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

Mesangial cell proliferation constitutes a frequent finding in a number of glomerular diseases that progress to glomerular sclerosis. The factors responsible for mesangial cell growth regulation in vivo are ill defined. However, cell culture data indicate that an array of mediators may have mitogenic or antimitogenic effects on these cells. This brief review discusses the relevance of selected factors such as platelet-derived growth factor (PDGF) in this context. In vitro data indicate that PDGF is one of the most potent mesangial cell mitogens, that it may have autoregulatory properties, and that it may represent the final common pathway for a number of other mitogenic peptides. In contrast to PDGF, the relevance of inflammatory cytokines such as interleukin-1 (IL-1), tumor necrosis factor (TNF) or interleukin-6 (IL-6) for mesangial cell proliferation is less evident, with growth-inhibitory to weakly growth-promoting effects on mesangial cells. Transforming growth factor beta (TGF beta) appears to be unique in that it has a concentration-dependent mitogenic or antimitogenic effect on mesangial cells. Prostaglandins may also have variable effects, ranging from mitogenic (PGE2 alpha) to growth inhibitory (PGI2, PGF2, TxA2). These data support the notion that mesangial cell growth in vivo is regulated by a complex network of synergistic or antagonistic growth factors. The relative importance of each of these growth factors in the in vivo situation will have to be elucidated by future studies using specific receptor antagonists or neutralizing antibodies.
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PMID:Regulation of mesangial cell proliferation. 204 47

The interleukin-6 (IL-6) promoter is rapidly and transiently activated with other cytokines, including IL-1, tumor necrosis factor, and platelet-derived growth factor, as well as phorbol esters and agents that increase intracellular cyclic AMP. In this study, we have investigated cis-acting regulatory elements and trans-acting factors responsible for IL-1-induced IL-6 gene expression. Studies on the 5' deletion mutants of the human IL-6 gene suggested that the IL-1-responsive element was mapped within the IL-6 promoter region (-180 to -123) which was homologous to the c-fos serum-responsive enhancer element. Gel retardation assay identified two types of nuclear factors that bound to this region, one constitutive and the other inducible. These two factors recognized a 14-base-pair (bp) palindromic sequence, ACATTGCACAATCT. Furthermore, three copies of this 14-bp palindrome conferred IL-1 responsiveness to the basal enhancerless IL-6 promoter, indicating that a 14-bp-dyad symmetry sequence was an IL-1-responsive element in the IL-6 gene.
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PMID:Constitutive and interleukin-1 (IL-1)-inducible factors interact with the IL-1-responsive element in the IL-6 gene. 211 42

Communication between cells determines the steady-state composition of the lung in health and becomes a critical determinant of outcome in pathologic processes resulting in anatomic remodeling. This review presents the evolving concepts of the biology of cytokines (also known as peptide growth factors or biological response modifiers) in maintaining normal tissue growth and homeostasis. How these extracellular signaling proteins are involved in such pathologic disorders as spontaneous pulmonary fibrosis, sarcoidosis, pneumoconiosis, and the evolution and recovery from acute lung injury is also discussed. During the past decade the cytokines have come to the fore as important multifunctional mediators of cell behavior and cell-cell communication. A wide range of cellular responses are influenced or triggered when cytokines interact with cells. These include mitosis, chemotaxis, angiogenesis, cytoskeleton arrangement, immunomodulation, and extracellular matrix production. Cytokines influence cell behavior by binding to specific high affinity surface receptors on target cells. These receptors are linked in turn at the cell membrane to a complex array of intracellular signaling pathways. Individual cytokines may inhibit as well as promote cellular functions such as mitosis and thereby play a critical role in homeostasis of normal tissue elements. Hence, cytokines are intimately involved in normal tissue homeostasis as well as in processes eventuating in growth and remodeling. All cells produce and secrete cytokines at some time during their life. Each cytokine is capable of modulating more than one cellular function. Although produced by a variety of cell types, the triggers that induce a specific cytokine to be produced differ between cells. Many of the cytokines share regions of homologous nucleic acid sequences, suggesting that they are members of larger gene families. Given that tissues and cells are exposed to complex cytokine mixtures rather than to individual cytokines, recent attention has turned to understanding how cytokines interact. The combined effects of cytokine mixtures have proved to be both complex and unpredictable based on knowledge of the separate actions of the individual cytokines involved. In studies of the role of cytokines in lung disease, early research attention has focused on those cytokines released by alveolar macrophages (the so-called macrophage-derived growth factors). However, structural cells as well as immune effector cells of the lung are capable of cytokine production and release. The cytokines receiving the most attention to date in relation to pulmonary diseases include platelet-derived growth factor (PDGF), interleukin-1 (IL-1), transforming growth factor-beta (TGF-beta), tumor necrosis factor-alpha (TNF-alpha), insulinlike growth factor I (IGF-I), and, most recently, interleukin-6 (IL-6).(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Cytokines of the lung. 224 Aug 51

Interleukin-6 (IL-6), a multifunctional cytokine produced in monocytes, fibroblasts, endothelial cells, and keratinocytes, is induced by a variety of stimulating signals, including lipopolysaccharide (LPS), poly (I), poly (C), IL-1, tumor necrosis factor (TNF), and platelet-derived growth factor. Some of these signals induce IL-6 effectively only in one cell type, and this selectivity of induction may explain selectivity of biologic effects. In the present study, we show that IL-1 beta, previously known to be a potent inducer of IL-6 in fibroblasts, endothelial cells, and keratinocytes, but not in monocytes, is also a potent inducer of IL-6 in peripheral blood monocytes. High level IL-6 activity that could be neutralized by specific antibodies to IL-6 was detected in supernatants of IL-1-stimulated monocytes. Maximal induction required IL-1 concentrations of 10 ng/mL. As judged by sodium dodecyl sulfate-polyacrylamide gel electrophoresis under reducing conditions, IL-6 species of relative molecular mass of 19 to 26 Kd could be specifically immunoprecipitated from supernatants of IL-1-induced monocytes. Size heterogeneity is a reported feature of IL-6 produced in a variety of cell types, and monocyte-derived IL-6 induced by either IL-1 or LPS displayed similar size heterogeneity. The highly purified recombinant IL-1 beta preparation used contained little, if any, LPS. In addition, monocyte production of IL-6, induced by IL-1 beta, was specifically neutralized by anti-IL-1 beta antibodies, demonstrating that IL-1, rather than a contaminant in the IL-1 preparation, was responsible for IL-6 induction. A number of biologic activities have been ascribed both to IL-1 and IL-6. The finding that IL-1 induced IL-6 in monocytes may help in defining the spectrum of biologic activities of each of these interactive cytokines.
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PMID:Interleukin-1 induces interleukin-6 production in peripheral blood monocytes. 231 Aug 29

The cells that make up blood vessel walls appear to participate actively in local immune and inflammatory responses, as well as in certain vascular diseases. We tested here whether smooth muscle cells (SMC) can produce the important inflammatory mediator IL6. Unstimulated SMC in vitro elaborated 5 X 10(3) pg recIL6/24h (i.e., biological activity equivalent to 5 X 10(3) pg recombinant IL6 (recIL6), as determined in B9-assay with a recIL6 standard). Several pathophysiologically relevant factors augmented IL6 release from SMC including 10 micrograms LPS/ml (10(4) pg recIL6), 10 ng tumor necrosis factor/ml (4 X 10(4) pg recIL6), and most notably 10 ng IL1/ml (greater than or equal to 3.2 X 10(5) pg recIL6). Production of IL6 activity corresponded to IL6 mRNA accumulation and de novo synthesis. SMC released newly synthesized IL6 rapidly, as little metabolically labeled material remained cell-associated. In supernatants of IL1-stimulated SMC, IL6 accounted for as much as 4% of the secreted proteins. In normal vessels SMC seldom divide, but SMC proliferation can occur in hypertension or during atherogenesis. We therefore tested the relationship between IL6 production and SMC proliferation in response to platelet-derived growth factor (PDGF) in vitro. Quiescent SMC released scant IL6 activity, whereas PDGF (1-100 ng/ml) produced concentration-dependent and coordinate enhancement of SMC proliferation and IL6 release (linear regression of growth vs. IL6 release yielded r greater than 0.9). IL6 itself neither stimulated nor inhibited SMC growth or IL6 production. Intact medial strips studied in short-term organoid culture produced large quantities of IL6, similar to the results obtained with cultured SMC. These findings illustrate a new function of vascular SMC by which these cells might participate in local immunoregulation and in the pathogenesis of various important vascular diseases as well as in inflammatory responses generally.
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PMID:Proliferating or interleukin 1-activated human vascular smooth muscle cells secrete copious interleukin 6. 231 24

alpha 2-Macroglobulin (alpha 2M) is a broad spectrum protease inhibitor associated with inflammatory responses and proposed to be important in tissue remodeling. alpha 2 M also functions as a carrier of specific growth factors and cytokines, including platelet-derived growth factor, transforming growth factor-beta, basic fibroblast growth factor, interleukin-1, interleukin-6. To determine whether alpha 2M is associated with remodeling phenomena in the rat ovary, the expression of alpha 2M mRNA and protein has been analyzed in specific ovarian cell types during ovulation, luteinization, and luteolysis. Before ovulation, alpha 2M mRNA is not detectable in granulosa cells. Twelve hours after injection of an ovulatory dose of hCG a 5.2-kilobase alpha 2M mRNA is detectable in luteinizing follicles, which is increased further by 48 h and maintained in corpora lutea (CL) for up to 96 h. Administration of PRL from 24-96 h results in both inhibition of luteolysis and marked increases in alpha 2M mRNA in CL, but not in residual tissues, of these same ovaries, isolated 48, 72, and 96 h after an ovulatory dose of hCG, alpha 2M mRNA is also induced by PRL in cultures of luteinized granulosa cells. These changes in alpha 2M mRNA in follicles or developing CL do not appear to reflect the amount of alpha 2M protein present: alpha 2M protein (188K monomer) is present (immunoblot and immunofluorescence data) in small antral and preovulatory follicles even though mRNA is not detectable; after an ovulatory dose of hCG the protein level transiently increases by 12 h (approximately 5-fold) and declines thereafter through 96 h; the decrease in alpha 2M protein observed at 48-96 h is delayed but not abolished by treatment with PRL, even though the mRNA levels continue to rise during this same time period. In contrast, changes in alpha 2M mRNA and protein are regulated coordinately in CL of pregnant rats. alpha 2M mRNA is present, but in low concentration, from days 4-11 of gestation, increases markedly between days 11-21, and decreases at parturition, when functional luteolysis occurs. Hysterectomy of day 10 pregnant rats combined with hormone replacement determined that alpha 2M mRNA levels are regulated primarily by PRL through day 12 and by placental lactogens during midgestation (days 12-15). The increase in alpha 2M mRNA during pregnancy precedes the 40-fold increase (peak) in a alpha 2M protein observed on day 15, which remains elevated through day 21.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Hormonal regulation and tissue-specific localization of alpha 2-macroglobulin in rat ovarian follicles and corpora lutea. 247 32

The intrathyroidal production of Interferon gamma, tumour necrosis factor alpha and beta, Interleukin-1 alpha and beta, Interleukin-6, platelet-derived growth factor A and of transforming growth factor-beta was analysed in patients with autoimmune and non-autoimmune thyroid disease. Cytokines were assessed indirectly by slot blot mRNA analysis in fresh tissue samples (unpurified cells, infiltrating mononuclear cells and thyroid follicular cells), in thyroid follicular cells in primary culture, as well as in thyroid-derived T-cell clones. The production of Interleukin-1 alpha and beta, Interleukin-6 and transforming growth factor beta was additionally measured by bioassay. Cytokine production by thyroid-infiltrating mononuclear cells generally did not differ between autoimmune and non-autoimmune samples, the whole panel of all cytokines being found in freshly purified cells as well as in thyroid-derived T-cell clones from patient with Graves' disease, as well as with multinodular non-toxic goitre. Thyroid follicular cells produced Interleukin-1 alpha, Interleukin-6 and transforming growth factor beta. Interleukin-1 and Interleukin-6 production did not differ between thyroid follicular cells from autoimmune and non-autoimmune thyroids. Transforming growth factor beta was, however, lower in non-toxic goitre than in Graves' disease and in normal thyroid tissue, but could be increased by exposure of the cells to micromolar concentrations of iodide. This seemed of special interest, as transforming growth factor beta proved to inhibit thyroid follicular cell growth in response to known growth stimuli, such as insulin-like growth factor I or epidermal growth factor.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Intrathyroidal cytokine production in thyroid disease. 267 71

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

The gene of thrombopoietin (TPO) has been cloned and identified to be identical to gene of the c-mpl ligand. It is known that the mRNA of TPO is expressed in liver and kidney. However, it is not clarified which cells in the liver produce TPO. Using a human hepatoma cell line, HepG2, we demonstrated that the TPO mRNA was expressed by liver parenchymal cells without any stimulation. To clarify the regulation of the expression of the TPO mRNA in HepG2 cells by cytokines, we assessed the effects of 5 cytokines, transforming growth factor-beta 1, activin A, platelet-derived growth factor, hepatocyte growth factor, and interleukin-6. These cytokines have no significant regulative effect on the expression of the TPO mRNA in HepG2 cells. Our results suggest that liver parenchymal cells may be the TPO producing cells and also suggest that some hepatoma cells may produce TPO constitutively.
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PMID:Constitutive expression of the thrombopoietin gene in a human hepatoma cell line. 750 24

Cytokines and growth factors elicit responses in target cells through induction of gene expression. Signaling mechanisms leading to gene transcription from cell surface receptors often require tyrosine phosphorylation. A family of transcription factors comprising the interferon (IFN)-stimulated gene factor 3 (ISGF3) multimeric complex are phosphorylated and activated in response to interferon. We describe a protein 50% identical to the 91-kDa subunit of ISGF3 that constitutes the acute phase response factor (APRF). This protein was rapidly activated by interleukin-6 to bind an enhancer element common to genes activated in liver cells during the acute phase response to inflammation. Remarkably, APRF was also activated by IFN alpha, IFN gamma, epidermal growth factor, platelet-derived growth factor, colony stimulating factor-1, and the cytokines leukemia inhibitory factor and oncostatin M. The growth factors also activated a third, distinct but related, DNA-binding protein in addition to APRF and p91. This novel factor or a closely related one, but neither APRF nor p91, was also activated in lymphoid cells by interleukin-2, erythropoietin, and interleukin-3. Activation of APRF, p91, and additional members of the ISGF3 family is thus a general feature of a wide variety of signaling pathways, integrating diverse signals through common transcriptional regulators.
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PMID:Acute phase response factor and additional members of the interferon-stimulated gene factor 3 family integrate diverse signals from cytokines, interferons, and growth factors. 752 73


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