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Heme oxygenase-1 dysregulates macrophage polarization and the immune response to Helicobacter pylori.
Gobert AP, Verriere T, Asim M, Barry DP, Piazuelo MB, de Sablet T, Delgado AG, Bravo LE, Correa P, Peek RM, Chaturvedi R, Wilson KT
(2014) J Immunol 193: 3013-22
MeSH Terms: Animals, Antigens, Bacterial, Bacterial Proteins, Cell Line, Enzyme Inhibitors, Gastric Mucosa, Gastritis, Helicobacter Infections, Helicobacter pylori, Heme Oxygenase-1, Humans, Imidazoles, Inflammation, Interleukin-10, MAP Kinase Signaling System, Macrophages, Membrane Proteins, Mice, Mice, Inbred C57BL, Mice, Knockout, NF-E2-Related Factor 2, Nitric Oxide Synthase Type II, Phagocytosis, Phosphorylation, Pyridines, Signal Transduction, Stomach, Th1 Cells, Th17 Cells, p38 Mitogen-Activated Protein Kinases
Show Abstract · Added January 20, 2015
Helicobacter pylori incites a futile inflammatory response, which is the key feature of its immunopathogenesis. This leads to the ability of this bacterial pathogen to survive in the stomach and cause peptic ulcers and gastric cancer. Myeloid cells recruited to the gastric mucosa during H. pylori infection have been directly implicated in the modulation of host defense against the bacterium and gastric inflammation. Heme oxygenase-1 (HO-1) is an inducible enzyme that exhibits anti-inflammatory functions. Our aim was to analyze the induction and role of HO-1 in macrophages during H. pylori infection. We now show that phosphorylation of the H. pylori virulence factor cytotoxin-associated gene A (CagA) in macrophages results in expression of hmox-1, the gene encoding HO-1, through p38/NF (erythroid-derived 2)-like 2 signaling. Blocking phagocytosis prevented CagA phosphorylation and HO-1 induction. The expression of HO-1 was also increased in gastric mononuclear cells of human patients and macrophages of mice infected with cagA(+) H. pylori strains. Genetic ablation of hmox-1 in H. pylori-infected mice increased histologic gastritis, which was associated with enhanced M1/Th1/Th17 responses, decreased regulatory macrophage (Mreg) response, and reduced H. pylori colonization. Gastric macrophages of H. pylori-infected mice and macrophages infected in vitro with this bacterium showed an M1/Mreg mixed polarization type; deletion of hmox-1 or inhibition of HO-1 in macrophages caused an increased M1 and a decrease of Mreg phenotype. These data highlight a mechanism by which H. pylori impairs the immune response and favors its own survival via activation of macrophage HO-1.
Copyright © 2014 by The American Association of Immunologists, Inc.
0 Communities
3 Members
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30 MeSH Terms
Haem oxygenase-1 inhibits phosphorylation of the Helicobacter pylori oncoprotein CagA in gastric epithelial cells.
Gobert AP, Verriere T, de Sablet T, Peek RM, Chaturvedi R, Wilson KT
(2013) Cell Microbiol 15: 145-56
MeSH Terms: Antigens, Bacterial, Bacterial Proteins, Cell Line, Epithelial Cells, Helicobacter pylori, Heme Oxygenase-1, Host-Pathogen Interactions, Humans, Oncogene Proteins, Phosphorylation, Protein Processing, Post-Translational
Show Abstract · Added September 3, 2013
The cytotoxin-associated gene A protein (CagA) plays a pivotal role in the aetiology of Helicobacter pylori-associated gastric diseases. CagA is injected into the cytoplasm of host cells by a type IV secretion system, and is phosphorylated on tyrosine residues by the host enzyme c-Src. We previously reported that the enzyme haem oxygenase-1 (HO-1) inhibits IL-8 secretion by H. pylori-infected cells. However, the cellular mechanism by which HO-1 regulates the innate immune function of infected cells remains unknown. We now show that nitric oxide and haemin, two inducers of HO-1, decrease the level of phosphorylated CagA (p-CagA) in H. pylori-infected gastric epithelial cells and this is blocked by either pharmacological inhibition of HO-1 or siRNA knockdown of hmox-1. Moreover, forced expression of HO-1 by transfection of a plasmid expressing hmox-1 also results in a strong attenuation of CagA phosphorylation. This occurs through the inhibition of H. pylori-induced c-Src phosphorylation/activation by HO-1. Consequently, H. pylori-induced cytoskeletal rearrangements and activation of the pro-inflammatory response mediated by p-CagA are inhibited in HO-1-expressing cells. These data highlight a mechanism by which the innate immune response of the host can restrict the pathogenicity of H. pylori by attenuating CagA phosphorylation in gastric epithelial cells.
© 2012 Blackwell Publishing Ltd.
0 Communities
4 Members
0 Resources
11 MeSH Terms
Heme oxygenase-1 gene promoter polymorphism is associated with reduced incidence of acute chest syndrome among children with sickle cell disease.
Bean CJ, Boulet SL, Ellingsen D, Pyle ME, Barron-Casella EA, Casella JF, Payne AB, Driggers J, Trau HA, Yang G, Jones K, Ofori-Acquah SF, Hooper WC, DeBaun MR
(2012) Blood 120: 3822-8
MeSH Terms: Acute Chest Syndrome, Adolescent, Anemia, Sickle Cell, Child, Child, Preschool, Dinucleotide Repeats, Female, Genetic Predisposition to Disease, Heme Oxygenase-1, Hospitalization, Humans, Incidence, Male, Multiplex Polymerase Chain Reaction, Pain, Polymorphism, Genetic, Promoter Regions, Genetic
Show Abstract · Added November 27, 2013
Sickle cell disease is a common hemolytic disorder with a broad range of complications, including vaso-occlusive episodes, acute chest syndrome (ACS), pain, and stroke. Heme oxygenase-1 (gene HMOX1; protein HO-1) is the inducible, rate-limiting enzyme in the catabolism of heme and might attenuate the severity of outcomes from vaso-occlusive and hemolytic crises. A (GT)(n) dinucleotide repeat located in the promoter region of the HMOX1 gene is highly polymorphic, with long repeat lengths linked to decreased activity and inducibility. We examined this polymorphism to test the hypothesis that short alleles are associated with a decreased risk of adverse outcomes (hospitalization for pain or ACS) among a cohort of 942 children with sickle cell disease. Allele lengths varied from 13 to 45 repeats and showed a trimodal distribution. Compared with children with longer allele lengths, children with 2 shorter alleles (4%; ≤ 25 repeats) had lower rates of hospitalization for ACS (incidence rate ratio 0.28, 95% confidence interval, 0.10-0.81), after adjusting for sex, age, asthma, percentage of fetal hemoglobin, and α-globin gene deletion. No relationship was identified between allele lengths and pain rate. We provide evidence that genetic variation in HMOX1 is associated with decreased rates of hospitalization for ACS, but not pain. This study is registered at www.clinicaltrials.gov as #NCT00072761.
1 Communities
1 Members
0 Resources
17 MeSH Terms
Induction of hemeoxygenase-1 reduces glomerular injury and apoptosis in diabetic spontaneously hypertensive rats.
Elmarakby AA, Faulkner J, Baban B, Saleh MA, Sullivan JC
(2012) Am J Physiol Renal Physiol 302: F791-800
MeSH Terms: Animals, Apoptosis, Blood Glucose, Blood Pressure, Diabetes Mellitus, Experimental, Diabetic Nephropathies, Drug Evaluation, Preclinical, Heme Oxygenase-1, Hypertension, Inflammation, Kidney Glomerulus, Male, Nephrosclerosis, Oxidative Stress, Permeability, Proteinuria, Protoporphyrins, Random Allocation, Rats, Rats, Inbred SHR
Show Abstract · Added July 31, 2014
Induction of hemeoxygenase-1 (HO-1) lowers blood pressure and reduces organ damage in hypertensive animal models; however, a potential protective role for HO-1 induction against diabetic-induced glomerular injury remains unclear. We hypothesize that HO-1 induction will protect against diabetes-induced glomerular injury by maintaining glomerular integrity and inhibiting renal apoptosis, inflammation, and oxidative stress. Diabetes was induced with streptozotocin in spontaneously hypertensive rats (SHR) as a model where the coexistence of hypertension and diabetes aggravates the progression of diabetic renal injury. Control and diabetic SHR were randomized to receive vehicle or the HO-1 inducer cobalt protoporphyrin (CoPP). Glomerular albumin permeability was significantly greater in diabetic SHR compared with control, consistent with an increase in apoptosis and decreased glomerular nephrin and α(3)β(1)-integrin protein expression in diabetic SHR. CoPP significantly reduced albumin permeability and apoptosis and restored nephrin and α(3)β(1)-integrin protein expression levels in diabetic SHR. Glomerular injury in diabetic SHR was also associated with increases in NF-κB-induced inflammation and oxidative stress relative to vehicle-treated SHR, and CoPP significantly blunted diabetes-induced increases in glomerular inflammation and oxidative stress in diabetic SHR. These effects were specific to exogenous stimulation of HO-1, since incubation with the HO inhibitor stannous mesoporphyrin alone did not alter glomerular inflammatory markers or oxidative stress yet was able to prevent CoPP-mediated decreases in these parameters. These data suggest that induction of HO-1 reduces diabetic induced-glomerular injury and apoptosis and these effects are associated with decreased NF-κB-induced inflammation and oxidative stress.
0 Communities
1 Members
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20 MeSH Terms
Disruption of nitric oxide signaling by Helicobacter pylori results in enhanced inflammation by inhibition of heme oxygenase-1.
Gobert AP, Asim M, Piazuelo MB, Verriere T, Scull BP, de Sablet T, Glumac A, Lewis ND, Correa P, Peek RM, Chaturvedi R, Wilson KT
(2011) J Immunol 187: 5370-9
MeSH Terms: Animals, Antigens, Bacterial, Bacterial Proteins, Cell Line, Cell Line, Transformed, Gastric Mucosa, Helicobacter pylori, Heme Oxygenase-1, Humans, Inflammation Mediators, Male, Mice, Mice, Inbred C57BL, Nitric Oxide, Signal Transduction, Up-Regulation, Virulence Factors
Show Abstract · Added March 5, 2014
A strong cellular cross-talk exists between the pathogen Helicobacter pylori and high-output NO production. However, how NO and H. pylori interact to signal in gastric epithelial cells and modulate the innate immune response is unknown. We show that chemical or cellular sources of NO induce the anti-inflammatory effector heme oxygenase-1 (HO-1) in gastric epithelial cells through a pathway that requires NF-κB. However, H. pylori decreases NO-induced NF-κB activation, thereby inhibiting HO-1 expression. This inhibitory effect of H. pylori results from activation of the transcription factor heat shock factor-1 by the H. pylori virulence factor CagA and by the host signaling molecules ERK1/2 and JNK. Consistent with these findings, HO-1 is downregulated in gastric epithelial cells of patients infected with cagA(+) H. pylori but not in gastric epithelial cells of patients infected with cagA(-) H. pylori. Enhancement of HO-1 activity in infected cells or in H. pylori-infected mice inhibits chemokine generation and reduces inflammation. These data define a mechanism by which H. pylori favors its own pathogenesis by inhibiting HO-1 induction through the action of CagA.
0 Communities
4 Members
0 Resources
17 MeSH Terms
HO-1 in control of a self-eating kidney.
Kapitsinou PP, Haase VH
(2010) J Am Soc Nephrol 21: 1600-2
MeSH Terms: Acute Kidney Injury, Animals, Autophagy, Heme Oxygenase-1, Kidney Tubules, Proximal
Added February 27, 2014
0 Communities
2 Members
0 Resources
5 MeSH Terms
Peripheral nerve and brain differ in their capacity to resolve N,N-diethyldithiocarbamate-mediated elevations in copper and oxidative injury.
Valentine HL, Viquez OM, Valentine WM
(2010) Toxicology 274: 10-7
MeSH Terms: Animals, Blotting, Western, Brain, Copper, Ditiocarb, Glutathione Transferase, Heme Oxygenase-1, Liver, Male, Mass Spectrometry, Myelin Sheath, Oxidation-Reduction, Oxidative Stress, Peripheral Nerves, Rats, Rats, Sprague-Dawley, Sciatic Nerve, Spinal Cord, Superoxide Dismutase, Superoxide Dismutase-1
Show Abstract · Added May 27, 2014
Previous studies have demonstrated that N,N-diethyldithiocarbamate (DEDC) elevates copper and promotes oxidative stress within the nervous system. However, whether these effects resolve following cessation of exposure or have the potential to persist and result in cumulative injury has not been determined. In this study, an established model for DEDC myelin injury in the rat was used to determine whether copper levels, oxidative stress, and neuromuscular deficits resolve following the cessation of DEDC exposure. Rats were exposed to DEDC for 8 weeks and then either euthanized or maintained for 2, 6 or 12 weeks after cessation of exposure. At each time point copper levels were measured by inductively coupled mass spectrometry to assess the ability of sciatic nerve, brain, spinal cord and liver to eliminate excess copper post-exposure. The protein expression levels of glutathione transferase alpha, heme oxygenase 1 and superoxide dismutase 1 in peripheral nerve and brain were also determined by western blot to assess levels of oxidative stress as a function of post-exposure duration. As an initial assessment of the bioavailability of the excess copper in brain the protein expression levels of copper chaperone for superoxide dismutase 1, and prion protein were determined by western blot as a function of exposure and post-exposure duration. Neuromuscular function in peripheral nerve was evaluated using grip strengths, nerve conduction velocities, and morphologic changes at the light microscope level. The data demonstrated that in peripheral nerve, copper levels and oxidative stress return to control levels within several weeks after cessation of exposure. Neuromuscular function also showed a trend towards pre-exposure values, although the resolution of myelin lesions was more delayed. In contrast, total copper and antioxidant enzyme levels remained significantly elevated in brain for longer post-exposure periods. The persistence of effects observed in brain suggests that the central nervous system is more susceptible to long-term cumulative adverse effects from dithiocarbamates. Additionally, significant changes in expression levels of chaperone for superoxide dismutase 1, and prion protein were observed consistent with at least a portion of the excess copper being bioactive.
2010 Elsevier Ireland Ltd. All rights reserved.
0 Communities
1 Members
0 Resources
20 MeSH Terms
Selenium deficiency activates mouse liver Nrf2-ARE but vitamin E deficiency does not.
Burk RF, Hill KE, Nakayama A, Mostert V, Levander XA, Motley AK, Johnson DA, Johnson JA, Freeman ML, Austin LM
(2008) Free Radic Biol Med 44: 1617-23
MeSH Terms: Animals, Antioxidants, Gene Deletion, Glutathione Transferase, Heme Oxygenase-1, Liver, Male, Membrane Proteins, Mice, Mice, Transgenic, NF-E2-Related Factor 2, Oxidative Stress, Quinone Reductases, Selenium, Vitamin E Deficiency
Show Abstract · Added March 5, 2014
Selenium (Se) and vitamin E are antioxidant micronutrients. Se functions through selenoproteins and vitamin E reacts with oxidizing molecules in membranes. The relationship of these micronutrients with the Nrf2-antioxidant response element (ARE) pathway was investigated using ARE-reporter mice and Nrf2-/- mice. Weanling males were fed Se-deficient (0 Se), vitamin E-deficient (0 E), or control diet for 16 or 22 weeks. The ARE reporter was elevated 450-fold in 0 Se liver but was not elevated in 0 E liver. Antioxidant enzymes induced by Nrf2-ARE (glutathione S-transferase (GST), NAD(P)H quinone oxidoreductase (NQOR), and heme oxygenase-1 (HO-1)) were elevated in 0 Se livers but not in 0 E livers. Deletion of Nrf2 had varying effects on the inductions, with GST induction being abolished by it but induction of NQOR and HO-1 still occurring. Thus, Se deficiency, but not vitamin E deficiency, induces a number of enzymes that protect against oxidative stress and modify xenobiotic metabolism through Nrf2-ARE and other stress-response pathways. We conclude that Se deficiency causes cytosolic oxidative stress but that vitamin E deficiency does not. This suggests that the oxidant defense mechanisms in which these antioxidant nutrients function are independent of one another.
0 Communities
1 Members
0 Resources
15 MeSH Terms
Long-term tolerance to retinal ischemia by repetitive hypoxic preconditioning: role of HIF-1alpha and heme oxygenase-1.
Zhu Y, Zhang Y, Ojwang BA, Brantley MA, Gidday JM
(2007) Invest Ophthalmol Vis Sci 48: 1735-43
MeSH Terms: Animals, Electroretinography, Heme Oxygenase-1, Hypoxia, Hypoxia-Inducible Factor 1, alpha Subunit, Immunoblotting, Immunoenzyme Techniques, Ischemic Preconditioning, Male, Mice, Reperfusion Injury, Retinal Vessels
Show Abstract · Added December 10, 2013
PURPOSE - To determine whether the duration of ischemic tolerance in the retina could be extended by repetitive presentations of the preconditioning stimulus and to begin to elucidate the mechanistic underpinnings of the resultant novel phenotype.
METHODS - Adult male Swiss-Webster ND4 mice were repeatedly preconditioned with systemic hypoxia (RHP) over 12 days; 4 weeks later, the mice were subjected to 30 minutes of unilateral retinal ischemia. Protection was quantified morphologically and functionally 1 week after ischemia by histologic analyses and scotopic electroretinography, respectively. Temporal expression patterns of hypoxia-inducible factor (HIF)-1alpha and heme oxygenase (HO)-1 were measured in response to RHP and after retinal ischemia by immunoblot analysis and immunohistochemistry.
RESULTS - Morphologic and functional protection against ischemia-induced reductions in retinal layer thicknesses and layer cell counts, and a- and b-wave amplitudes, was documented for at least 4 weeks after RHP. There was no evidence of tissue injury or dysfunction by RHP alone. Temporally associated with this period of long-term tolerance (LTT) to retinal ischemia were sustained increases in retinal levels of HIF-1alpha and HO-1 protein lasting at least 1 and 4 weeks, respectively, after the last RHP stimulus.
CONCLUSIONS - A novel form of sustained retinal ischemic tolerance is described, wherein endogenous adaptive responses triggered by repeated hypoxia afford protection against injury many weeks after the preconditioning stimulus. HIF-1alpha-mediated, long-lasting increases in retinal HO-1 expression may contribute to the LTT phenotype. Further elucidation of the genetic and molecular basis of such adaptive plasticity could provide therapeutic targets for preventing and/or treating a variety of ischemic retinopathies.
0 Communities
1 Members
0 Resources
12 MeSH Terms
Selective induction of liver parenchymal cell heme oxygenase-1 in selenium-deficient rats.
Mostert V, Hill KE, Ferris CD, Burk RF
(2003) Biol Chem 384: 681-7
MeSH Terms: Animals, Blotting, Northern, Cell Nucleus, Electrophoretic Mobility Shift Assay, Endothelial Cells, Enzyme Induction, Heme Oxygenase (Decyclizing), Heme Oxygenase-1, Hepatocytes, Immunohistochemistry, Isoenzymes, Kupffer Cells, Liver, Male, Phenobarbital, RNA, Messenger, Rats, Rats, Sprague-Dawley, Selenium, Tissue Distribution
Show Abstract · Added March 5, 2014
Liver heme oxygenase (HO) activity is higher in selenium-deficient rats than in control animals under basal conditions and is further increased in them, but not in controls, by phenobarbital treatment. In the present study we characterized liver HO induction by selenium deficiency using molecular methods. Severe selenium deficiency in rats caused a doubling of liver HO activity without affecting spleen, kidney, brain, or testis HO activities. HO-1 protein and mRNA were increased to accompany the increased HO activity, but HO-2 protein and mRNA were not increased. Fractionation of the liver into hepatocyte and Kupffer cell/endothelial cell fractions revealed that the increased HO activity resides in the hepatocyte fraction. Immunohistochemical localization of HO-1 protein confirms the induction of HO-1 taking place solely in hepatocytes and throughout the liver lobule. Phenobarbital treatment sharply increased HO-1 mRNA and protein expression in selenium-deficient liver and HO activity in hepatocytes, but had no effect in control liver or in the Kupffer cell/endothelial cell fraction of selenium-deficient liver. Electrophoretic mobility shift assays showed increased AP-1 binding activity, suggesting an involvement of this redox-sensitive transcription factor in the induction by phenobarbital of HO-1 in selenium deficiency. We speculate that selenium deficiency affects hepatic antioxidant selenoproteins, resulting in an up-regulation of HO-1.
0 Communities
1 Members
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20 MeSH Terms