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)

The effects of arachidonic acid ethanolamide (anandamide), palmitoylethanolamide and delta9-tetrahydrocannabinol on the production of tumor necrosis factor-alpha (TNF-alpha), interleukin-4, interleukin-6, interleukin-8, interleukin-10, interferon-gamma, p55 and p75 TNF-alpha soluble receptors by stimulated human peripheral blood mononuclear cells as well as [3H]arachidonic acid release by non-stimulated and N-formyl-Met-Leu-Phe (fMLP)-stimulated human monocytes were investigated. Anandamide was shown to diminish interleukin-6 and interleukin-8 production at low nanomolar concentrations (3-30 nM) but inhibited the production of TNF-alpha, interferon-gamma, interleukin-4 and p75 TNF-alpha soluble receptors at higher concentrations (0.3-3 microM). Palmitoylethanolamide inhibited interleukin-4, interleukin-6, interleukin-8 synthesis and the production of p75 TNF-alpha soluble receptors at concentrations similar to those of anandamide but failed to influence TNF-alpha and interferon-gamma production. The effect of both compounds on interleukin-6 and interleukin-8 production disappeared with an increase in the concentration used. Neither anandamide nor palmitoylethanolamide influenced interleukin-10 synthesis. delta9-Tetrahydrocannabinol exerted a biphasic action on pro-inflammatory cytokine production. TNF-alpha, interleukin-6 and interleukin-8 synthesis was maximally inhibited by 3 nM delta9-tetrahydrocannabinol but stimulated by 3 microM delta9-tetrahydrocannabinol, as was interleukin-8 and interferon-gamma synthesis. The level of interleukin-4, interleukin-10 and p75 TNF-alpha soluble receptors was diminished by 3 microM delta9-tetrahydrocannabinol. [3H]Arachidonate release was stimulated only by high delta9-tetrahydrocannabinol and anandamide concentrations (30 microM). These results suggest that the inhibitory properties of anandamide, palmitoylethanolamide and delta9-tetrahydrocannabinol are determined by the activation of the peripheral-type cannabinoid receptors, and that various endogenous fatty acid ethanolamides may participate in the regulation of the immune response.
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PMID:Influence of fatty acid ethanolamides and delta9-tetrahydrocannabinol on cytokine and arachidonate release by mononuclear cells. 925 58

The interleukin-6 (IL-6)/gp-80 and hepatocyte growth factor (HGF)/met ligand/receptor systems have been shown to stimulate biliary epithelial cell (BEC) DNA synthesis in vitro. The mRNA and protein production of these two in vitro mitogens were mapped in vivo during the first week after bile duct ligation (BDL) when peak BEC DNA synthesis is seen. Changes around the biliary tree were compared with those seen in the peripheral liver using a combination of Northern blotting and a unique biliary tree isolation technique, in which the bile ducts and the surrounding portal stroma and inflammatory cells are separated from the hepatocytes by perfusion digestion. Further localization was performed with in situ hybridization and immunohistochemistry. In the normal liver, there is low-level expression of HGF mRNA by periportal stellate cells, and HGF protein localizes to these cells and to neutrophils; extracellular HGF protein is present in the bile. There is no detectable IL-6 mRNA by Northern analysis or IL-6 protein expression in the normal liver, but both met and IL-6 receptor (IL-6R) mRNA are detectable; met mRNA is expressed strongly in the biliary tree, and met protein is expressed weakly on hepatocytes and strongly on BEC. IL-6R mRNA is weakly expressed in the biliary tree, and IL-6R protein is detectable on hepatocytes, with a periportal-to-perivenular gradient, but not on BEC. During the first 3 days after BDL, HGF mRNA expression is increased in both the biliary tree and in the peripheral liver, and production is localized to stellate cells, periductal neutrophils, and stromal cells, which typically accompany the proliferating ductules. IL-6 mRNA and protein were detected only near the biliary tree after BDL, and not in the peripheral liver, and the production was localized to periductal hematolymphoid cells, which had the morphological appearance of macrophages and/or dendritic cells. There is also a distinct up-regulation of met and gp-80 mRNA and protein in the biliary tree, which is stronger than that seen in the peripheral liver. Met protein expression is increased, and IL-6R(gp-80) protein is induced on the proliferating BEC, consistent with the participation of both the HGF/met and IL-6/gp-80 systems in the early phases of type I ductular reactions. These observations show that periductal hematolymphoid and stromal cells are the source of BEC growth factors, and receptors for these factors are up-regulated on BEC during active ductular proliferation. Complex interactions between the inflammatory, stromal, and BEC results in a dysmorphogenic repair response that eventually leads to cirrhosis.
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PMID:Interleukin-6, hepatocyte growth factor, and their receptors in biliary epithelial cells during a type I ductular reaction in mice: interactions between the periductal inflammatory and stromal cells and the biliary epithelium. 979 10

Neuropeptide Y (NPY) and endogenous opioids (EOPs) such as methionine-enkephalin (Met-enk) regulate similar physiological responses, but it is not known whether nociceptive and immune responses also show analogy after intracerebroventricular (i.c.v.) application. Dose-response studies show that Met-enk stimulates the blood granulocyte and splenic natural killer (NK) cell function of Lewis rats at a low dose (10(2) ng/kg, i.c.v.), whereas a high dose (10(5) ng/kg) causes suppression of innate immune functions associated with analgesia in the hot-plate test. At 15 min, 1 h and 24 h after i.c.v. application, both Met-enk (10(2) ng/kg) and NPY (1 ng/kg) produced similar effects: An initial suppression of innate immune function was followed by a long lasting stimulatory action on cell functions and serum interleukin-6 (sIL-6) levels. Thus, central NPY application resembles Met-enk-induced immunostimulation at doses not affecting nociception, suggesting an involvement of both peptides in shaping stress-induced immunomodulation of the non-analgetic form, possibly via activation of a common immunomodulatory effector mechanism.
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PMID:Centrally applied NPY mimics immunoactivation induced by non-analgesic doses of met-enkephalin. 987 22

The oxidation of methionine residues in many proteins, including the serine proteinase inhibitor alpha1-antitrypsin (AAT), can result in functional inactivation. In this study we investigated the pro-inflammatory properties of oxidized AAT (oxAAT), specifically its ability to activate human monocytes in culture. Monocytes stimulated with oxAAT at concentrations up to 0.2 mg/ml for 24 h showed significant elevation in monocyte chemoattractant protein-1, cytokine interleukin-6, and tumor necrosis factor-alpha expression and increased NADPH oxidase activity. Monocytes activated with oxAAT showed surprising effects on lipid metabolism. Expression of low density lipoprotein (LDL) receptors increased by up to 76% compared with controls but was not accompanied by any changes in (125)I-labeled LDL binding and, paradoxically, decreased LDL uptake, degradation, and intracellular cholesterol synthesis. oxAAT also down-regulated the scavenger receptor CD36, which takes up and is up-regulated by oxidized LDL and is down-regulated by cholesterol efflux. As a by-product of oxidative events accompanying inflammation, oxAAT has multiple effects on cytokine expression, generation of reactive oxygen species, and on intracellular lipid metabolism. The up-regulation of monocyte-derived reactive oxygen by oxAAT could potentially result in self-amplification of AAT oxidation and, thereby, the other effects deriving from it. This implies that there are as yet unidentified regulatory processes that control this cycle.
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PMID:Activation of primary human monocytes by the oxidized form of alpha1-antitrypsin. 1071 80

The effects of methionine-enkephalin on the production of interleukin-6 by activated peritoneal murine macrophages were studied. Macrophage were activated with interleukin-1beta or interferon-gamma in the presence or absence of graded concentrations of methionine-enkephalin. Methionine-enkephalin combined with interleukin-1beta or interferon-gamma caused an increase in IL-6 release from cultured macrophages. The opioid receptor antagonist naloxone did not change the stimulatory effect of methionine-enkephalin on IL-6 production by stimulated macrophages. Methionine-enkephalin added to the culture medium of resting macrophages increased IL-6 release from macrophages which were later induced with interleukin-1beta or interferon-gamma. The results of this study suggest that methionine-enkephalin can modulate the proinflammatory cytokine response by controlling, via non-opioid receptor mechanism, the production of IL-6.
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PMID:Augmenting effect of methionine-enkephalin on interleukin-6 production by cytokine-stimulated murine macrophages. 1102 79

Gold was first used 90 years ago by Robert Koch for the treatment of tuberculosis based on the assumption that rheumatoid arthritis was caused by microbacteria. It soon became clear that this would not explain the action of gold in rheumatoid arthritis, and since then scientists have been struggling to elucidate the mechanisms of gold's action in the treatment of rheumatic diseases. In nearly every area of immunology inhibiting actions of gold could be documented; however, it is still unclear if there is a common denominator or if there are parallel modes of actions which are independent of each other. In any case, also based on recent studies the reactivity of gold compounds with thiol groups appears to the predominant factor. Analyzing the actions of gold in the different phases of an immune reaction suggested that gold plays an important role already in the initiation, namely the uptake and presentation of foreign antigens. Thus, gold is taken up by the macrophages and stored in the lysosomes which are called aureosomes where gold inhibits antigen processing. Especially peptide antigens, which contain sulfur such as cysteine and methionine, are important. Moreover, it could be shown that gold suppresses NF-kappa B binding activity as well as the activation of the I-kappa B-kinase. This mechanism results in a subsequently reduced production of pro-inflammatory cytokines, most notably TNF-alpha, interleukin-1 and interleukin-6. On the subsequent T-cell level, gold has been shown to induce an upregulation of IL-4 mRNA, resulting in a shift of the T-cell population to the Th2 phenotype. Moreover, the activation of T-cells is inhibited. On the effector level, gold inhibits proteolytic enzymes and can result in the destruction of synovial fibroblasts. In conclusion, gold remains one of the most fascinating antirheumatic drugs with multiple modes of actions. The future analysis of molecular mechanisms, especially with regard to signal transduction, will lead to new fundamental knowledge of gold action, possible allowing a further understanding of the pathogenesis of rheumatoid arthritis.
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PMID:[Molecular mechanisms of action of gold in treatment of rheumatoid arthritis--an update]. 1147 4

An infrared multiphoton dissociation (IRMPD) spectrum, obtained by Fourier transform ion cyclotron resonance mass spectrometry (FTICRMS), was used to dissociate and to identify fragment ions from recombinant human interleukin-6 (IL-6; 21 KDa). The entire sequence was assigned by a single IRMPD experiment, and the observed fragment ions reflected the IL-6 secondary structure. This method was combined with H/D off-exchange to identify IL-6 and anti-human IL-6 mouse monoclonal antibody MH166 (150-kDa) binding sites in the IL-6 molecule. To facilitate the data analysis, the protein complex formation and the hydrogen exchange were performed with an immobilized antibody. Quenching of the hydrogen exchange reaction and collection of the deuterated IL-6 were performed by elution under acidic conditions to measure the mass spectrum directly. IL-6 was dissociated by using IRMPD, and the interface of IL-6 bound to anti-IL-6 antibody MH166 was determined to analyze the deuterium incorporation level of each fragment ion. Thus, two discontinuous regions, Leu 126-Lys 131 and Asp 160-Met 184, were identified as the antibody binding sites. These regions are adjacent to each other on the tertiary structures determined by NMR and X-ray analyses.
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PMID:Identification of the interface of a large protein-protein complex using H/D exchange and Fourier transform ion cyclotron resonance mass spectrometry. 1181 44

The diet of industrialised countries is usually rich in amino acids, which are in part used as a source of calories. However, metabolic alterations are observed in diseased patients and a preferential retention of Sulphurated Amino Acids (SAA) occurs during the inflammatory response. Moreover, it has been demonstrated in a model of an acute sepsis phase of rats that the metabolism of Cysteine is modified. The liver converts Cysteine at a different ratio of Sulphate to Taurine (Tau) i.e. the sulphate production decreases while the Tau conversion increases. The Glutathione (GSH) concentration is greater in the liver, kidneys and other organs and the Cysteine incorporation into proteins is higher in the spleen, lungs and plasma (Acute Phase Proteins) while the Albumin level decreases. The pro-inflammatory cytokines such as Interleukin-1, Interleukin-6 and TNF- alpha are the main initiators that alter protein and amino acid metabolism. Another important phenomenon is the impairment of Methionine conversion to Cysteine during stress. For example, premature infants or AIDS patients are capable of synthesizing Cysteine from Methionine at a much lower rate. Thus, the metabolic flow through the trans-sulphuration path may be inadequate to meet the Cysteine demand under critical conditions. In this complex picture, an SAA supply may contribute to an immune system regulation.
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PMID:The regulation of sulphurated amino acid junctions: fact or fiction in the field of inflammation? 1243 3

Interleukin-6 (IL-6) is a multifunctional cytokine having primarily anti-apoptotic and anti-inflammatory effects. Recent reports have documented that IL-6 plays a key role in liver regeneration. Intracellular deficiency of S-adenosylmethionine (SAMe) is a hallmark of toxin-induced liver injury. Although the administration of exogenous SAMe attenuates liver injury, its mechanisms of action are not fully understood. Here we investigated the effects of exogenous SAMe on IL-6 production in monocytes and Kupffer cells. RAW 264.7 cells, a murine monocyte cell line, and isolated rat Kupffer cells were stimulated with lipopolysaccharide (LPS) in the absence or presence of exogenous SAMe. IL-6 production was assayed by ELISA and intracellular SAMe concentrations were measured by HPLC. We have found that exogenous SAMe administration enhanced both IL-6 protein production and gene expression in LPS-stimulated monocytes and Kupffer cells. Cycloleucine (CL), an inhibitor for extrahepatic methionine adenosyltransferases (MAT), inhibited LPS-stimulated IL-6 production. The enhancement of LPS-stimulated IL-6 production by SAMe was inhibited by ZM241385, a specific antagonist of adenosine (A2) receptor. Our results demonstrate that SAMe administration may exert its anti-inflammatory and hepatoprotective effects, at least in part, by enhancing LPS-stimulated IL-6 production.
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PMID:Modulation of endotoxin stimulated interleukin-6 production in monocytes and Kupffer cells by S-adenosylmethionine (SAMe). 1556 50

Obesity as well as low physical fitness and inactivity are associated with an increased incidence of cardiovascular risk factors and coronary artery disease (CAD). Increased inflammation has recently been addressed to play an important role for the relationship between obesity and CAD, as adipose tissue expresses and releases pro-inflammatory cytokines such as interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-alpha). As this relationship is less clear in childhood, we investigated 197 children aged 10-15 years assessing obesity, physical fitness, and a metabolic cardiovascular risk profile including markers of inflammation. Obese children had significantly higher concentrations of inflammatory parameters such as fibrinogen, ferritin, IL-6, and TNF-alpha than non-obese subjects (P<0.01). When dividing the children into groups regarding obesity (BMI < 22.5 kg/mz, BMI > or = 22.5 kglm2) and fitness (< 5 MET, > or = 5 MET), we found that obese, unfit children showed the highest systemic inflammation, whereas fit but obese individuals had as low levels as lean and fit children. These data reveal that even in childhood inflammatory parameters are elevated in obesity and that physical fitness counteracts this association.
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PMID:Low-grade systemic inflammation in overweight children: impact of physical fitness. 1563 87


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