Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:1.14.99.3 (heme oxygenase)
 4,196 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The effects of human interleukin-6 (hIL-6), the major acute-phase inducer, on the level of the transcript of microsomal heme oxygenase (HO) were examined in a human hepatoma cell line, Hep3B. Messenger RNAs (mRNAs) encoding HO and haptoglobin (Hpt) increased after hIL-6 treatment in a time- and dose-dependent manner. hIL-6 had no effect on the induction of heat-shock protein 70 (hsp70) mRNA, suggesting that the induction of HO by hIL-6 is regulated by a different mechanism from that which mediates the heat-shock induction of this enzyme. The hIL-6-mediated induction of HO mRNA was completely abrogated by simultaneous treatment of cells with actinomycin D, but not with cycloheximide, suggesting that the induction occurs at the level of transcription. A nuclear factor was shown both in untreated, and in the hIL-6-treated Hep3B cells that binds specifically to the IL-6-responsive element (IL6-RE) of the human HO gene. These findings suggest that HO is a positive acute-phase reactant in this human liver-derived cell line, and that the nuclear factor specific to the IL6-RE may be involved in the activation of the HO gene after hIL-6 treatment.
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PMID:Heme oxygenase is a positive acute-phase reactant in human Hep3B hepatoma cells. 137 18

Cytokines are a group of regulatory and immunomodulatory proteins involved in a number of physiological processes. Various disease states are believed to involve alteration of normal cytokine activity, including insulin-dependent diabetes mellitus, an autoimmune disease in which insulin secreting beta cells within pancreatic islets of Langerhans are selectively destroyed. Glucose-induced insulin secretion is inhibited by the cytokines interleukin-1 beta (IL-1 beta), interleukin-6 and tumour necrosis factor alpha (TNF) when combined with IL-1 beta in cultured rat islets, by IL-1 beta, TNF and interferon gamma in mouse islets, and by combined treatment of IL-1 beta, TNF and interferon gamma in human islets. Continued cytokine treatment in many cases leads to destruction of some, if not all, islet cells. A key factor in the inhibitory effect of IL-1 beta and TNF in rat islets is the generation of nitric oxide which inactivates enzymes such as aconitase and ribonucleotide reductase by formation of iron-nitrosyl complexes. This in turn may lead to reduced oxidation of glucose and synthesis of ATP and DNA respectively. The causes of cytokine-induced beta cell death are less well defined, but important factors may be nitric oxide-mediated DNA damage, depletion of NAD levels and toxic effects of oxygen free radicals and eicosanoids generated in addition to nitric oxide. Potentially important defence and repair responses induced by IL-1 beta treatment of rat islets are formation of heat shock protein, haem oxygenase, and superoxide dismutase. Other protective responses may be induction of cytokines and cytokine receptor antagonists.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Cytokines, nitric oxide and insulin secreting cells. 775 73

The effects of interleukin-6 (IL-6), the major inducer of the acute-phase reaction, on the expression of cytochrome P450IA1 (CYPIA1) were examined using human HepG2 hepatoma cells. Treatment of cells with IL-6 decreased the level of 3-methylcholanthrene-induced CYPIA1 protein and its mRNA. Nuclear runoff analysis revealed that the effect of IL-6 was largely transcriptional. IL-6 treatment of HepG2 cells increased mRNA for microsomal heme oxygenase, the rate-limiting enzyme in heme catabolism, suggesting that the suppressive effect of IL-6 on CYPIA1 mRNA may be due to a loss of heme. Consistent with this hypothesis, simultaneous treatment of cells with Sn-mesoporphyrin, an inhibitor of heme oxygenase, prevented the IL-6-mediated suppression of CYPIA1. These findings suggest that the suppression of P450IA1 mRNA by IL-6 appears to occur, at least in part, from the decline in free heme content as a result of the induction of heme oxygenase. Our results raise the possibility that other physiological as well as environmental stimuli which affect cellular heme concentrations may also modulate the expression of P450s.
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PMID:Suppression of cytochrome P450IA1 by interleukin-6 in human HepG2 hepatoma cells. 816 48

Effect of recombinant human interleukin-11 (rhIL-11) on the expression of transcripts encoding microsomal heme oxygenase (HO), the rate-limiting enzyme in heme catabolism, and haptoglobin (Hpt), a major acute-phase protein, were examined in human HepG2 hepatoma cells. Treatment of HepG2 cells with rhIL-11 elicited an increase in HO mRNA in a dose- and a time-dependent fashion. The dose response curve, its magnitude of response and its time course were similar to those observed with recombinant human interleukin-6 (rhIL-6). In contrast, rhIL-11 had a far smaller effect on the level of Hpt mRNA than did rhIL-6. These findings demonstrate that the two cytokines are similar in regulating heme catabolism, while markedly different in inducing certain acute-phase proteins.
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PMID:Effect of interleukin-11 on the levels of mRNAs encoding heme oxygenase and haptoglobin in human HepG2 hepatoma cells. 850 20

Ozone (O(3)) and nitrogen dioxide (NO(2)) are highly reactive and toxic oxidant pollutants. The objective of this study is to compare chemokine, cytokine, and antioxidant changes elicited by acute exposures of O(3) and NO(2) in a genetically sensitive mouse. Eight-week-old C57Bl/6J mice were exposed to 1 or 2.5 ppm ozone or 15 or 30 ppm NO(2) for 4 or 24 h. Changes in mRNA abundance in lung were assayed by slot blot and ribonuclease protection assay (RPA). Messages encoding metallothionein (Mt), heme oxygenase I (HO-I), and inducible nitric oxide synthase (iNOS) demonstrated increased message abundance after 4 and 24 h of exposure to either O(3) or NO(2). Furthermore, increases in message abundance were of a similar magnitude for O(3) and NO(2). Messages encoding eotaxin, macrophage inflammatory protein (MIP)-1alpha, and MIP-2 were elevated after 4 and 24 h of exposure to 1 ppm ozone. Interleukin-6 was elevated after 4 h of exposure to ozone. After 4 h of 2.5 ppm ozone exposure, increased mRNAs of eotaxin, MIP-1alpha, MIP-2, Mt, HO-I, and iNOS were elevated to a higher magnitude than were detected after 1 ppm ozone. Monocyte chemoattractant protein (MCP-1) was elevated following 15 ppm NO(2) exposure. After 4 h of 30 ppm NO(2) exposure, messages encoding eotaxin, MIP-1alpha, MIP-2, and MCP-1 were elevated to levels similar to those detected after ozone exposure. Our results demonstrate a similar antioxidant and chemokine response during both O(3) and NO(2) exposure. Induction of these messages is associated with the duration and concentration of exposure. These studies suggest that these gases exert toxic action through a similar mechanism.
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PMID:Antioxidant and inflammatory response after acute nitrogen dioxide and ozone exposures in C57Bl/6 mice. 1071 24

Reactive oxygen species are thought to be involved in the pathogenesis of septic multiple organ dysfunction syndrome (MODS). It has been reported that heme oxygenase-1 (HO-1) (EC 1.14.99.3) is induced in septic animal models and is thought to confer protection against oxidative tissue injury. In this study, we examined changes in gene expression of HO-1 and non-specific delta-aminolevulinate synthase (ALAS-N) (EC 2.3.1.37), the rate-limiting enzymes in heme catabolism and heme synthesis, respectively, after intraperitoneal administration of bacterial lipopolysaccharide (LPS) to rats. LPS treatment caused the elevation of body temperature, increases in white blood cell counts, and marked elevation of serum interleukin-6 levels associated with liver, lung, and kidney injuries, characteristic of septic MODS. LPS administration significantly induced HO-1 mRNA, protein, and enzyme activity in the liver, lung, and kidney. In contrast, ALAS-N mRNA was decreased rapidly in the liver, followed by an oscillating recovery pattern. Induction of hepatic HO-1 mRNA and rapid suppression of ALAS-N mRNA were likely the result of a rapid increase in hepatic free heme concentration as judged by the increase in heme saturation of tryptophan pyrrolase. In contrast to that in the liver, the ALAS-N mRNA level in the lung and kidney was increased significantly after LPS administration, suggesting a novel mechanism of ALAS-N regulation in these tissues. These findings suggest that HO-1 and ALAS-N mRNA are regulated in a tissue-specific manner in a rat model of septic MODS.
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PMID:Tissue-specific gene expression of heme oxygenase-1 (HO-1) and non-specific delta-aminolevulinate synthase (ALAS-N) in a rat model of septic multiple organ dysfunction syndrome. 1082 73

We investigated the effect of N-acetyl-l-cysteine (NAC) on the expression of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase, antioxidant enzymes, and inflammatory markers in diabetic rat hearts. Metabolic parameters, free 15-F(2t)-isoprostane level, protein expression of NADPH oxidase, superoxide dismutase (SOD), heme oxygenase (HO-1), interleukin-6 (IL-6), and cyclooxygenase-2 (COX-2) were analyzed in control and streptozotocin-induced diabetic rats treated with or without NAC in drinking water for 8 wk. The cardiac protein expression of p67(phox) and p22(phox) was increased in diabetic rats, accompanied by increased NADPH-dependent superoxide production. As a compensatory response to the increased NADPH oxidase, the protein expression of Cu-Zn-SOD and HO-1 and the total SOD activity were also increased in diabetic rat hearts. Consequently, cardiac free 15-F(2t)-isoprostane, an index of oxidative stress, was increased in diabetic rats, indicating that the production of reactive oxygen species becomes excessive in diabetic rat hearts. Cardiac inflammatory markers IL-6 and COX-2 were also increased in diabetic rats. NAC treatment prevented the increased expression of p22(phox) and translocation of p67(phox) to the membrane in diabetic rat hearts. Subsequently, the levels of cardiac free 15-F(2t)-isoprostane, HO-1, Cu-Zn-SOD, total SOD, IL-6, and COX-2 in diabetic rats were decreased by NAC. Consequently, cardiac hypertrophy was attenuated in diabetic rats treated with NAC. The protective effects of NAC on diabetic rat hearts may be attributable to its protection of hearts against oxidative damage induced by the increased NADPH oxidase and to its reduction in cardiac inflammatory mediators IL-6 and COX-2.
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PMID:Downregulation of NADPH oxidase, antioxidant enzymes, and inflammatory markers in the heart of streptozotocin-induced diabetic rats by N-acetyl-L-cysteine. 1712 89

We previously described the physicochemical characteristics (particle size, adsorbed polynuclear aromatic hydrocarbons [PAHs], oxygen, and metal content) of butadiene soot (BDS) nanoparticles generated during incomplete combustion of the high-volume industrial petrochemical, 1,3-butadiene. We also demonstrated localization of BDS-delivered PAHs to lipid droplets of murine and human respiratory cells in vitro and up-regulation of biotransformation and oxidative stress responses in these cells. Here, the objective was to determine whether inhalation of BDS nanoparticles promotes up-regulation of Phase I biotransformation enzymes, oxidative stress responses, and inflammation in the lungs of mice. Female Balb/c mice exposed to BDS (5 mg/m(3), 4 h/d, 4 d) were killed immediately or 1 day after final exposure; bronchoalveolar lavage fluid (BALF) was collected from the lungs; total RNA was extracted from one lung and histopathology performed on the other. Histopathology and BALF analysis revealed particle-laden macrophages in airways of BDS-treated mice, accompanied by neutrophilia and epithelial damage. Microarray and qRT-PCR analyses revealed up-regulation of (1) aryl hydrocarbon receptor (AhR)-responsive genes: AhR repressor (Ahrr) and cytochrome P450 IA1 and IB1(Cyp1a1, Cyp1b1); (2) oxidative stress response genes: heme oxygenase 1 (Hmox1), nuclear factor erythroid-derived 2-like 2 (Nfe2l2), NADPH dehydrogenase quinone 1 (Nqo1), and glutathione peroxidase 2 (Gpx2); and (3) pro-inflammatory genes: interleukin-6 (IL-6), C-X-C motif ligand 2 (Cxcl2; analog to human IL-8) and ligand 3 (Cxcl3), and granulocyte chemotactic protein (Cxcl6). Inhalation of PAH-rich, petrochemical combustion-derived nanoparticles causes airway inflammation and induces expression of AhR-associated and oxidative stress response genes, as seen in vitro, plus pro-inflammatory genes.
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PMID:Soot nanoparticles promote biotransformation, oxidative stress, and inflammation in murine lungs. 1836 23

We previously reported that interleukin-6 (IL-6) was locally produced in the early period after intraperitoneal (i.p.) or subcutaneous carbon tetrachloride (CCl4) administration, but not after oral (p.o.) administration. In the present study, we focused on the up-regulation of stress-inducible proteins induced by IL-6 after i.p. CCl4 administration. The expression of heme oxygenase-1 (HO-1) (EC 1.14.99.3) mRNA and protein were induced more in rats administered CCl4 via the i.p. route, compared with the p.o. route; however, expression of heat shock protein (HSP) 72 and HSP90 mRNA were increased to similar extents in both experimental groups. The induction of HO-1 mRNA and protein after i.p. CCl4 administration were significantly reduced after pretreatment with anti-rat IL-6 antibody. Activation of the signal transducer and activator of transcription factor 3 (STAT3), which promotes HO-1 expression, peaked together with plasma levels of IL-6 after i.p. CCl4 administration, suggesting that hepatic HO-1 expression was increased by IL-6 via the Janus kinase/STAT3 pathway. The present data indicate that hepatic HO-1 is up-regulated by endogenously produced IL-6, in addition to its up-regulation by heme derived from cytochrome P450 which has already been reported in rats administered i.p. CCl4. The up-regulation of hepatic HO-1 expression may reduce the tissue injury to livers caused by CCl4.
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PMID:Up-regulation of hepatic heme oxygenase-1 expression by locally induced interleukin-6 in rats administered carbon tetrachloride intraperitoneally. 1854 52

Metallothionein (MT) is a free radical scavenger induced by inflammatory stimuli; however, its roles in inflammation have not been fully investigated. In the present study, we genetically determined the role of MT in ozone (O(3))-induced lung inflammation using MT-I/II null (-/-) mice. Subacute (65 h) exposure to O(3) (0.3 ppm) induced lung inflammation and enhanced vascular permeability, which was significantly greater in MT(-/-) than in corresponding wild-type mice. Electron microscopically, O(3) exposure induced vacuolar degeneration of pulmonary endothelial and epithelial cells, and interstitial edema with focal loss of the basement membrane, which was more prominent in MT(-/-) than in wild-type mice. O(3) -induced lung expression of interleukin-6 was significantly greater in MT(-/-) than in wild-type mice; however, lung expression of the chemokines examined was comparable in both genotypes of mice in the presence of O(3). Following O(3) exposure, the formation of oxidative stress-related molecules/adducts, such as heme oxidase-1, inducible nitric oxide synthase, 8-hydroxy-2'-deoxyguanosine, and nitrotyrosine, in the lung was significantly greater in MT(-/-) than in wild-type mice. Collectively, MT protects against O(3)-induced lung inflammation, at least partly, via the regulation of pulmonary endothelial and epithelial integrity and its antioxidative property.
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PMID:Role of metallothionein in lung inflammation induced by ozone exposure in mice. 1892 43


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