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)

Interleukin-6 (IL-6) is a cytokine released by thyrocytes and is involved in disease processes such as autoimmune thyroid disease. The secretion of IL-6 can be stimulated by interleukin-1 (IL-1), tumour necrosis factor-alpha (TNF), serum, TSH and agents which increase intracellular cyclic AMP levels. Antithyroid drugs such as methimazole inhibit IL-6 production by thyrocytes but the effects of glucocorticoids and oestrogen have not been investigated. The effects of dexamethasone and 17 beta-oestradiol on IL-1-, TNF-, TSH-, forskolin- and phorbol 12-myristate 13-acetate (PMA)-stimulated IL-6 release in serum-free conditions were studied in human thyrocytes derived from patients with Graves' disease and toxic multinodular goitres, and in the immortalised human thyrocyte cell line, HTori3. Dexamethasone inhibited IL-6 production under stimulated conditions. In serum-free conditions, no basal release of IL-6 was assayable. In all but one of the primary thyroid cultures, TSH did not stimulate IL-6 release above the lower detectable limit of the assay. In Graves' and multinodular goitre thyrocytes, inhibition of IL-1 (100 U/ml)-stimulated IL-6 release by dexamethasone (100 nmol/l) was 62.51% +/- 10.43 (S.E.M.), and in HTori3 cells it was 78.35% +/- 3.9. The degree of IL-1 stimulation of IL-6 release and inhibition by dexamethasone was not significantly different in thyrocytes derived from either Graves' or multinodular glands. 17 beta-Oestradiol had no effect on IL-1-stimulated IL-6 release in either primary thyroid cell culture or in HTori3 cells.
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PMID:Effect of glucocorticoids and oestrogen on interleukin-6 production by human thyrocytes from patients with Graves' disease and toxic multinodular goitre and from HTori3 cells. 936 13

We have monitored glial cell line-derived neurotrophic factor (GDNF) secretion from rat C6 glioblastoma cells by ELISA. Representative cytokines, neurotrophins, growth factors, neuropeptides, and pharmacological agents were tested for their ability to modulate GDNF release. Whereas most factors tested had minimal effect, a 24-h treatment with fibroblast growth factor-1, -2, or -9 elevated secreted GDNF protein levels five- to 10-fold. The proinflammatory cytokines interleukin-1beta, interleukin-6, tumor necrosis factor-alpha, and lipopolysaccharide elevated GDNF release 1.5- to twofold. Parallel studies aimed at elucidating intracellular events that may regulate GDNF synthesis/release demonstrated the involvement of multiple signaling pathways. GDNF levels were increased by phorbol 12,13-didecanoate (10 nM) activation of protein kinase C, the Ca2+ ionophore A23187 (1 microM), okadaic acid (10 nM) inhibition of type-2A protein phosphatases, nitric oxide donors (1 mM), and H2O2 (1 mM)-induced oxidative stress. Elevation of cyclic AMP levels by either forskolin (10 microM) or dibutyryl cyclic AMP (1 mM) repressed GDNF secretion, as did treatment with the glucocorticoid dexamethasone (1 microM). Our results demonstrate that diverse biological factors are capable of modulating GDNF protein levels and that multiple signal transduction systems can regulate GDNF synthesis and/or release.
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PMID:Regulation of glial cell line-derived neurotrophic factor release from rat C6 glioblastoma cells. 945 47

We have studied the production of interleukin-11 (Il-11) in 13 breast cancer cell (BCC) lines. Two of these cell lines (MDA-MB-231 and Hs578T) expressed the cytokine at both the protein and mRNA levels. Il-11 did not modulate the growth of five BCC lines examined, including the two cytokine-producing BCC lines. The production of Il-11 was increased by transforming growth factor-beta1 in a dose-dependent manner with a rapid (2 h) and transient (24 h) mRNA induction, but not by epidermal growth factor, insulin-like growth factor-I and -II, basic fibroblast growth factor, platelet-derived growth factor or parathyroid hormone. The cyclic AMP inducer, forskolin, and the activator of protein kinase C, phorbol 12-myristate 13-acetate, also stimulated the production of Il-11. Besides Il-11, MDA-MB-231 and Hs578T were the only BCC lines to produce interleukin-6 (Il-6) protein and mRNA. Since Il-11 and Il-6 are potent stimulators of osteoclast development and bone is a major source of TGF-beta1, our data suggest that Il-11, together with Il-6, contributes to the high bone destructive capacity of MDA-MB-231 cells and could play a role in breast cancer-induced osteolysis.
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PMID:Production and regulation of interleukin-11 by breast cancer cells. 961 55

The presence of GABA(A)-receptors on astrocytes was studied in explant and primary cultures of rat cerebellum, hippocampus and spinal cord by means of immunohistochemistry. For these studies we have used the monoclonal antibody bd 17 against the beta2- and beta3-subunits of GABA(A)-receptor. In explant cultures many neurones were intensely stained with the GABA(A)-receptor antibody whereas adjacent astrocytes revealed little or no immunoreactivity. In the far outgrowth zone of explant culture, however, many immunostained astrocytes were observed. In primary astrocyte cultures, only a few cells were stained by the antibody. Astrocytes which became reactive after producing an artificial scar or after addition of certain compounds such as dibutyryl cyclic AMP, interleukin-6, basic fibroblast growth factor and kainic acid, also revealed GABA(A)-receptor immunoreactivity. Furthermore, these astrocytes were intensely stained for glial fibrillary acidic protein and vimentin. From our studies we conclude that only a sub-population of normal astrocytes are immunopositive for the GABA(A)-receptor antibody whereas astrocytes which become reactive following injury of the tissue or after addition of dibutyryl cyclic AMP, the cytokine interleukin-6, fibroblast growth factor or the neurotoxin kainic acid express GABA(A)-sites.
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PMID:Expression of GABA(A) receptors by reactive astrocytes in explant and primary cultures of rat CNS. 964 26

Serotonin (5-hydroxytryptamine (5-MT)) has been shown to be a regulator of gene expression in rat myometrial smooth muscle cells (SMC). Serotonin activates the genes for interstitial collagenase, interleukin-1alpha, -1beta and interleukin-6, among others. On the other hand, serotonin down-regulates the genes for types I and III collagen and fibronectin. Here we show that serotonin is also a negative regulator of the expression of anti-protease alpha2-macroglobulin (alpha2M) in SMC. The serotonin-dependent repression occurs at both the mRNA and protein levels, and is mediated by the 5-HT2A receptor subtype. The inhibitory effect is prevented by cycloheximide, indicating the requirement for the synthesis of one or more proteins. Interleukin-1 (IL-1), which is induced by serotonin in SMC and is required for subsequent interstitial collagenase induction, appears not to be one of these intermediates. On the other hand, progesterone, the major steroid hormone of pregnancy, is capable of reversing the serotonin-mediated inhibition of alpha2M. The phorbol myristate acetate (PMA), which mimics the induction of interstitial collagenase by serotonin, fails to affect the inhibition of alpha2M production. The cell-permeable cyclic AMP analogue 8-bromoadenosine 3':5'-cyclic monophosphate sodium salt (8-bromo-cAMP), is, however, capable of fully reproducing the action of serotonin on alpha2M. These results further speak to the ability of serotonin to regulate gene expression in the myometrial SMC, both positively and negatively. In addition, although all the effects of serotonin so far identified are mediated by the 5-HT2A receptor, different post-receptor pathways appear to mediate the positively and negatively regulated genes.
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PMID:Serotonin regulates the expression of the gene for alpha2-macroglobulin in myometrial smooth muscle cells. 970 76

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 cytokine, interleukin-6 (IL-6), is produced by osteoblasts and may in part mediate parathyroid hormone (PTH)-stimulated bone resorption. The goals of the present study were: (1) to examine PTH induction of IL-6 expression in 7-day-old mouse calvarial organ cultures; (2) to assess the role of intracellular signaling pathways in this model; and (3) to determine whether PTH regulates IL-6 expression by a transcriptional mechanism. Northern blot analysis of calvarial RNA showed that PTH(1-34) at 0.1-100 nmol/L induced IL-6 mRNA at 0.5 h with a peak at 2 h. Forskolin at 10 micromol/L and 8-bromocyclic-AMP at 3 mmol/L also induced IL-6 mRNA with a peak at 2 h. Phorbol myristate acetate induced IL-6 expression, whereas ionomycin and PTH(3-34) amide, an N-terminal-truncated PTH analog that has reduced ability to activate the cAMP-PKA pathway, were much less effective. PMA pretreatment of calvariae greatly blocked IL-6 mRNA induction by a subsequent dose of PMA and decreased induction by PTH and forskolin to a much lesser extent. A reverse-transcriptase polymerase chain reaction (RT-PCR) assay was used to measure IL-6 heterogeneous nuclear RNA (hnRNA) and mRNA. A 5' primer spanning exons 1 and 2 and a 3' primer complementary to exon 5 of the murine IL-6 gene were used to detect IL-6 mRNA as a 638 bp product. A 5' primer corresponding to intron 4 of the murine IL-6 gene and the 3' primer were used to detect IL-6 hnRNA as a 370 bp product. RT-PCR of total calvarial RNA showed that the induction of IL-6 hnRNA by PTH and other agonists was similar to their induction of IL-6 mRNA. These data support the conclusion that PTH transcriptionally induces IL-6 gene expression in murine calvarial organ cultures mainly through the cAMP-PKA signaling pathway.
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PMID:Parathyroid hormone induces interleukin-6 heterogeneous nuclear and messenger RNA expression in murine calvarial organ cultures. 976 44

We have examined the cytotoxic effects of cyclic adenosine-3', 5'-monophosphate (cAMP) derivatives on multiple myeloma cells lines and determined that the 8-Chloro substituted derivative (8Cl-cAMP) is one of the most potent. We report here that 8Cl-cAMP is cytotoxic to both steroid sensitive and insensitive myeloma cells with a half maximal concentration of approximately 3 micromol/L. 8Cl-cAMP toxicity in myeloma cells is dependent on phosphodiesterase activity in the serum of cell culture medium. A metabolite of 8Cl-cAMP, 8-Chloro-adenosine (8Cl-AD), kills myeloma cells as effectively as 8Cl-cAMP. Adenosine deaminase (ADA) converts 8Cl-AD into 8Cl-inosine and abrogates the cytotoxic effects of 8Cl-cAMP, 8Cl-AMP, and 8Cl-AD, as does 5-(p-Nitrobenzyl)-6-Thio-Inosine (NBTI), an inhibitor of nucleoside uptake. These data suggest that 8Cl-cAMP must be converted to 8Cl-AD and that 8Cl-AD is the compound that enters the cell. Contrary to glucocorticoid-mediated cell death in myeloma cells, the pathway of 8Cl-AD-mediated cell death appears to be independent of interleukin-6 (IL-6) actions. Although the exact mode of action for this agent is currently unknown, its ability to kill steroid sensitive and insensitive multiple myeloma cells in an IL-6 independent fashion may offer exciting new therapeutic options.
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PMID:8Cl-cAMP cytotoxicity in both steroid sensitive and insensitive multiple myeloma cell lines is mediated by 8Cl-adenosine. 976 75

Cyclooxygenase-2 (COX-2) is involved in the biosynthesis of prostanoids in the course of inflammatory reactions. This isoenzyme is regulated at the transcription level and many cells express COX-2 upon challenge with lipopolysaccharide (LPS) or pro-inflammatory cytokines. Since hepatocytes respond to LPS and pro-inflammatory stimuli, we investigated the expression of COX-2 in foetal and adult hepatocytes upon challenge with these substances. COX-2 was expressed in foetal hepatocytes incubated with LPS, tumour necrosis factor-alpha and interleukin-1beta. This response rapidly decreased after birth and was absent in hepatocytes from animals aged 2 days or more and treated under identical conditions. The expression of COX-2 was determined at the mRNA, protein and enzyme activity levels using Northern and Western blot, and following the synthesis of prostaglandin E2, respectively. The use of NS 398, a specific pharmacological inhibitor of COX-2, confirmed the expression of this isoenzyme in activated foetal hepatocytes. Synergism in COX-2 expression was observed between LPS, tumour necrosis factor-alpha and interleukin-1beta. Interleukin-6 and permeant analogues of cyclic AMP failed to induce COX-2 or to synergize with LPS. Also, transforming growth factor-beta inhibited the LPS- and pro-inflammatory cytokines-dependent expression of COX-2. These results indicate that foetal hepatocytes are competent to express COX-2 upon challenge with pro-inflammatory stimuli, a process lost completely in hepatocytes isolated from animals aged 2 days.
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PMID:Expression of cyclooxygenase-2 in foetal rat hepatocytes stimulated with lipopolysaccharide and pro-inflammatory cytokines. 986 62

In the thymus, sympathetic nerves run in septa in close connection to subcapsular/perivascular thymic epithelial cells (TEC). Since TEC are supposed to create a microenvironment of cytokines necessary for the development of thymocytes to T cells, we investigated the influence of sympathetic transmitters and co-transmitters on interleukin-6 (IL-6) synthesis in cultivated rat TEC that express markers of perivascular/subcapsular TEC. Noradrenaline and ATP stimulated IL-6 production in the culture supernatants 14- and 23-fold over basal values after 24 h. Co-stimulation with noradrenaline and ATP yielded an additive effect. Synthesis of IL-6 was concentration-dependent upon ATP and appeared to be mediated by P2 purinoceptors. During 24 h stimulation with 1 mM ATP, two thirds of the ligand was degraded mainly to ADP, production of AMP and adenosine was minor or negligible. Thus, in TEC, transmitters and co-transmitters of the sympathetic nervous system have a co-stimulatory effect on synthesis of IL-6 that is an important factor for thymocyte differentiation and proliferation.
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PMID:Effect of transmitters and co-transmitters of the sympathetic nervous system on interleukin-6 synthesis in thymic epithelial cells. 987 34


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