UNIPROT:P05231 - FACTA Search

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

The gene expression of five matrix metalloproteinases (MMPs) and two tissue inhibitors of metalloproteinases (TIMPs) was studied in human gliomas in vivo and in vitro to evaluate their roles in glioma invasion. Simultaneous expression of one to four MMP genes and two TIMP genes was found in 17 surgical glioma specimens, and one MMP (gelatinase A) gene and two TIMP genes were simultaneously expressed in tissue of three brains. The concomitant overexpression of gelatinase A, gelatinase B, and occasional matrilysin genes was associated with the malignancy of gliomas and accompanied by overexpression of the TIMP-1 gene. In five human glioma cell lines, gelatinase A, TIMP-1, and TIMP-2 genes were constitutively expressed in alll cell lines: the matrilysin gene in three cell lines; the stromelysin gene in two cell lines; and the interstitial collagenase gene in one cell line. There was a clear difference in the expression of gelatinase B and stromelysin genes between surgical glioma specimens and glioma cell lines: the gelatinase B gene was not expressed constitutively in vitro but was overexpressed in vivo, whereas the stromelysin gene was not expressed in vivo but was expressed in some cell lines. To find the cause of that difference in vivo and in vitro, the transcriptional regulations of MMP and TIMP genes by tumor promoter, growth factors, or cytokines were studied in vitro. Interstitial collagenase, gelatinase B, stromelysin, and TIMP-1 genes were upregulated in many cell lines by phorbol-12-myristate-13-acetate (PMA) and in some cell lines by epidermal growth factor, tumor necrosis factor-alpha, or interleukin-1 beta. Transforming growth factor-beta 1 (TGF beta 1) upregulated gelatinase A and matrilysin genes in some cell lines, and there were no clear responses from any MMP and TIMP genes to interleukin-6. Thus, the transcriptional modulation of MMP genes by these growth factors and cytokines seemed insufficient to explain the difference in gelatinase B and stromelysin gene expressions in vivo and in vitro and was suggestive of the genetic alteration of glioma cells in vitro, the heterogeneous cell population in glioma tissues, or both. Furthermore, the in vitro invasion of glioma cells through Matrigel in response to PMA, TGF beta 1, or TIMP-1 was assessed by chemoinvasion assay. In most cell lines, invasion was significantly stimulated by PMA or TGF beta 1 but suppressed by TIMP-1.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Matrix metalloproteinases and tissue inhibitors of metalloproteinases in human gliomas. 761 76

Fibronectin fragments have both catabolic and anabolic activities toward articular cartilage explants in vitro. Whereas a 1 nM concentration of an N-terminal 29 kDa fibronectin fragment (Fn-f) increases the proteoglycan (PG) content of cartilage without induction of matrix metalloproteinases (MMPs), 0.1-1 microM Fn-f temporarily suppresses PG synthesis and enhances MMP release. The higher concentrations cause an initially rapid PG depletion during the first week of culture, followed by much slower PG loss and gradually increasing rates of PG synthesis. To test for the involvement of mediators, human articular cartilage was cultured with Fn-f, and conditioned media were assayed for selected cytokines and factors. With 1 nM Fn-f, the release of the anabolic factors, insulin growth factor-I and transforming growth factor beta1, from cultured cartilage was enhanced by 50-100% during the entire 28-day culture period and this was associated with both supernormal rates of PG synthesis and PG content. However, the higher concentrations of Fn-f additionally enhanced release, by at least 10-fold, of the cytokines, tumour necrosis factor alpha, interleukin-1alpha, interleukin-1beta and interleukin-6 while causing depletion of cartilage PG. Release of tumour necrosis factor alpha, interleukin 1beta and interleukin 1alpha peaked at days 2, 3 and 9 during or slightly after the period of maximal PG depletion and decreased to control levels by days 7, 7 and 21 respectively, whereas release of interleukin 6 was enhanced throughout the culture period. Neutralizing antibodies to the catabolic cytokines reduced Fn-f-mediated MMP-3 release and suppression of PG synthesis. The temporal aspects of this interplay between catabolic and anabolic factors are consistent with the kinetics of Fn-f-mediated cartilage damage and attempted repair and may be relevant to cartilage damage and repair in vivo.
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PMID:Fibronectin-fragment-induced cartilage chondrolysis is associated with release of catabolic cytokines. 903 63

The response of human T lymphocytes to various stimuli includes the expression of the matrix metalloproteinase (MMP) genes stromelysin 2, gelatinase A and gelatinase B. The proteins encoded by these genes could confer the capacity to degrade macromolecular components of the extracellular matrix (ECM), and to shed transmembrane proteins such as tumor necrosis factor (TNF), TNF receptor, Interleukin-6 receptor and Fas ligand. To identify further MMP genes transcribed in T lymphocytes exposed to phorbol 12-myristate 13-acetate and a calcium ionophore, we combined reverse transcription and polymerase chain reaction using primers specific for conserved domains and detected collagenase 3 transcripts, first described in a human breast cancer. However, when the sequence of the complementary DNA was compared, additional 23 nucleotides were found in the 5' nontranslated region of the lymphocyte messenger RNA (mRNA). Northern blot analysis revealed 2 major inducible mRNA species of 1.9 and 2.8 kilobases, whose levels were lower than those of stromelysin 2. The observation that activated T lymphocytes transcribe several MMP genes, including a collagenase, indicates that the effector functions of these cells include enzymatic activities towards most constituents of the ECM, as well as some transmembrane proteins relevant to inflammation and apoptosis.
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PMID:A matrix metalloproteinase gene expressed in human T lymphocytes is identical with collagenase 3 from breast carcinomas. 956 63

Human leukemic early T cells of the HSB.2 line coexpress the EP2, EP3 and EP4 subtypes of prostaglandin E2 (PGE2) receptors (Rs). EP3 Rs have previously been demonstrated to transduce PGE2 stimulation of secretion of matrix metalloproteinase (MMP)-9 by HSB.2 T cells through Ca++-dependent enhancement of MMP-9 mRNA transcription. We now show that PGE2 and the EP4/EP2/EP3 R-selective agonist misoprostol, but not the EP3 R-directed agonists sulprostone and M&B28767, induced increases in HSB.2 T cell interleukin-6 (IL-6) mRNA and secretion. Pharmacological agents that increase intracellular concentration of cyclic AMP ([cAMP]i) mimicked and synergistically enhanced induction of IL-6 secretion by PGE2, whereas inhibitors of protein kinase A (PKA) but not protein kinase C suppressed PGE2-evoked increases in IL-6 secretion, suggesting that cAMP and PKA are the intracellular messengers of the PGE2 effect. Exposure of HSB.2 T cells to the mitogenic lectin concanavalin A (Con A) increased basal IL-6 secretion, without a change in IL-6 mRNA level. Con A-stimulated HSB.2 T cells responded to PGE2 with greater increases in IL-6 mRNA and secretion of IL-6. Con A also down-regulated mRNA encoding both EP3 Rs and EP2 Rs, and concurrently up-regulated mRNA encoding EP4 Rs of HSB.2 T cells. Therefore, EP4 and EP2 Rs mediate PGE2-induced increases in IL-6 secretion by HSB.2 T cells through a transcriptional and cAMP dependent-mechanism. The increased ratio of EP4 Rs/EP3 Rs may contribute to Con A enhancement of PGE2-elicited increases in IL-6 secretion by HSB.2 T cells.
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PMID:EP4/EP2 receptor-specific prostaglandin E2 regulation of interleukin-6 generation by human HSB.2 early T cells. 973 6

The therapeutic antitumor effect of clarithromycin (CAM) was examined with the 13762NF mammary adenocarcinoma and F-344 rat system. When CAM treatment at a dosage of 2 mg/kg of body weight orally for 21 days was commenced after inoculation of the tumor, no significant decrease in death rate was observed, although the loss in body weight was less than that in the untreated group. When tumor-bearing (TB) rats were treated with CAM in combination with carboplatin or cyclophosphamide, a significant decrease in the death rate was obtained, although neither treatment alone proved to be effective. A beneficial effect was also observed when CAM treatment was combined with surgical treatment. CAM showed no direct cytotoxicity to this tumor in vitro according to the MTT (3-[4, 5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide) assay. Spleen cells obtained from TB rats receiving CAM treatment showed a stronger tumor-neutralizing activity than those from rats which had not received CAM treatment (Winn assay). Enhanced induction of cytotoxic cells to allogeneic tumor was also observed in rats immunized with allogeneic tumor cells together with CAM treatment (51Cr release assay). The 13762NF tumor produces transforming growth factor-beta (TGF-beta), tumor necrosis factor alpha, and matrix metalloproteinase-9, and treatment of tumor cells with CAM in vitro for 24 h significantly inhibited the expression of the genes coding for these proteins (reverse transcription-PCR). Levels of expression of the TGF-beta and interleukin-6 genes of spleen cells obtained from CAM-treated TB rats were both significantly lower than those of spleen cells from CAM-untreated TB rats. This study suggests that CAM has biological response modifier activities resulting in a beneficial therapeutic antitumor effect and might be useful for the treatment of human cancers.
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PMID:Therapeutic effect of clarithromycin on a transplanted tumor in rats. 986 67

Cytokines constitute a major class of mediators responsible for "activation" of hepatic stellate cells (HSCs) in vitro and in vivo. They are largely divided into mitogenic (transforming growth factor-alpha, platelet-derived growth factor, interleukin-1, tumor necrosis factor-alpha, and insulin-like growth factor) and fibrogenic (transforming growth factor-beta and interleukin-6) cytokines. In addition to their mitogenic (stimulation of cell proliferation) and fibrogenic (induction of matrix proteins) properties, they are also shown to confer in vitro unique cellular changes known to be the key features of HSC "activation," including loss of vitamin A, stimulation of migration, enhanced cellular contractility, and matrix metalloproteinase and tissue inhibitor of metalloproteinase induction. Potential cellular sources of the cytokines consist of hepatic macrophages, endothelial cells, biliary epithelial cells, lymphocytes, platelets, hepatocytes, and activated HSCs. To better understand the mode of actions and the pathogenetic significance of cytokines/chemokines involved in "activation" of HSCs, the following four questions need to be addressed: (1) What other cytokines are expressed by HSCs to establish critical autocrine stimulation? (2) What are endogenous or exogenous priming factors for HSC stimulation? (3) What is the mechanism of activation for transforming growth factor-beta, the pivotal fibrogenic cytokine? (4) How important are HSC-derived proinflammatory mediators in liver fibrosis? This review will discuss these questions, along with the current understanding of the role of cytokines in HSC activation.
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PMID:Cytokine regulation of hepatic stellate cells in liver fibrosis. 1037 13

Tumour necrosis factor-alpha (TNF-alpha), secreted by cells of the macrophage-monocyte lineage, has a well established role in inflammation and host-defence. The more recent discovery that adipocytes also secrete TNF-alpha has led to a substantial body of research implicating this molecule in the insulin resistance of obesity. However, little is known about the normal regulation of TNF-alpha release from human adipose tissue. In particular, it is not known whether adipocyte production of TNF-alpha is responsive to similar or different molecular regulators than those relevant to macrophages. TNF-alpha release from cultured human adipose tissue and isolated adipocytes was examined using an ELISA. Insulin, cortisol or the thiazolidinedione, BRL 49653, did not have a significant effect on TNF-alpha release from adipose tissue or isolated adipocytes. In contrast, lipopolysaccharide (LPS), a major stimulus of TNF-alpha protein production in monocytes and macrophages, resulted in a fivefold stimulation of TNF-alpha release from human adipose tissue. Significant stimulation of TNF-alpha release was also seen from isolated adipocytes, indicating that the increase in TNF-alpha release from adipose tissue in the presence of LPS is unlikely to be entirely attributable to contaminating monocytes or macrophages. Consistent with this observation was the finding that mRNA for CD14, a known cellular receptor for LPS, is expressed in human adipocytes. The increase in TNF-alpha protein release in response to LPS was blocked by an inhibitor of the matrix metalloproteinase responsible for the cleavage of the membrane-bound proform of TNF-alpha, indicating that this release represented regulated secretion and was not due to cell lysis. In conclusion, the regulation of TNF-alpha protein release from human adipose tissue and isolated adipocytes appears to be similar to its regulation in cell types more traditionally implicated in host defence. The production by the adipocyte of a range of molecules involved in host defence-TNF-alpha, factors D, B and C3, interleukin-6, and macrophage colony-stimulating factor--suggest that this cell type may make a significant contribution to innate immunity.
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PMID:Regulation of tumour necrosis factor-alpha release from human adipose tissue in vitro. 1049 4

In vitro treatment with clarithromycin inhibited the expression of the matrix metalloproteinase-9, transforming growth factor beta, and tumor necrosis factor alpha genes in 13762NF rat mammary adenocarcinoma cells. Transient enhancement, rather than inhibition, was observed for the interleukin-6 gene, and no significant change was observed for the tissue inhibitor of metalloproteinase-2 gene. Such an effect was not observed for cefotiam or gentamicin.
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PMID:Differential modulatory effects of clarithromycin on the production of cytokines by a tumor. 1054 65

Interleukin-6 and matrix metalloproteinase-9 concentrations in the wound fluid and their associations to cellular changes were determined in early wound healing. Wound healing of 75 children who underwent elective operations was studied with the Cellstick(R) device, which was inserted into the wound at the end of the operation and removed 3 or 24 hours post-wounding. Differential counts of the wound cells and interleukin-6 and matrix metalloproteinase-9 concentrations in the wound fluid were analyzed. Interleukin-6 and the matrix metalloproteinase-9 concentrations increased in parallel (r = 0.81). The proportion of wound neutrophils increased (p < 0.0001) and lymphocytes decreased (p < 0. 0001) between the observation times. The number of wound neutrophils had a strong correlation with both interleukin-6 (adjusted R2 = 0.41, p < 0.0001) and matrix metalloproteinase-9 concentrations (adjusted R2 = 0.37, p < 0.0001). The extracellular matrix degradation process of the early wound healing seems to be closely linked to the inflammatory response. Both of these measured markers are associated significantly with the neutrophil proportion in the wound.
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PMID:Correlation between interleukin-6 and matrix metalloproteinase-9 in early wound healing in children. 1063 4

Peroxisome proliferator-activated receptors (PPAR) are ligand-activated transcription factors which form a subfamily of the nuclear receptor gene family. PPAR activators have effects on both metabolic risk factors and on vascular inflammation related to atherosclerosis. PPAR have profound effects on the metabolism of lipoproteins and fatty acids. PPAR alpha binds hypolipidemic fibrates, whereas PPAR gamma has a high affinity for antidiabetic glitazones. Both PPAR are activated by fatty acids and their derivatives. Activation of PPAR alpha increases the catabolism of fatty acids at several levels. In the liver, it increases uptake of fatty acids and activates their beta-oxidation. The effects that PPAR alpha exerts on triglyceride-rich lipoproteins is due to their stimulation of lipoprotein lipase and repression of apolipoprotein CIII expression, while the effects on high-density lipoproteins depend upon the regulation of apolipoproteins AI and AII. PPAR gamma has profound effects on the differentiation and function of adipose tissue, where it is highly expressed. PPAR are also expressed in atherosclerotic lesions. PPAR are present in vascular endothelial cells, smooth muscle cells, monocytes, and monocyte-derived macrophages. Via negative regulation of nuclear factor-kappa B and activator protein-1 signalling pathways, PPAR alpha inhibits expression of inflammatory genes, such as interleukin-6, cyclooxygenase-2, and endothelin-1. Furthermore, PPAR alpha inhibits expression of monocyte-recruiting proteins such as vascular cell adhesion molecule (VCAM)-1 and induces apoptosis in monocyte-derived macrophages. PPAR gamma activation in macrophages and foam cells inhibits the expression of activated genes such as inducible nitric oxide synthase, matrix metalloproteinase-9 and scavenger receptor A. PPAR gamma may also affect the recruitment of monocytes in atherosclerotic lesions as it is involved in the expression of VCAM-1 and intracellular adhesion molecule-1 in vascular endothelial cells. The involvement of PPAR in atherosclerosis, a disease with a chronic inflammatory character, suggests that they may play a role in other inflammatory-related diseases as well.
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PMID:Role of the peroxisome proliferator-activated receptors (PPAR) in atherosclerosis. 1100 63

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