Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P05231 (interleukin-6)
 23,907 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

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 potent vasoconstrictor peptide endothelin-1 (ET-1) has been implicated in the pathophysiology of atherosclerosis and its complications. Since inflammation of the vessel wall is a hallmark of atherosclerosis, the purpose of the present study was to investigate the influence of ET-1 on cytokine production in human vascular smooth muscle cells (SMC) as a marker of inflammatory cell activation. ET-1 (100 pM - 1 microM) stimulated interleukin-6 (IL-6) secretion from human vascular SMC in a concentration-dependent manner. The ET-A-receptor antagonist BQ-123 (10 microM), but not the ET-B-receptor antagonist BQ-788, inhibited IL-6 release. ET-1 also transiently increased IL-6 mRNA compatible with regulation of IL-6 release at the pretranslational level. Electrophoretic mobility shift assays demonstrated time- and concentration-dependent activation of the proinflammatory transcription factor nuclear factor-kappaB (NF-kappaB) in ET-1-stimulated human vascular SMC. A decoy oligodeoxynucleotide bearing the NF-kappaB binding site inhibited ET-1-stimulated IL-6 release to a great extent suggesting that this transcription factor plays a key role for cytokine production elicited by ET-1. Moreover, the antioxidant pyrrolidine dithiocarbamate (10 microM) inhibited ET-1-induced IL-6 release indicating involvement of reactive oxygen species in ET-1 signaling. ET-1-stimulated IL-6 secretion was also suppressed by diphenylene iodonium (40 microM), an inhibitor of flavon-containing enzymes such as NADH/NADPH oxidase. The results demonstrate the ability of ET-1 to induce an inflammatory response in human vascular SMC. These observations may contribute to a better understanding of the role of ET-1 in inflammatory activation of the vessel wall during atherogenesis.
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PMID:Endothelin-1 induces interleukin-6 release via activation of the transcription factor NF-kappaB in human vascular smooth muscle cells. 1082 1

Inflammatory processes involve both synthesis of inflammatory cytokines, such as interleukin-6 (IL-6), and the activation of their distinct signaling pathways, eg, the janus kinases (JAKs) and signal transducers and activators of transcription (STAT). Superoxide (O(2)(-)) anions activate this signaling cascade, and the vasoconstrictor angiotensin II (Ang II) enhances the formation of O(2)(-) anions via the NAD(P)H oxidase system in rat aortic smooth muscle cells. Ang II activates the JAK/STAT cascade via its type 1 (AT(1)) receptor and induces synthesis and release of IL-6. Therefore, we investigated the role of O(2)(-) anions generated by the NAD(P)H oxidase system on the Ang II activation of the JAK/STAT cascade and its impact on IL-6 synthesis. Ang II stimulation of rat aortic smooth muscle cells induced a rapid increase in O(2)(-) anions determined by laser fluoroscopy, which can be abolished by DPI, a flavoprotein inhibitor. Ang II-induced phosphorylation of JAK2, STAT1alpha/ss, STAT3, and IL-6-synthesis can be abolished by DPI, as determined by immunoprecipitations and Northern blot analysis. Electroporation of neutralizing antisera targeted against p47(phox), a NAD(P)H oxidase subunit, abolished Ang II-induced JAK/STAT activation and IL-6 synthesis. Inhibition of JAK2 by its inhibitor AG490 (10 micromol/L) blocked not only JAK2 activation but also IL-6 synthesis. These results suggest that stimulation of the JAK/STAT cascade by Ang II requires O(2)(-) anions generated by the NAD(P)H oxidase system, and O(2)(-) anion-dependent activation of the JAK/STAT cascade seems to be additionally involved in Ang II-induced IL-6 synthesis. Thus, Ang II-induced inflammatory effects seem to require O(2)(-) anions generated by the NAD(P)H oxidase system.
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PMID:Role of NAD(P)H oxidase in angiotensin II-induced JAK/STAT signaling and cytokine induction. 1111 Jul 59

Endothelial cells increase their secretion of the cytokine interleukin-6 (IL-6) during hypoxia, which then acts in an autocrine fashion to increase the permeability of cell monolayers. These responses are attenuated by antioxidants, suggesting that reactive oxygen species (ROS) participate in signaling in hypoxic endothelium. We tested whether mitochondria are responsible for these ROS in human umbilical vein endothelial cells exposed to hypoxia. Oxidation of the probe 2', 7'-dichlorodihydrofluorescein to fluorescent dichlorofluorescein or the probe dihydroethidium was used to assess oxidant signaling, whereas permeability was assessed by using transendothelial electrical resistance. Hypoxia elicited increases in dichlorofluorescein and dihydroethidium fluorescence that were abrogated by the mitochondrial electron transport (ET) inhibitors rotenone (2 micromol/L) and diphenyleneiodonium (5 micromol/L). The same ET inhibitors also attenuated hypoxia-induced increases in nuclear factor-kappaB (NF-kappaB) activation, although they did not abrogate NF-kappaB activation in response to endotoxin (lipopolysaccharide). ET inhibition also abolished the hypoxia-induced increases in IL-6 mRNA expression, hypoxia-stimulated IL-6 secretion into the media, and the hypoxia-induced increases in transendothelial electrical resistance of human umbilical vein endothelial cell monolayers. By contrast, the above responses to hypoxia were not significantly affected by treatment with the NAD(P)H oxidase inhibitor apocynin (30 micromol/L), the xanthine oxidase inhibitor allopurinol (100 micromol/L), or the NO synthase inhibitor N-nitro-L-arginine (100 micromol/L). We conclude that ROS signals originating from the mitochondrial ET chain trigger the increase in NF-kappaB activation, the transcriptional activation of IL-6, the secretion of IL-6 into the cell culture media, and the increases in endothelial permeability observed during hypoxia.
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PMID:Role of mitochondrial oxidant generation in endothelial cell responses to hypoxia. 1195 Jun 85

Amyloid precursor protein (AbetaPP), a precursor of amyloid beta (Abeta) peptide, is one of the molecules involved in the pathogenesis of Alzheimer's disease (AD). Specific mutations in AbetaPP have been found in patients inheriting familial AD (FAD). These mutant AbetaPP proteins cause cell death in neuronal cell lines in vitro, but the molecular mechanism of cytotoxicity has not yet been clarified completely. We analyzed the cytotoxic mechanisms of the London-type AbetaPP mutant, V642I-AbetaPP, in primary cortical neurons utilizing an adenovirus-mediated gene transfer system. Expression of V642I-AbetaPP protein induced degeneration of the primary neurons. This cytotoxicity was blocked by pertussis toxin, a specific inhibitor for heterotrimeric G proteins, Go/i, and was suppressed by an inhibitor of caspase-3/7 and an antioxidant, glutathione ethyl ester. A specific inhibitor for NADPH oxidase, apocynin, but not a xanthine oxidase inhibitor or a nitric oxide inhibitor, blocked V642I-AbetaPP-induced cytotoxicity. Among mitogen-activated protein kinase (MAPK) family proteins, c-Jun N-terminal kinase (JNK) and p38MAPK, but not extracellular regulated kinase (ERK), were involved in this cytotoxic pathway. The V642I-AbetaPP-induced cytotoxicity was not suppressed by two secretase inhibitors, suggesting that Abeta does not play a major role in this cytotoxicity. Two neuroprotective factors, insulin-like growth factor I (IGF-I) and Humanin, protected these primary neurons from V642I-AbetaPP-induced cytotoxicity. Furthermore, interleukin-6 and -11 also attenuated this cytotoxicity. This study demonstrated that the signaling pathway activated by mutated AbetaPP in the primary neurons is the same as that by the other artificial insults such as antibody binding to AbetaPP and the artificial dimerization of cytoplasmic domain of AbetaPP. The potential of neurotrophic factors and cytokines in AD therapy is also indicated.
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PMID:Characterization of V642I-AbetaPP-induced cytotoxicity in primary neurons. 1519 38

The advanced glycation end products (AGEs) are a heterogeneous class of molecules, including the following main subgroups: bis(lysyl)imidazolium cross-links, hydroimidazolones, 3-deoxyglucosone derivatives, and monolysyl adducts. AGEs are increased in diabetes, renal failure, and aging. Microvascular lesions correlate with the accumulation of AGEs, as demonstrated in diabetic retinopathy or renal glomerulosclerosis. On endothelial cells, ligation of receptor for AGE (RAGE) by AGEs induces the expression of cell adhesion molecules, tissue factor, cytokines such as interleukin-6, and monocyte chemoattractant protein-1. A chief means by which AGEs via RAGE exert their effects is by generation of reactive oxygen species, at least in part via stimulation of NADPH oxidase. Diabetes-associated vascular dysfunction in vivo can be prevented by blockade of RAGE. Thus, agents that limit AGE formation, increase the catabolism of these species, or antagonize their binding to RAGE may provide new targets for vascular protection in diabetes.
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PMID:Protein glycation: a firm link to endothelial cell dysfunction. 1529 85

NADPH oxidase produces a large amount of reactive oxygen species (ROS) mainly in phagocytic cells. ROS are involved in NF-kappaB activation, cytokine expression and thus, pathogenesis of pancreatitis. However, the source of ROS in pancreatic acinar cells has not been clarified. Cerulein rapidly induces acute and edematous form of pancreatitis. We investigated whether pancreatic acinar cells contain NADPH oxidase, and whether NADPH oxidase mediates interleukin-6 (IL-6) in pancreatic acinar AR42J cells stimulated with cerulein. Expression of NADPH oxidase subunits and NADPH oxidase activity were determined in the cells by immunofluorescence staining and lucigenin luminescence, respectively. Oxidant-sensitive nuclear transcription factor NF-kappaB activation was monitored by electrophoretic mobility shift assay. IL-6 expression was determined by reverse transcription-polymerase chain reaction and enzyme-linked immunosorbant assay. NADPH oxidase inhibitor diphenylene iodonium (DPI), antioxidant rebamipide, and antisense oligonucleotides (AS ODNs) for NADPH oxidase subunits p22phox and p47phox were used to determine the involvement of NADPH oxidase in NF-kappaB activation and IL-6 expression in AR42J cells. As a result, pancreatic acinar AR42J cells constitutively express NADPH oxidase subunits p67phox and p47phox in the cytosol and Nox1 and p22phox in the membrane. Cerulein-stimulated NADPH oxidase activity and induced NF-kappaB activation and IL-6 expression in AR42J cells. Treatment of DPI or rebamipide and transfection of AS ODNs for NADPH oxidase subunits suppressed cerulein-induced NF-kappaB activation and IL-6 expression compared to S ODNs. In conclusion, NADPH oxidase may mediate the expression of inflammatory cytokines by stimulating NF-kappaB activation in pancreatic acinar cells during the course of pancreatitis.
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PMID:NADPH oxidase mediates interleukin-6 expression in cerulein-stimulated pancreatic acinar cells. 1583 77

Platelet-activating factor (PAF) and interleukin-6 (IL-6) are produced in the esophagus in response to HCl and affect ACh release, causing changes in esophageal motor function similar to esophagitis (Cheng L, Cao W, Fiocchi C, Behar J, Biancani P, and Harnett KM. Am J Physiol Gastrointest Liver Physiol 289: G418-G428, 2005). We therefore examined HCl-activated mechanisms for production of PAF and IL-6 in cat esophageal mucosa and circular muscle. A segment of normal mucosa was tied at both ends, forming a mucosal sac (Cheng L, Cao W, Fiocchi C, Behar J, Biancani P, and Harnett KM. Am J Physiol Gastrointest Liver Physiol 289: G860-G869, 2005) that was filled with acidic Krebs buffer (pH 5.8) or normal Krebs buffer (pH 7.0) as control and kept in oxygenated Krebs buffer for 3 h. The supernatant of the acidic sac (MS-HCl) abolished contraction of normal muscle strips in response to electric field stimulation. The inhibition was reversed by the PAF antagonist CV3988 and by IL-6 antibodies. PAF and IL-6 levels in MS-HCl and mucosa were significantly elevated over control. IL-6 levels in mucosa and supernatant were reduced by CV3988, suggesting that formation of IL-6 depends on PAF. PAF-receptor mRNA levels were not detected by RT-PCR in normal mucosa, but were significantly elevated after exposure to HCl, indicating that HCl causes production of PAF and expression of PAF receptors in esophageal mucosa and that PAF causes production of IL-6. PAF and IL-6, produced in the mucosa, are released to affect the circular muscle layer. In the circular muscle, PAF causes production of additional IL-6 that activates NADPH oxidase to induce production of H(2)O(2). H(2)O(2) causes formation of IL-1beta that may induce production of PAF in the muscle, possibly closing a self-sustaining cycle of production of inflammatory mediators.
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PMID:HCl-induced inflammatory mediators in cat esophageal mucosa and inflammatory mediators in esophageal circular muscle in an in vitro model of esophagitis. 1643 66

Genetics, oxidative stress: superoxide anion (O2*-) and hydrogen peroxide (H2O2), endothelial nitric oxide (eNO), lipid peroxides, anti-oxidants, endothelin, angiotensin converting enzyme (ACE) activity, angiotensinII, transforming growth factor-beta (TGF-beta), insulin, homocysteine, asymmetrical dimethyl arginine, proinflammatory cytokines: interleukin-6 (IL-6), tumor necrosis factor-a (TNF-alpha), C-reactive protein (hs-CRP), and long-chain polyunsaturated fatty acids (LCPUFAs), and activity of NAD(P)H oxidase have a role in human essential hypertension. There is a close interaction between endogenous molecules: eNO, endothelin, cytokines, and nutrients: folic acid, L-arginine, tetrahydrobiopterin (H4B), vitamin B6, vitamin B12, vitamin C, and LCPUFAs. Statins mediate some, if not all, of their actions through LCPUFAs, whereas these fatty acids (especially omega-3 fatty acids) suppress cyclo-oxygenase activity and the synthesis of pro-inflammatory cytokines, and activate parasympathetic nervous system, actions that reduce the risk of major vascular events. Some LCPUFAs form precursors to lipoxins and resolvins that have anti-inflammatory actions. Low-grade systemic inflammation seen in hypertension seems to have its origins in the perinatal period and availability of adequate amounts of LCPUFAs during the critical periods of brain growth prevents the development of hypertension. This indicates that preventive strategies aimed at decreasing the incidence of hypertension and its associated conditions such as atherosclerosis, type 2 diabetes, coronary heart disease (CHD), and cardiac failure in adulthood need to be instituted during the perinatal period if they are to be effective.
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PMID:Hypertension as a low-grade systemic inflammatory condition that has its origins in the perinatal period. 1671 19

Albumin induces oxidative stress and cytokine production in proximal tubular cells (PTECs). Albumin-bound fatty acids (FAs) enhance tubulopathic effects of albumin in vivo. We proposed that FA aggravation of albumin-induced oxidative stress in PTECs might be involved. We hypothesized that mitochondria could be a source of such stress. Using a fluorescent probe, we compared reactive oxygen species (ROS) production after exposure of PTECs to bovine serum albumin (BSA) alone or loaded with oleic acid (OA-BSA) (3-30 g/l for 2 h). There was no difference in cellular albumin uptake, but OA-BSA dose-dependently induced more ROS than BSA alone (P<0.001). OA-BSA-induced ROS was significantly alleviated by mitochondrial inhibition, but not by inhibitors of nicotinamide adenine dinucleotide phosphate hydrogenase (NADPH) oxidase, xanthine oxidase, or nitric oxide synthase. Gene expression analysis showed that neither the NADPH oxidase component p22phox nor xanthine oxidase was induced by BSA or OA-BSA. OA-BSA, in contrast to BSA, failed to induce mitochondrial manganese superoxide dismutase 2 (SOD2) expression. OA-BSA showed a greater capacity than BSA to downregulate heme oxygenase-1 mRNA expression and accentuate inflammatory cytokine mRNA and protein. Supplementation of SOD activity with EUK-8 reduced ROS, and interleukin-6 protein expression was suppressed by both mitochondrial inhibition and SOD augmentation. Thus, in PTECs, FAs accentuate albumin-induced oxidative stress and inflammatory cytokine expression via increased mitochondrial ROS, while frustrating protective antioxidant responses.
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PMID:Albumin-bound fatty acids induce mitochondrial oxidant stress and impair antioxidant responses in proximal tubular cells. 1683 28


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