19,000 or 21,000. Purified BCDF induced Ig secretion in Epstein-Barr virus-transformed cell lines; as little as 3 pM gave 50% of the maximum reaction achieved by 30-80 pM BCDF. Purified BCDF induced Ig production in activated B cells without any effect on cell growth. Purified BCDF did not show any activity of interleukin 1 or 2, B-cell stimulatory factor (BSF)p-1, B-cell growth factor II (BCGF-II), or interferon. Since BCDF was isolated and characterized as described, we propose that the BCDF that induces the final differentiation of B cells into high-rate Ig-secreting cells be designated BSFp-2.
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PMID:Purification to homogeneity and characterization of human B-cell differentiation factor (BCDF or BSFp-2). 241 Sep 27

Treatment of Daudi B-lymphoblastoid cells with low concentrations of either natural or recombinant human alpha-interferons inhibits cell proliferation and modulates the expression of a number of cell-surface antigens. Using a panel of monoclonal antibodies (MAbs) identifying determinants expressed at the surface of normal plasma cells, and polyclonal antibodies against surface and cytoplasmic immunoglobulin, we have found that growth inhibition is accompanied by plasmacytoid differentiation. Assays of growth stimulation of heterologous cells indicate that the culture medium from interferon-treated Daudi cells contains substantially more B-cell growth factor activity than that from control cells. However, the interferon-treated cells exhibit an impaired ability to respond to both these autocrine factors and exogenous factors produced by another Burkitt lymphoma line. These findings show that, in the case of Daudi cells, growth inhibition by interferons is closely associated with both terminal differentiation and a refractoriness to growth factors. In this system IFN-alpha may therefore be considered to be a B-cell differentiation factor, suggesting a possible basis for the anti-proliferative effects observed with certain human B-cell malignancies.
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PMID:Anti-proliferative effects of interferons on Daudi Burkitt lymphoma cells: induction of cell differentiation and loss of response to autocrine growth factors. 243 66

Endogenous interferons (IFNs) with antiviral activity have been detected in human fetal annexes, without any apparent induction. Some are of unusually high molecular weight and antigenic properties (Duc-Goiran P., Robert-Galliot, B., Lopez, J., and Chany, C. (1985) Proc. Natl. Acad. Sci. U.S.A. 82, 5010-5014). We study here the expression of IFN genes from the three antigenically distinct groups, in placental tissues taken during third-trimester pregnancies. We show by Northern blot analysis with RNA probes that IFN-alpha-like transcripts correlate with the presence of functionally active protein, purified by immunoaffinity chromatography. We fractionate on a formamide sucrose gradient, identify, and characterize a large 4.3-kb IFN-alpha-like transcript, which may be specifically expressed during fetal development. Despite the absence of IFN-beta transcript, a protein with an antiviral activity which was neutralized with a polyclonal anti-IFN-beta serum was detected in the placenta and could be related to a beta-like IFN. Besides IFNs, various growth factors and cytokines can be found in the placenta. We report here the presence of interleukin-6 expressed at high levels in fetal annexes. The coexpression of Interleukin-6 and endogenous IFNs suggests that they play an important role during development.
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PMID:Unusually large interferon-alpha-like mRNAs and high expression of interleukin-6 in human fetal annexes. 278 20

The human beta 2 interferon (IFN-beta 2) gene, a gene that also codes for B cell differentiation factor 2 (BSF-2), plasmacytoma/hybridoma growth factor (HGF), and hepatocyte-stimulating factor (HSF), is expressed in a variety of lymphoid and nonlymphoid tissues. Endotoxin, or bacterial lipopolysaccharide (LPS) preparations derived from the outer membrane of Escherichia coli or Salmonella typhimurium rapidly elevate IFN-beta 2 mRNA level in human skin fibroblasts (FS-4 strain). E. coli-derived LPS enhances IFN-beta 2 mRNA expression in FS-4 fibroblasts at a concentration as low as 0.3 ng/ml; this response is near-maximal in the range of 0.1-1 microgram/ml LPS. The increase in IFN-beta 2 mRNA level caused by LPS in FS-4 cells is detected within 30 min after addition of LPS, is sustained for at least 20 h thereafter, appears to involve the protein kinase C signal transduction pathway, does not require new protein synthesis, and is inhibited by dexamethasone in a dose-dependent fashion (in the range 10(-6)-10(-8) M). Cultures of LPS-treated FS-4 cells exhibit an antiviral state against vesicular stomatitis virus, which can be prevented by anti-IFN-beta antiserum. Medium obtained from LPS-treated FS-4 cell cultures enhances the number of immunoglobulin-secreting cells in cultures of human B-lymphoblastoid (CESS) cells. Thus, LPS may trigger a number of host defense mechanisms in the course of infection due to Gram-negative bacteria by enhancing IFN-beta 2 production by the ubiquitous fibroblast.
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PMID:Bacterial lipopolysaccharide (endotoxin) enhances expression and secretion of beta 2 interferon by human fibroblasts. 282 51

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

The expression in human fibroblasts of the beta 2-interferon (IFN-beta 2) gene, which is now recognized to be identical to the gene encoding B-cell differentiation factor BSF-2, is enhanced by several cytokines that affect cell growth (tumor necrosis factor, interleukin 1, platelet-derived growth factor, and beta 1-interferon). We have examined the possibility that IFN-beta 2 gene expression is regulated through activation, by diacylglycerol, of the protein kinase C pathway. The synthetic diacylglycerols 1,2-dioctanoylglycerol (diC8) and 1-oleoyl-2-acetylglycerol strongly enhanced IFN-beta 2, but not IFN-beta 1, gene expression in human fibroblasts (FS-4 strain). An increase in IFN-beta 2 mRNA level was detected within 15 min after addition of diC8 (290 microM) to FS-4 cells and was maximal approximately 20 hr later. An increase in IFN-beta 2 gene transcription was detected within 5 min of addition of diC8, and the rate of transcription was near-maximal by 15-30 min. The enhancement of IFN-beta 2 gene expression by diC8, interleukin 1, or tumor necrosis factor was not prevented by H8, a preferential inhibitor of cAMP- and cGMP-dependent protein kinases, but was blocked by H7, an inhibitor of protein kinase C as well as of cyclic nucleotide-dependent protein kinases. diC8 was found to protect FS-4 cells from the cytopathic effect of vesicular stomatitis virus; this protection was blocked by polyclonal or monoclonal antibodies that neutralize IFN-beta, suggesting that the antiviral effect was due to the secretion of IFN-beta 2 by the diC8-treated fibroblasts. The calcium ionophore A23187 (1-10 microM) also elicited an increase in the level of IFN-beta 2 mRNA in FS-4 fibroblasts; appropriate combinations of A23187 and diC8 had at least an additive effect in enhancing IFN-beta 2 mRNA levels. These results show that protein kinase C-activating or [Ca2+]-elevating agents rapidly increase the expression of the IFN-beta 2 gene in human fibroblasts.
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PMID:Rapid enhancement of beta 2-interferon/B-cell differentiation factor BSF-2 gene expression in human fibroblasts by diacylglycerols and the calcium ionophore A23187. 310 77

We have cloned the cDNAs of both human and mouse TNF and expressed them to high efficiency in Escherichia coli. Many transformed cell lines are sensitive to the cytotoxic action of TNF, especially in the presence of gamma-interferon, whereas normal cells either are unaffected or respond mitogenically. A number of human-mouse chimeric TNF genes have been constructed and expressed. All show biological activity but none of the chimeric proteins is neutralized by monoclonal antibodies to TNF. TNF has potent antitumour activity in nude mice carrying human xenografts or in mice bearing syngeneic tumours. In some systems direct effects can be demonstrated (in combination with species-specific gamma-interferon) but in others TNF acts indirectly. Combination of TNF with cytostatic drugs can also be effective in curing in vivo. The major limitation of the use of TNF is its toxicity. On many cell types TNF has an action similar to interleukin 1 (IL-1). At least some of the secondary, intracellular events may be identical for the two effectors. A possible mechanism of action of TNF is the release and metabolism of polyunsaturated fatty acids, which would explain the synthesis of prostaglandins and leukotrienes by many cell types after TNF treatment. The activation of the phospholipase can be blocked by corticoids. Some protease inhibitors protect cells from TNF-induced cytotoxicity but the target of these inhibitors has not been identified. Several genes are switched on by TNF (and by IL-1), including the gene for the 26 kDa protein recently identified as B cell stimulation factor 2. Events preceding death in rats include hypothermia, hypotension, acidosis and hypoglycaemia. All these effects can be largely eliminated by indomethacin pretreatment, with a resulting improvement in survival. As indomethacin does not inhibit the cytotoxic action of TNF on malignant cells it may form the basis for improved treatment protocols.
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PMID:Structure-function relationship of tumour necrosis factor and its mechanism of action. 313 Oct 72

The cDNA for human beta 2-interferon (IFN-beta 2)/B-cell differentiation factor 2/hepatocyte-stimulating factor was expressed in Escherichia coli to yield a fusion protein which contains the 182 carboxyl-terminal amino acids of IFN-beta 2 fused to a 34-amino acid prokaryotic leader peptide (rIFN-beta 2). When added to cultures of human hepatoma cell line Hep3B2, rIFN-beta 2 as well as preparations of natural IFN-beta 2 enhance secretion of positive acute phase reactants such as alpha 1-antichymotrypsin, complement C3, fibrinogen, and alpha 1-acid glycoprotein and inhibit secretion of albumin, confirming that a protein derived from the IFN-beta 2 gene can have hepatocyte-stimulating factor activity. We have prepared a rabbit polyclonal antiserum to the E. coli-derived human IFN-beta 2 fusion protein. This polyclonal antiserum inhibits the hepatocyte-stimulating and B-cell differentiation activities of appropriate IFN-beta 2 preparations. The anti-rIFN-beta 2 antiserum has been used in immunoprecipitation experiments and in Western blots to help define the secretory proteins derived from the IFN-beta 2 gene in fibroblasts and monocytes. "Uninduced" human FS-4 fibroblasts as well as those induced with interleukin-1 alpha, tumor necrosis factor, or bacterial lipopolysaccharide secrete at least five forms of IFN-beta 2 of apparent molecular mass in the range from 23 to 30 kDa which can be resolved by polyacrylamide gel electrophoresis under denaturing and reducing conditions. The three higher molecular mass forms are not observed when FS-4 cells are induced in the presence of tunicamycin, suggesting that these forms are N-glycosylated (gp28, gp29, and gp30). Although secretion of the two lower molecular mass forms is resistant to tunicamycin, they are labeled by [3H]glucosamine (gp23-gp25). The inclusion of cycloheximide during the [35S]methionine labeling of induced FS-4 cells results in the preferential synthesis and secretion of the 29-kDa triplet. Human monocytes induced with bacterial lipopolysaccharide also secrete several distinct forms of IFN-beta 2 in the size range from 23 to 30 kDa which co-migrate in polyacrylamide gels with those obtained from FS-4 cells. Our observations help relate previous descriptions of multiple forms of hepatocyte-stimulating factor to specific proteins derived from the IFN-beta 2 gene.
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PMID:Synthesis and secretion of multiple forms of beta 2-interferon/B-cell differentiation factor 2/hepatocyte-stimulating factor by human fibroblasts and monocytes. 313 26

Tumour Necrosis Factor (TNF) was discovered on the basis of its capability to induce necrosis of certain tumours in vivo. A brief overview is given of the pleiotropic effects of TNF on a variety of cells, either transformed cells or normal, diploid cells. Many transformed cells are killed by TNF, especially in the presence of interferon-gamma or inhibitors of transcription or translation. Various activities of TNF on normal cells have been studied, especially those on the endothelial system; these effects may be relevant to an understanding of its toxicity. TNF presumably acts by activation of phospholipase-A2. A number of genes are induced by TNF and, for example, many cells produce interleukin-6. The latter acts on B-cells, on T-cells, on bone marrow cells and, last but not least, on hepatocytes, which results in the synthesis of acute phase proteins. Although the toxicity of TNF, especially in the presence of interferon, limits its wide applicability, it can nevertheless lead to complete tumour curing in experimental animals. Reduction of its toxicity, e.g. by indomethacin treatment, opens new possibilities for TNF as an antitumour drug, alone or in combination with interferon.
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PMID:TNF: its potential as an antitumour agent. 322 63


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