Myeloperoxidase-derived Hypochlorous Acid Antagonizes the Oxidative Stress-mediated Activation of Iron Regulatory Protein 1

Mütze, Sebastian; Hebling, Ulrike; Stremmel, Wolfgang; Wang, Jian; Arnhold, Jürgen; Pantopoulos, Kostas; Mueller, Sebastian

doi:10.1074/jbc.m307159200

Cited by 81 publications

(59 citation statements)

References 53 publications

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“…In Spearman's partial rank-order analysis (Table 4), Fe level correlated significantly (negatively) with Al-S of smelters (in active smokers) and positively with Al-U (in nonsmokers), confirming the effect of Al and Fe competition with transferrin (a transfer ligand) in serum [79,80]. In our study, we noted a negative correlation between IgE, MPO and Fe levels in non-smoking smelters, while dislocation of iron in chronic inflammation may be an additional factor affecting serum transferrin iron level [81] (Table 4). Al affects various stages of heme biosynthesis by changing the activity of some enzymes [82][83][84][85], iron metabolism [86][87][88][89] or disrupting erythrocyte membrane [90].…”

Section: Ijomeh 2006;19(4)supporting

confidence: 64%

Serum Clara Cell Protein as an Indicator of Pulmonary Impairment in Occupational Exposure at Aluminum Foundry

Hałatek¹,

Trzcinka-Ochocka²,

Matczak³

et al. 2006

International Journal of Occupational Medicine and Environmental Health

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Objectives: Although some of the exposures in aluminum (Al) smelting have been well characterized, and respiratory disorders in aluminum production workers are well known, the relationship between internal aluminum loads and appropriate lung biomarkers have not been elucidated. The aim of our work was to carry out a comprehensive investigation in workers employed in the Aluminum Foundry Casting Department with special reference to currently existing hygiene standards, known as threshold limit values (TLV) based on aluminum effects on the respiratory system. The measurement of serum anti-inflammatory Clara cell protein (CC16) was employed as a peripheral marker of the lung epithelium function. Materials and Methods: A group of 50 casting smelters, 5 locksmiths, 11 sawyers and auxiliary workers exposed to dust containing 14% of aluminum, and a group of 42 controls were examined. Respiratory function tests were performed and forced volume capacity (FVC), forced expiratory volume in 1 s (FEV 1 ), forced expiratory volume in the first percent (FEV 1 %), forced expiratory flows in 50% VC (FEV 50 ), and markers of foundry workers' exposure and body burden, Al concentration in the breathing zone, blood and urine, biomarkers of the effects of exposure, concentration of CC16 and hyaluronic acid (HA) in serum were determined in all examined workers. Additional measurements comprised determinations of serum iron (Fe) levels, myeloperoxidase (MPO), eosinophil cationic protein (ECP), immunoglobulin E (IgE), glutathione S-transferase (GST), and superoxide dismutase (SOD) activity in erythrocytes. Results: The group of casting smelters was characterized by the highest levels of aluminum in urine (Al-U) (43.7 mg L -1 ), high levels of MPO, ECP and IgE, high SOD activity, low CC16 levels, and low activity of GST. Lower Al-U excretion was observed in locksmiths (35.2 mg L -1 ) and sawyers (21.7 mg L -1 ). Serum CC16 proved to be the most sensitive biomarker, showing high inverse relationship with serum Al (Al-S) concentrations in casting smelters (p = 0.006). Conclusions: The study showed that in conditions of occupational exposure, dusts containing Al 2 O 3 < 1 mg m -3 cause changes in the respiratory system and biomarkers in serum, especially in CC16, connected with altered functioning of this system. Changes in concentrations of the examined biomarkers and also in respiratory parameters of the study subjects were observed when Al-U concentration was > 40 mg L -1 .

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Section: Ijomeh 2006;19(4)supporting

confidence: 64%

Serum Clara Cell Protein as an Indicator of Pulmonary Impairment in Occupational Exposure at Aluminum Foundry

Hałatek¹,

Trzcinka-Ochocka²,

Matczak³

et al. 2006

International Journal of Occupational Medicine and Environmental Health

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“…It has been pointed out in in vitro studies that the maximal chemiluminescence intensity produced by MPO in a system with H 2 O 2 and tyrosine increased linearly with increasing H 2 O 2 concentrations [43]. The excess of ROS induced by the half-marathon could activate MPO in both groups, because it has been evidenced that H 2 O 2 is an activator of peroxidases [44,45] The excess in ROS produced by the exercise-activated neutrophils could act by inhibiting the neutrophil inflammatory response in order to avoid oxidative damage and could inhibit MPO synthesis de novo [46]. The drop in neutrophil MPO levels during recovery, probably by the activation of the degranulation process, could explain the decrease in HOCl production.…”

Section: Discussionmentioning

confidence: 99%

Antioxidant supplementation influences the neutrophil tocopherol associated protein expression, but not the inflammatory response to exercise

et al. 2007

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Abstract:Intense exercise induces inflammatory-like changes and oxidative stress in immune cells. Our aim was to study the effects of antioxidant diet supplementation on the neutrophil inflammatory response and on the tocopherol associated protein (TAP) expression after exhaustive exercise. Fourteen male-trained amateur runners were randomly divided in two placebo and supplemented groups. Vitamins C (152 mg/d) and E (50 mg/d) supplementation were administrated to the athletes for a month, using an almond based isotonic and energetic beverage. Non-enriched beverage was given to the placebo group. After one month, the subjects participated in a half-marathon race (21 km-run). Neutrophil TAP mRNA expression and markers of the inflammatory response were determined before, immediately after, and 3 h after finishing the half-marathon race. TAP expression increased after exercise mainly in the neutrophils of the placebo group. Exercise induced an inflammatory response in both placebo and supplemented groups, manifested with neutrophilia, increased creatine kinase and lactate dehydrogenase serum activities, neutrophil luminol chemiluminescence and myeloperoxidase release. Plasma malondialdehyde only increased in the placebo group after exercise. Diet supplementation with moderate levels of antioxidant vitamins avoids plasma damage in response to exhaustive exercise without the effects on the inflammatory process. Neutrophil degranulation and increased tocopherol associated protein could contribute to the neutrophil protection from the oxidative stress.

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“…Fetal calf serum was purchased from Greiner Labortechnik. Stock solutions of luminol, NaOCl, and H 2 O 2 were prepared as described recently (32).…”

Section: Methodsmentioning

confidence: 99%

Sustained Hydrogen Peroxide Induces Iron Uptake by Transferrin Receptor-1 Independent of the Iron Regulatory Protein/Iron-responsive Element Network

Andriopoulos

Hegedüsch

Mangin

et al. 2007

Journal of Biological Chemistry

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Local and systemic inflammatory conditions are characterized by the intracellular deposition of excess iron, which may promote tissue damage via Fenton chemistry. Because the Fenton reactant H 2 O 2 is continuously released by inflammatory cells, a tight regulation of iron homeostasis is required. Here, we show that exposure of cultured cells to sustained low levels of H 2 O 2 that mimic its release by inflammatory cells leads to upregulation of transferrin receptor 1 (TfR1), the major iron uptake protein. The increase in TfR1 results in increased transferrin-mediated iron uptake and cellular accumulation of the metal. Although iron regulatory protein 1 is transiently activated by H 2 O 2 , this response is not sufficient to stabilize TfR1 mRNA and to repress the synthesis of the iron storage protein ferritin. The induction of TfR1 is also independent of transcriptional activation via hypoxia-inducible factor 1␣ or significant protein stabilization. In contrast, pulse experiments with 35 Slabeled methionine/cysteine revealed an increased rate of TfR1 synthesis in cells exposed to sustained low H 2 O 2 levels. Our results suggest a novel mechanism of iron accumulation by sustained H 2 O 2 , based on the translational activation of TfR1, which could provide an important (patho)physiological link between iron metabolism and inflammation.Systemic iron homeostasis undergoes typical changes during inflammatory or infectious conditions. A decrease in plasma iron concentration limits the availability of the metal for erythropoiesis, ultimately leading to the so-called anemia of chronic disease (1). In addition to iron retention within the reticuloendothelial system, parenchymal cells such as hepatocytes also accumulate iron under inflammatory conditions (2-8), and this iron deposition has been identified as an important factor in tissue damage by free radicals (9). In addition, hepatic iron accumulation appears to be an important cofactor in the development of fibrosis and end stage liver disease in such common chronic liver pathologies such as hepatitis C or alcoholic steatohepatitis (4 -8).Significant progress has been made toward understanding the molecular basis of iron retention within the reticuloendothelial system during inflammation (10 -12). The mechanism involves the interleukin-6-mediated induction of the iron-regulatory peptide hepcidin (13, 14), which inhibits iron efflux from macrophages and intestinal enterocytes (15, 16) by binding to and promoting the degradation of the transporter ferroportin 1 (IREG1 or MTP1) (17). The ensuing hypoferremia is thought to be part of a physiological defense strategy to deplete invading bacteria from the growth-essential iron. Thus far, the possibility that inflammation-mediated accumulation of iron in parenchymal cells may also contribute to hypoferremia has not received much attention. Nevertheless, the expression of transferrin receptor 1 (TfR1), 2 the major iron uptake protein, is induced in several models of inflammation (2, 18).Upon activation, inflammatory cells su...

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Myeloperoxidase-derived Hypochlorous Acid Antagonizes the Oxidative Stress-mediated Activation of Iron Regulatory Protein 1

Cited by 81 publications

References 53 publications

Serum Clara Cell Protein as an Indicator of Pulmonary Impairment in Occupational Exposure at Aluminum Foundry

Serum Clara Cell Protein as an Indicator of Pulmonary Impairment in Occupational Exposure at Aluminum Foundry

Antioxidant supplementation influences the neutrophil tocopherol associated protein expression, but not the inflammatory response to exercise

Sustained Hydrogen Peroxide Induces Iron Uptake by Transferrin Receptor-1 Independent of the Iron Regulatory Protein/Iron-responsive Element Network

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