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)

In previous studies, we have reported that PGF2alpha stimulates phosphoinositide hydrolysis by phospholipase C and phosphatidylcholine hydrolysis by phospholipase D through heterotrimeric GTP-binding protein in osteoblast-like MC3T3-E1 cells, and that PGF2alpha and PGE1 induce interleukin-6 (IL-6) synthesis via activation of protein kinase C and protein kinase A, respectively. In the present study, we investigated the effect of tiludronate, a bisphosphonate known to inhibit bone resorption, on the PGF2alpha- and PGE1-induced IL-6 synthesis in these cells. Tiludronate significantly suppressed the PGF2alpha-induced IL-6 secretion in a dose-dependent manner in the range between 0.1 and 30 microM. However, the IL-6 secretion induced by PGE1 or (Bu)2cAMP was hardly affected by tiludronate. The choline formation induced by PGF2alpha was reduced by tiludronate dose-dependently in the range between 0.1 and 30 microM. On the contrary, tiludronate had no effect on PGF2alpha-induced formation of inositol phosphates. Tiludronate suppressed the choline formation induced by NaF, known as an activator of heterotrimeric GTP-binding protein. However, tiludronate had little effect on the formation of choline induced by TPA, a protein kinase C activator. Tiludronate significantly inhibited the NaF-induced IL-6 secretion in human osteoblastic osteosarcoma Saos-2 cells. These results strongly suggest that tiludronate inhibits PGF2alpha-induced IL-6 synthesis via suppression of phosphatidylcholine-hydrolyzing phospholipase D activation in osteoblasts, and that the inhibitory effect is exerted at the point between heterotrimeric GTP-binding protein and phospholipase D.
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PMID:Tiludronate inhibits interleukin-6 synthesis in osteoblasts: inhibition of phospholipase D activation in MC3T3-E1 cells. 958 64

We previously reported that prostaglandin E1 (PGE1) induces the synthesis of interleukin-6 (IL-6) via cAMP production in osteoblast-like MC3T3-E1 cells, and that, on the other hand, prostaglandin F2alpha (PGF2alpha) stimulates IL-6 synthesis via activation of protein kinase C. In the present study, we examined the effect of retinoic acid on IL-6 synthesis induced by these two prostaglandins in MC3T3-E1 cells. Retinoic acid inhibited the IL-6 synthesis induced by PGF2alpha or PGE1 in a dose-dependent manner in the range between 0.1 and 10 nM. Retinoic acid also suppressed the IL-6 synthesis stimulated by 12-O-tetradecanoylphorbol-13-acetate, an activator of protein kinase C. The IL-6 synthesis induced by cholera toxin, forskolin or dibutyryl cAMP was inhibited by retinoic acid. However, retinoic acid had little effect on the IL-6 synthesis induced by interleukin-1. These results indicate that retinoic acid inhibits IL-6 synthesis induced by prostaglandins in osteoblasts as follows: the inhibitory effect on the PGE1-induced IL-6 synthesis is exerted at a point downstream from cAMP, and the inhibitory effect on the PGF2alpha-induced IL-6 synthesis is exerted at a point downstream from protein kinase C.
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PMID:Retinoic acid suppresses interleukin-6 synthesis induced by prostaglandins in osteoblasts. 961 Aug 45

We previously reported that prostaglandin (PG)E1 and PGF2alpha induce the synthesis of interleukin-6 (IL-6) via activation of protein kinase (PK)A and PKC, respectively, in osteoblast-like MC3T3-E1 cells. In addition, we have shown that basic fibroblast growth factor (bFGF) elicits IL-6 synthesis through intracellular Ca2+ mobilization in these cells and that tumor necrosis factor-alpha (TNF) induces IL-6 synthesis through sphingosine 1-phosphate produced by sphingomyelin hydrolysis. In the present study, among sphingomyelin metabolites, we examined the effect of sphingosine on IL-6 synthesis induced by various agonists in MC3T3-E1 cells. Sphingosine inhibited the IL-6 synthesis induced by PGF2alpha or 12-O-tetradecanoylphorbol-13-acetate, an activator of PKC. Sphingosine suppressed the PGE1-induced IL-6 synthesis. The IL-6 synthesis induced by cholera toxin, forskolin, or dibutyryl cAMP was inhibited by sphingosine. Sphingosine inhibited the IL-6 synthesis induced by bFGF or A23187. However, sphingosine did not affect the IL-6 synthesis induced by interleukin-1. On the contrary, sphingosine enhanced the TNF-induced IL-6 synthesis. DL-threo-Dihydrosphingosine, an inhibitor of sphingosine kinase, reduced the enhancement by sphingosine as well as the TNF-effect. These results indicate that sphingosine modulates the IL-6 synthesis stimulated by various agonists in osteoblasts.
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PMID:Sphingosine modulates interleukin-6 synthesis in osteoblasts. 970 71

Prostaglandins (PGs) and cytokines, such as interleukin-1 (IL-1) and interleukin-6 (IL-6), have been implicated in the etiopathology of various inflammatory and degenerative disorders, including Alzheimer's disease (AD). Previously, we detected the presence of IL-6 in cortices of AD patients. On the other hand, non-steroidal antiinflammatory drugs (NSAIDs), potent inhibitors of prostaglandin synthesis, have been shown to be beneficial in the treatment of AD. Until now, it remained unclear whether and how these two observations were functionally connected. Here, we show that PGs are able to induce IL-6 synthesis in a human astrocytoma cell line. PGE1 and PGE2, but not PGD2 and PGF2 alpha, led to a rapid and transient induction of astrocytic IL-6 mRNA, followed by IL-6 protein synthesis. Furthermore, PGE2 potentiated IL-1 beta-induced IL-6 mRNA synthesis. These results suggest a possible link between the release of PGs from activated microglia and the astrocytic synthesis of IL-6, which itself may affect neuronal cells, as hypothesized for Alzheimer's disease. Finally we demonstrate that microglia are a strong source of PGE2 synthesis indicating that these cells may act as the origin of the pathogenic cascade.
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PMID:Potential link between interleukin-6 and arachidonic acid metabolism in Alzheimer's disease. 985 Sep 35

We previously showed that prostaglandin (PG) E1 stimulates the synthesis of interleukin-6 (IL-6) through activation of protein kinase (PK) A in osteoblast-like MC3T3-E1 cells and that PGF2alpha induces IL-6 synthesis through PKC activation. In other studies, we demonstrated that thrombin stimulates IL-6 synthesis, which depends on intracellular Ca2+ mobilisation in these cells and that tumour necrosis factor-alpha (TNF) induces IL-6 synthesis through sphingosine 1-phosphate, a product of sphingomyelin turnover. In the present study, among sphingomyelin metabolites, we examined the effect of ceramide on the IL-6 synthesis induced by various agonists in MC3T3-E1 cells. C2-ceramide, a cell-permeable ceramide analogue, suppressed the PGE1-induced IL-6 synthesis. C2-ceramide inhibited the IL-6 synthesis induced by PGF2alpha or 12-O-tetradecanoylphorbol-13-acetate, an activator of PKC. C2-ceramide reduced the IL-6 synthesis induced by cholera toxin, forskolin or dibutyryl cAMP. C2-ceramide inhibited the IL-6 synthesis induced by thrombin. The IL-6 synthesis stimulated by thapsigargin, which is known to stimulate Ca2+ mobilisation from intracellular Ca2+ stores, or A23187, a Ca-ionophore, was also inhibited by C2-ceramide. C2-ceramide did not affect the IL-6 synthesis induced by interleukin-1. On the contrary, C2-ceramide enhanced the TNF-induced IL-6 synthesis. D,L-threo-dihydrosphingosine, an inhibitor of sphingosine kinase, inhibited the enhancement by C2-ceramide as well as the TNF-effect. These results strongly suggest that ceramide modulates the IL-6 synthesis stimulated by various agonists in osteoblasts.
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PMID:Effect of ceramide on interleukin-6 synthesis in osteoblast-like cells. 1040 Mar 16

Prostaglandins (PG) E1, E2 and F2alpha induce bone resorption in isolated neonatal parietal bone cultures, and an associated increase in interleukin-6 (IL-6) production. Indomethacin had little effect on the response to PGE2, or the relatively non-selective EP receptor agonists 11-deoxy PGE1 and misoprostol, but blocked the effects of PGF2alpha and the F receptor agonist fluprostenol, indicating an indirect action via release of other prostaglandins. It is more likely that there is positive autoregulation of prostaglandins production in this preparation mediated via stimulation of F receptors. The effects of selective EP receptor agonists sulprostone (EP1,3) and 17-phenyl trinor PGE2(EP1), indicated the involvement of EP2 and/or EP4 receptors, which signal via cAMP. The relatively weak increase in IL-6 production by misoprostol (with respect to resorption) suggests that these responses are controlled by different combination of EP2 and EP4 receptors. The PKA activator, forskolin, induced small increases in bone resorption at lower concentrations (50-500 ng/ml) but a reversal of this effect, and inhibition of resorption induced by other stimuli (PTH, PGE2), at higher concentrations (0.5-5 microg/ml). IL-6 production was markedly increased only at the higher concentrations. The inhibitory effect of forskolin may be a calcitonin-mimetic effect. PMA induced both resorption and IL-6 production which were both blocked by indomethacin, indicating a role for PKC in the control of prostaglandin production.
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PMID:Mechanisms involved in prostaglandin-induced increase in bone resorption in neonatal mouse calvaria. 1123 79

The generation of reactive oxygen species (free radicals) is an important factor in the development and maintenance of rheumatoid arthritis in humans and animal models. One source of free radicals is nitric oxide produced within the synoviocytes and chondrocytes and giving rise to the highly toxic radical peroxynitrite. Several cytokines, including tumour necrosis factor-alpha (TNFalpha) are involved in the formation of free radicals, partly by increasing the activity of nitric oxide synthase. Indeed, nitric oxide may mediate some of the deleterious effects of cytokines on bone resorption. Aspirin, tetracyclines, steroids and methotrexate can suppress nitric oxide synthase. Dietary antioxidants include ascorbate and the tocopherols and beneficial effects of high doses have been reported especially in osteoarthritis. There is also evidence for beneficial effects of beta-carotene and selenium, the latter being a component of the antioxidant enzyme glutathione peroxidase. The polyunsaturated fatty acids (PUFA) include the n-3 compounds, some of which are precursors of eicosanoid synthesis, and the n-6 group which can increase formation of the pro-inflammatory cytokines TNFalpha and interleukin-6, and of reactive oxygen species. Some prostaglandins, however, suppress cytokine formation, so that n-3 PUFA often oppose the inflammatory effects of some n-6-PUFA. gamma-linolenic acid (GLA) is a precursor of prostaglandin E1, a fact which may account for its reported ability to ameliorate arthritic symptoms. Fish oil supplements, rich in n-3 PUFA such as eicosapentaenoic acid have been claimed as beneficial in rheumatoid arthritis, possibly by suppression of the immune system and its cytokine repertoire. Some other oils of marine origin (e.g. from the green-lipped mussel) and a range of vegetable oils (e.g. olive oil and evening primrose oil) have indirect anti-inflammatory actions, probably mediated via prostaglandin E1. Overall, there is a growing scientific rationale for the use of dietary supplements as adjuncts in the treatment of inflammatory disorders such as rheumatoid arthritis and osteoarthritis.
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PMID:Antioxidants and fatty acids in the amelioration of rheumatoid arthritis and related disorders. 1129 72

We have evaluated the potential role of prostaglandins and their second-messenger Cyclic Adenosine Monophosphate (cAMP) in the activation of interleukin-6 (IL-6) promoter regulatory elements leading to IL-6 expression in monocytic cells. We demonstrate that prostaglandins of the E series and their second-messenger cAMP induce the IL-6 promoter in the murine monocytic cell line PU5-1.8. Stimulation with both cAMP and LPS results in a marked synergistic effect. We show that the endogenous IL-6 gene is induced by cAMP as well, even though to a lesser extent than by LPS, suggesting distinctive effects of cAMP and LPS on posttranscriptional events. Mutations eliminating potential transcription factor binding sites, including the multiple-response element (MRE), AP-1, NF-IL6, and NF-kappaB binding sites, significantly reduce, but do not completely abrogate, inducibility by cAMP or prostaglandin E1, whereas alterations of four additional putative regulatory elements have no effects. In contrast, LPS-induced promoter activity is almost completely abolished by mutations in the NF-kappaB binding site, suggesting that a single regulatory element is crucial for inducibility by LPS, whereas no individual element is absolutely essential for cAMP signaling. Induction of the AP-1, NF-IL-6, and NF-kappaB elements by cAMP is correlated with the appearance of inducible factors binding to these sites, whereas factors binding to the MRE are constitutively expressed. Our results suggest that cAMP and prostaglandins act through multiple, partially redundant, regulatory elements to induce IL-6 expression in monocytic cells.
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PMID:Interleukin-6 Gene Expression by Prostaglandins and Cyclic AMP Mediated by Multiple Regulatory Elements. 1185 43

Prostaglandins are hepatoprotective molecules generated in liver regeneration by the rapid induction of cyclooxygenase-2 (COX-2). Cardiotrophin-1 (CT-1) and vascular endothelial growth factor (VEGF) are other hepatoprotective mediators upregulated at 24 hours after partial hepatectomy. The interactions among these molecules during liver regeneration have not yet been defined. Here we show that rats subjected to partial hepatectomy treated with NS-398, a specific COX-2 inhibitor, exhibited cell cycle arrest, increased hepatocyte apoptosis, persistent extracellular signal-regulated kinase (ERK) 1/2 activation, and increased interleukin-6 production. These changes were associated with downregulation of CT-1 and COX-1 and altered pattern of VEGF expression. Administration of an adenovirus encoding CT-1 to NS-398-treated rats restituted normal levels of COX-1, prostaglandins, and VEGF in the liver after partial hepatectomy and restored normal liver regeneration. Furthermore, the stimulation of isolated rat hepatocytes with CT-1 increased COX-1, COX-2, and VEGF messenger RNAs and prostaglandin synthesis. Conversely, the addition of prostaglandin E1 to the culture increased CT-1 and VEGF production. In conclusion, COX-2 activation and production of prostaglandins soon after partial hepatectomy are essential requirements for hepatocyte proliferation and for the correct induction of both CT-1 and VEGF. CT-1 can restore liver regeneration after COX-2 inhibition by increasing VEGF, COX-1 expression, and prostaglandin synthesis.
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PMID:Interplay among cardiotrophin-1, prostaglandins, and vascular endothelial growth factor in rat liver regeneration. 1572 45

The inflammatory reactions and tissue response after oesophagectomy are leading causes of postoperative morbidity and mortality. We evaluated the effects of intraoperative infusion of prostaglandin E1 (PGE1) on interleukin-6 (IL-6) levels, (A-a) DO2, pulmonary function and complications. This randomised double-blind clinical trial study was performed on patients undergoing transthoracic oesophagectomy due to cancer Thirty patients were randomly allocated to two groups: the PGE1 group (infusion of PGE1 20 ng kg(-1) min(-1)) and a placebo group (infusion of normal saline 0.9%). The infusion was started before induction of anaesthesia and continued until the end of the operation. The groups were comparable in basic characteristics and preoperative pulmonary function. Patients in the PGE1 group were discharged significantly earlier from the intensive care unit (72+/-9 vs 83+/-17 hours) and hospital (13+/-4 vs 18+/-8 days) (P=0.04 and 0.03, respectively). The (A-a) DO2 was significantly less in the PGE1 group at 12 and 24 hours after the operation (P=0.001, P=0.003, respectively). Postoperatively, IL-6 levels were significantly higher in the placebo group than in the PGE1 group. There were no differences in the forced expiratory volume in the first second or forced vital capacity. The findings indicate that infusion of PGE1 attenuates the increase in serum levels of IL-6 in patients undergoing esophagectomy and improves the (A-a) DO2. Stays in the intensive care unit and hospital were shorter in the PGE1 group. However, there were no differences in pulmonary complications.
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PMID:The effects of prostaglandin E1 on interleukin-6, pulmonary function and postoperative recovery in oesophagectomised patients. 2001


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