Heme protein-induced chronic renal inflammation: Suppressive effect of induced heme oxygenase-1

Nath, Karl A.; Vercellotti, Gregory M.; Grande, Joseph P.; Miyoshi, Hideyuki; Payá, Carlos V.; Manivel, J. Carlos; Haggard, Jill J.; Croatt, Anthony J.; Payne, William D.; Alam, Jawed

doi:10.1046/j.1523-1755.2001.00471.x

Cited by 200 publications

(199 citation statements)

References 51 publications

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“…The anti-inflammatory roles of HO-1 have been clearly demonstrated in HO-1-deficient mice, which display chronic renal inflammation (Nath et al, 2001) and enhanced secretion of pro-inflammatory cytokines from splenocytes (Kapturczak et al, 2004). We previously demonstrated that in microglia, HO-1 products (bilirubin, ferrous iron, and CO) reduce iNOS expression/NO production in response to IFN-g (Min et al, 2006).…”

Section: Discussionmentioning

confidence: 99%

Adenosine induces hemeoxygenase‐1 expression in microglia through the activation of phosphatidylinositol 3‐kinase and nuclear factor E2‐related factor 2

Min

Kim

Jou

et al. 2008

Glia

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Adenosine, a purine nucleoside, has been reported to suppress the inflammatory responses of microglia in the brain. However, the underlying mechanisms of its anti-inflammatory action are unclear at present. Here we show that adenosine reduces the increase in intracellular reactive oxygen species (ROS) through expression of an antioxidant enzyme, hemeoxygenase-1 (HO-1). The H 2 O 2 -induced intracellular ROS level was significantly low in microglia pretreated with adenosine for 3-6 h, compared with that in untreated cells. Adenosine induced HO-1 mRNA and protein expression within 3 h, which was maintained for up to 12 h. Nuclear factor E2-related factor 2 (Nrf2), a transcription factor, and phosphatidylinositol 3-kinase (PI3K) and Akt pathways appear to mediate HO-1 expression. In response to adenosine, Nrf2 translocated from the cytosol to nuclei, and bound to the antioxidant response element (ARE). Adenosine enhanced HO-1 promoter activity in an ARE-dependent manner. Moreover, the nucleoside stimulated Akt phosphorylation, and suppressors of PI3K (LY294002 and wortmannin) reduced adenosine-induced HO-1 expression. However, we propose that the effects of adenosine are independent of adenosine receptors, since agonists and antagonists of A1, A2a, and A3 had little effect on the regulation of intracellular ROS and HO-1 expression. Our results collectively suggest that adenosine acts as an endogenous regulator of brain inflammation via modulation of microglial ROS production. V

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Section: Discussionmentioning

confidence: 99%

Adenosine induces hemeoxygenase‐1 expression in microglia through the activation of phosphatidylinositol 3‐kinase and nuclear factor E2‐related factor 2

Min

Kim

Jou

et al. 2008

Glia

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“…The anti-inflammatory properties of HO-1 have been described in many disease models (6,10,123,129). HO-1 can dampen the inflammatory response indirectly (i.e., extrinsic to the MPS) by preventing tissue injury and necrotic cell death (i.e., DAMP production).…”

Section: Mp Ho-1 In Tissue Homeostasismentioning

confidence: 99%

The Mononuclear Phagocyte System in Homeostasis and Disease: A Role for Heme Oxygenase-1

Hull

Agarwal

George

2014

Antioxidants & Redox Signaling

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Significance: Heme oxygenase-1 (HO-1) is a potential therapeutic target in many diseases, especially those mediated by oxidative stress and inflammation. HO-1 expression appears to regulate the homeostatic activity and distribution of mononuclear phagocytes ( MP) in lymphoid tissue under physiological conditions. It also regulates the ability of MP to modulate the inflammatory response to tissue injury. Recent Advances: The induction of HO-1 within MP-particularly macrophages and dendritic cells-modulates the effector functions that they acquire after activation. These effector functions include cytokine production, surface receptor expression, maturation state, and polarization toward a pro-or anti-inflammatory phenotype. The importance of HO-1 in MP is emphasized by their expression of specific receptors that primarily function to ingest heme-containing substrate and deliver it to HO-1. Critical Issues: MP are the first immunological responders to tissue damage. They critically affect the outcome of injury to many organ systems, yet few therapies are currently available to specifically target MP during disease pathogenesis. Elucidation of the role of HO-1 expression in MP may help to direct broadly applicable therapies to clinical use that are based on the immunomodulatory capabilities of HO-1. Future Directions: Unraveling the complexities of HO-1 expression specifically within MP will more completely define how HO-1 provides cytoprotection in vivo. The use of models in which HO-1 expression is specifically modulated in bone marrow-derived cells will allow for a more complete characterization of its immunoregulatory properties.

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“…Bilirubin is a powerful physiological antioxidant (3), but is neurotoxic at the high concentrations found in Criggler Najar patients and neonatal jaundice (4). CO, the second product of the reaction, is a gaseous messenger molecule that is thought to be involved in apoptosis (5), atherosclerosis (6), psoriasis (7), vascular constriction (8), cellular protection (9), and chronic renal inflammation (10). Finally, the ferrous iron released by heme oxygenase is normally recycled and serves as the major source of this metal for hemoglobin and other hemoprotein synthesis, as only 1-3% of the iron utilized daily in the synthesis of red blood cells is obtained from the diet (11).…”

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confidence: 99%

Human Heme Oxygenase Oxidation of 5- and 15-Phenylhemes

Wang

Niemevz

Lad

et al. 2004

Journal of Biological Chemistry

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Human heme oxygenase-1 (hHO-1) catalyzes the O 2 -dependent oxidation of heme to biliverdin, CO, and free iron. Previous work indicated that electrophilic addition of the terminal oxygen of the ferric hydroperoxo complex to the ␣-meso-carbon gives 5-hydroxyheme. Earlier efforts to block this reaction with a 5-methyl substituent failed, as the reaction still gave biliverdin IX␣. Surprisingly, a 15-methyl substituent caused exclusive cleavage at the ␥-meso-rather than at the normal, unsubstituted ␣-meso-carbon. No CO was formed in these reactions, but the fragment cleaved from the porphyrin eluded identification. We report here that hHO-1 cleaves 5-phenylheme to biliverdin IX␣ and oxidizes 15-phenylheme at the ␣-meso position to give 10-phenylbiliverdin IX␣. The fragment extruded in the oxidation of 5-phenylheme is benzoic acid, one oxygen of which comes from O 2 and the other from water. The 2.29-and 2.11-Å crystal structures of the hHO-1 complexes with 1-and 15-phenylheme, respectively, show clear electron density for both the 5-and 15-phenyl rings in both molecules of the asymmetric unit. The overall structure of 15-phenylheme-hHO-1 is similar to that of heme-hHO-1 except for small changes in distal residues 141-150 and in the proximal Lys 18 and Lys 22 . In the 5-phenylhemehHO-1 structure, the phenyl-substituted heme occupies the same position as heme in the heme-HO-1 complex but the 5-phenyl substituent disrupts the rigid hydrophobic wall of residues Met 34 , Phe 214 , and residues 26 -42 near the ␣-meso carbon. The results provide independent support for an electrophilic oxidation mechanism and support a role for stereochemical control of the reaction regiospecificity.Heme 1 oxygenase, the rate-limiting enzyme in the heme degradation pathway, oxidizes heme to biliverdin, carbon monoxide, and free iron (1) (Fig. 1). In humans and other mammals, the heme is cleaved exclusively at the ␣-meso position to give biliverdin IX␣. The biliverdin then is reduced to bilirubin by biliverdin reductase before it is conjugated with glucuronic acid and excreted in the bile (2). Bilirubin is a powerful physiological antioxidant (3), but is neurotoxic at the high concentrations found in Criggler Najar patients and neonatal jaundice (4). CO, the second product of the reaction, is a gaseous messenger molecule that is thought to be involved in apoptosis (5), atherosclerosis (6), psoriasis (7), vascular constriction (8), cellular protection (9), and chronic renal inflammation (10). Finally, the ferrous iron released by heme oxygenase is normally recycled and serves as the major source of this metal for hemoglobin and other hemoprotein synthesis, as only 1-3% of the iron utilized daily in the synthesis of red blood cells is obtained from the diet (11). Thus, in addition to its other functions, heme oxygenase plays a vital role in maintaining iron homeostasis.In mammals, there are three heme oxygenase isoforms, namely HO-1, HO-2, and HO-3. HO-1 is inducible and present in highest concentration in spleen and liver. It is a stress pro...

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Heme protein-induced chronic renal inflammation: Suppressive effect of induced heme oxygenase-1

Cited by 200 publications

References 51 publications

Adenosine induces hemeoxygenase‐1 expression in microglia through the activation of phosphatidylinositol 3‐kinase and nuclear factor E2‐related factor 2

Adenosine induces hemeoxygenase‐1 expression in microglia through the activation of phosphatidylinositol 3‐kinase and nuclear factor E2‐related factor 2

The Mononuclear Phagocyte System in Homeostasis and Disease: A Role for Heme Oxygenase-1

Human Heme Oxygenase Oxidation of 5- and 15-Phenylhemes

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