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)

Tumor necrosis factor-alpha (TNF-alpha) has been shown to enhance the synthesis of interleukin-6 (IL-6) and collagenase in human omental microvascular endothelial (HOME) cell (Mawatari, M., Kohno, K., Mizoguchi, H., Matsuda, T., Asoh, K., Van Damme, J. V., Welgus, H. G., and Kuwano, M. (1989) J. Immunol. 143, 1619-1627). In the present study, we have examined whether the TNF-alpha-induced synthesis of IL-6 or collagenase in HOME cells is mediated by an inducible growth factor. Among several growth factors examined, we found that the expression of basic fibroblast growth factor (bFGF) mRNA was the one most prominently enhanced when HOME cells were treated with TNF-alpha. The increase of bFGF mRNA by TNF-alpha in HOME cells was observed in both a dose- and time-dependent manner when assayed by Northern blot analysis. The induction of bFGF mRNA was observed by 3 h after incubation with TNF-alpha, and the maximal increase of 5-fold was obtained after 12 h of incubation with 100 units/ml TNF-alpha. Western blot analysis confirmed the enhanced synthesis of bFGF by TNF-alpha. Metabolic labeling and immunoprecipitation assays of bFGF showed that exposure to TNF-alpha enhanced secretion of bFGF into culture medium and also that TNF-alpha stimulated the production of bFGF molecules with molecular masses of 18, 21, and 22.5 kDa in HOME cells. TNF-alpha induced the expression of collagenase mRNA and IL-6 mRNA in HOME cells as well, and the coadministration of neutralizing anti-bFGF antibody almost completely blocked the effects of TNF-alpha. The treatment of HOME cells with exogenous bFGF significantly stimulated the expression of collagenase mRNA and IL-6 mRNA in HOME cells. Therefore, the biological effects of TNF-alpha on HOME cells may be mediated, at least in part, by TNF-alpha-induced bFGF.
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PMID:Endogenous basic fibroblast growth factor-dependent induction of collagenase and interleukin-6 in tumor necrosis factor-treated human microvascular endothelial cells. 165 76

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

We investigated the effects of various pro-inflammatory cytokines on the proliferation rate of isolated human osteoblastic cells in primary cultures. Interleukin-1 beta (IL-1 beta) and tumor necrosis factor-beta (TNF-beta) time- and dose-dependently enhanced the proliferation of human osteoblasts. Both of these cytokines also enhanced endogenous prostaglandin E2 (PGE2) formation. Exogenous PGE2 dose- and time-dependently-stimulated cell proliferation. However, the stimulatory effects of IL-1 beta and TNF-beta on osteoblast proliferation were not abolished by indomethacin, indicating a direct effect by these cytokines on the rate of proliferation. TNF-alpha stimulated proliferation at low doses, while it significantly inhibited proliferation at higher concentrations (at and above 100 pM) and with prolonged incubation times. This biphasic effect was unaffected by indomethacin. Interleukin-6, finally, did not affect the rate of proliferation. Our findings show that inflammatory cytokines may stimulate or inhibit the proliferation of isolated human osteoblasts, depending on concentration and time.
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PMID:Inflammatory cytokines regulate proliferation of cultured human osteoblasts. 917 41

Cytokines are hormone-like proteins which mediate and regulate inflammatory and immune responses. The purpose of this study was to investigate the effect of lipopolysaccharide (LPS) and inflammatory cytokines on regulation of interleukin-6 (IL-6) production by human gingival fibroblasts (HGF). The HGF cell lines used in this study, H-CL and F-CL, were established by the explant technique from healthy gingival tissue. Cultured cells were grown to confluency and incubated with various concentrations of LPS from Escherichia coli or Porphyromonas gingivalis or with the recombinant human cytokine tumor necrosis factor alpha (TNF-alpha), IL-1alpha, or IL-1beta. Culture supernatants were collected at various times and assessed for IL-6 production by enzyme-linked immunosorbent assay. Total RNA was isolated from the harvested cells and used to assess levels of IL-6 mRNA by the RNase protection assay. Both LPS preparations induced IL-6 production (1 to 4 ng of IL-6 per ml) by both HGF cell lines. Although TNF-alpha stimulated IL-6 production by HGF, > 10-fold-larger amounts were induced with IL-1alpha and IL-1beta. Furthermore, the addition of both IL-1alpha and TNF-alpha to cultured cells resulted in approximately 600- to 800-fold-higher levels of IL-6 than seen in control cultures, suggesting that these cytokines synergistically induced IL-6 production by HGF. IL-6 message in cultured cells was upregulated 20-fold by TNF-alpha, 1,000-fold by IL-1alpha and IL-1beta, and 1,400-fold by IL-1alpha plus TNF-alpha. IL-1alpha and TNF-alpha alone upregulate IL-6 production in a dose- and time-dependent fashion. The addition of IL-1alpha and TNF-alpha to cultured HGF cells resulted in a synergistic induction of IL-6 after 8 h of incubation and when greater than 10 pg of this combination per ml was used. Our studies show that inflammatory cytokines are hundreds of times more potent than LPS in stimulating IL-6 production by HGF.
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PMID:Effect of lipopolysaccharide and inflammatory cytokines on interleukin-6 production by healthy human gingival fibroblasts. 945 16

Since bisphosphonates prevent bone loss in osteoporosis and rheumatoid arthritis, diseases in which the osteoclastogenic and inflammatory cytokine interleukin-6 plays a pathophysiologic role, we studied whether these drugs regulate the production of this cytokine by osteoblasts. Spontaneous and IL-1 + TNF-alpha stimulated IL-6 release was measured in supernatants of cultures of human osteoblastic osteosarcoma cells MG-63, pretreated for 4 hours with different doses of etidronate, clodronate or alendronate using a specific bioassay. Etidronate [from 10(-4) to 10(-8) M] or alendronate [from 10(-6) to 10(-11) M] inhibited in a dose-dependent manner the cytokine-induced IL-6 secretion [60+/-9.5% at 10(-5) M and 65+/-12% at 10(-7) M, respectively; p < 0.01]. Though significant, the inhibitory effect of clodronate was less [35+/-7% at 10(-5) M, p < 0.05]. These in vitro observations might have in vivo relevance in explaining at least in part the mechanisms by which bisphosphonates inhibit systemic and periarticular bone resorption.
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PMID:Bisphosphonates inhibit IL-6 production by human osteoblast-like cells. 950 76

The induction of interleukin-6 (IL-6), using a proinflammatory cytokine (tumor necrosis factor-alpha), was studied in a human osteoblast cell line (MG-63) in relation to p38 mitogen-activated protein kinase (MAPK) and nuclear factor (NF)-kappaB transcription factor. When added to MG-63 cells, tumor necrosis factor-alpha (TNF-alpha) had a stimulatory effect on the production of IL-6, and this elevation was significantly reduced by SB203580, a specific p38 MAPK inhibitor. In addition, the stimulation of IL-6 release was also reduced by pyrrolidine dithiocarbamate (PDTC) or NF-kappaB SN50, which has been reported to be a potent NF-kappaB inhibitor. Both the NF-kappaB inhibitors in the presence of SB203580 had a more inhibitory effect on IL-6 release. In this study, TNF-alpha stimulated NF-kappaB binding affinity as well as p38 MAP kinase activation, leading to the release of IL-6. However, the specific inhibitor of p38 MAPK, SB203580, had no effect on TNF-alpha-induced NF-kappaB activation and both NF-kappaB inhibitors failed to reduce the p38 MAPK activation in the TNF-alpha-stimulated osteoblasts. In addition, inhibition of p38 MAPK partially, but significantly, impaired TNF-alpha-regulated release of osteocalcin, an important differentiation marker in osteoblasts. These results strongly suggest that both p38 MAPK and NF-kappaB are required in TNF-alpha-induced IL-6 synthesis and that these two TNF-alpha-activated pathways can be primarily dissociated. Furthermore, p38 MAPK may play a significant role in differentiation in MG-63 cells.
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PMID:The p38 mitogen-activated protein kinase pathway regulates interleukin-6 synthesis in response to tumor necrosis factor in osteoblasts. 1116 42

Congestive heart failure (CHF) induces a state of immune activation, and peritoneal macrophages (M phi s) may play an important role in the development and progression of one such condition. Moderate endurance training modulates peritoneal M phi function. We evaluated the effect of endurance training on different stages of the phagocytic process and in the production of interleukin-6 (IL-6), interleukin-1beta (IL-1beta) and tumor necrosis factor-alpha (TNF-alpha) after LPS stimulation. Either ligation of the left coronary artery or Sham operations were performed in adult Wistar rats. After 4 wk, control (Sham operated) and MI (ligation of the left coronary artery) animals were randomly assigned to either a sedentary (Sham-operated sedentary, n = 7 and MI sedentary, n = 10) or a trained group (Sham-operated trained, n = 8 and MI trained, n = 8). Trained rats ran on a treadmill (0% grade at 13-20 m/min) for 60 min/day, 5 days/wk, for 8-10 wk, whereas sedentary rats had only limited activity. Training increased maximal oxygen uptake normalized for body weight (ml.kg(-1).min(-1)), as well as skeletal muscle citrate synthase maximal activity, when compared with sedentary groups. The resident and total cell number, the chemotaxis index, and the production of TNF-alpha stimulated by LPS were significantly higher in the MI sedentary group when compared with the Sham sedentary group. Moderate endurance training reversed these alterations promoted by post-MI. These results demonstrate that moderate intensity exercise training modulates peritoneal M phi function and induces beneficial metabolic effects in rats with post-MI CHF.
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PMID:Endurance training restores peritoneal macrophage function in post-MI congestive heart failure rats. 1725 73

Increased indoor air concentrations of volatile organic compounds (VOC) have been shown to contribute to the risk of respiratory and allergic diseases. The aim of this study was to investigate the inflammatory potential of single VOC and mixtures using an in vitro model. TNF-alpha stimulated human lung epithelial cells (A549) were exposed to VOC (1 ng/m3-100g/m3) via gas phase. After 20 h of exposure cytotoxicity and the release of the pro-inflammatory molecules monocyte chemoattractant protein-1 (MCP-1), Interleukin-6 (IL-6) and IL-8 was analysed. Exposure of A549 cells to chlorobenzene, styrene or m-xylene increased the MCP-1 production within the indoor relevant concentration range (1-25,000 microg/m3), higher concentrations increased the secretion of IL-8. Mixtures of aromatic compounds caused comparable effects to the single compounds on MCP-1 and IL-8 with a shift to lower concentration ranges. Neither the aliphatic compounds n-nonane, n-decane, n-undecane, n-dodecane, n-tridecane, and methylcyclopentane nor the mixture of these VOC showed any effects on MCP-1 and IL-8 production. Cytotoxic effects were not observed. These results show that aromatic, but no aliphatic compounds stimulate the release of pro-inflammatory mediators from lung epithelial cells. When aromatic compounds were mixed the sensitivity of lung cells to these compounds was increased.
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PMID:Release of MCP-1 and IL-8 from lung epithelial cells exposed to volatile organic compounds. 1799 53

Elevated placental proinflammatory cytokine release is associated with miscarriage, preterm labor and preeclampsia. Specifically, tumor necrosis factor-alpha (TNF-alpha)-induced cytokines may threaten pregnancy outcome. Since trophoblasts produce calcitriol, a hormone with strong immunosuppressive properties, we assessed the effects of this secosteroid on inflammatory cytokines induced in trophoblasts by challenge with TNF-alpha. The effects of calcitriol on synthesis of mRNAs encoding interleukin-6 (IL-6), interferon-gamma (IFN-gamma), and TNF-alpha were measured by real time RT-PCR. Secreted cytokines were quantified by ELISA. The effects of TNF-alpha on CYP24A1, chorionic gonadotropin (hCG), 3beta-hydroxysteroid dehydrogenase (HSD3B1) and P(450)-aromatase (CYP19) mRNA expression were also studied. TNF-alpha stimulated IL-6, IFN-gamma and its own expression more than 3-fold over controls (P<0.05). Calcitriol inhibited the expression profile of inflammatory cytokine genes in a dose-response manner (P<0.05). This effect was prevented by addition of the vitamin D receptor antagonist TEI-9647. TNF-alpha also significantly inhibited expression of hCG, HSD3B1 and CYP19 genes, and stimulated CYP24A1 gene expression. These data show that calcitriol prevents TNF-alpha induction of inflammatory cytokines through a process likely to be mediated by the vitamin D receptor. We conclude that TNF-alpha inhibits placental hormone synthesis and stimulates calcitriol catabolism by regulating enzymes involved in these processes.
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PMID:Calcitriol inhibits TNF-alpha-induced inflammatory cytokines in human trophoblasts. 1950 15