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)

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

Linkage maps of rat chromosomes 15, 16, 17, 19, and X were constructed by multipoint genetic linkage analysis of 22 polymorphic markers in 40 F2 progeny of Fischer (F344/N) and Lewis (LEW/N) inbred rat strains. These markers are associated with eight genes (angiotensin receptor A, M3 muscarinic acetylcholine receptor, heme oxygenase, endothelin receptor A, haptoglobin, tyrosine aminotransferase, phosphoribosylpyrophosphate synthetase subunit II, and 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase) and 14 anonymous loci. Linkage analysis placed the markers into five linkage groups covering 11.7,7.9,11.6,42.5, and 5.1cM. These linkage groups were assigned to rat chromosomes 15, 16, 17, 19, and X, respectively, either by mouse x rat somatic cell hybrid analysis or based on previously identified locations of severalloci. In polymorphism analysis, these markers exhibited two to nine different alleles in 16 inbred rat strains.
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PMID:Linkage maps of rat chromosomes 15, 16, 17, 19, and X. 878 96

Interleukin 11 (IL-11) is a pleiotropic cytokine with biological activities on many different cell types. Recombinant human IL-11 (rhIL-11) is produced by recombinant DNA technology in Escherichia coli. Both in vitro and in vivo, rhIL-11 has shown effects on multiple hematopoietic cell types. Its predominant in vivo hematopoietic activity is the stimulation of peripheral platelet counts in both normal and myelosuppressed animals. This activity is mediated through effects on both early and late progenitor cells to stimulate megakaryocyte differentiation and maturation. rhIL-11 has been approved for the treatment of chemotherapy-induced thrombocytopenia. The hematopoietic effects of rhIL-11 are most likely direct effects on progenitor cells and megakaryocytes in combination with other cytokines or growth factors. rhIL-11 also induces secretion of acute phase proteins (ferritin, haptoglobin, C-reactive protein, and fibrinogen) from the liver. The induction of heme oxidase and inhibition of several P450 oxidases have been reported from in vitro studies. In vivo, rhIL-11 treatment decreases sodium excretion by the kidney by an unknown mechanism and induces hemodilution. rhIL-11 also exhibits anti-inflammatory effects in a variety of animal models of acute and chronic inflammation, including inflammatory bowel disease, inflammatory skin disease, autoimmune joint disease, and various infection-endotoxemia syndromes. rhIL-11 has trophic effects on non-transformed intestinal epithelium under conditions of mucosal damage. The mechanism of the anti-inflammatory activity of rhIL-11 has been extensively studied. rhIL-11 directly affects macrophage and T cell effector function. rhIL-11 inhibits tumor necrosis factor-alpha (TNF alpha), interleukin 1beta (IL-1beta), interleukin 12 (IL-12), interleukin 6 (IL-6), and nitric oxide (NO) production from activated macrophages in vitro. The inhibition of cytokine production was associated with inhibition of nuclear translocation of the transcription factor, nuclear factor kappa B (NF-kappaB). The block to NF-kappaB nuclear translocation correlates with the ability of rhIL-11 to maintain or enhance production of the inhibitors of NF-kappaB, IkappaB-alpha and IkappaB-beta. In addition to effects on macrophages, rhIL-11 also reduces CD4+ T cell production of Th1 cytokines, such as IFN gamma induced by IL-12, while enhancing Th2 cytokine production. rhIL-11 also blocks IFN gamma production in vivo. The molecular effects of rhIL-11 have also been studied in a clinical trial. Molecular analysis of skin biopsies of patients with psoriasis before and during rhIL-11 treatment demonstrates a decrease in mRNA levels of TNF alpha, IFN gamma and iNOS. These activities suggest that in addition to its thrombopoietic clinical use, rhIL-11 may also be valuable in the treatment of inflammatory diseases. The clinical utility of the anti-inflammatory properties of rhIL-11 is being investigated in patients with Crohn's disease, psoriasis and rheumatoid arthritis. These diseases are believed to be initiated and maintained by activated CD4+ Th1 cells in conjunction with activated macrophages.
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PMID:Hematopoietic, immunomodulatory and epithelial effects of interleukin-11. 1048 79

Gram-negative pathogenic bacteria have evolved novel strategies to obtain iron from host haem-sequestering proteins. These include the production of specific outer membrane receptors that bind directly to host haem-sequestering proteins, secreted haem-binding proteins (haemophores) that bind haem/haemoglobin/haemopexin and deliver the complex to a bacterial cell surface receptor and bacterial proteases that degrade haem-sequestering proteins. Once removed from haem-sequestering proteins, haem may be transported via the bacterial outer membrane receptor into the cell. Recent studies have begun to define the steps by which haem is removed from bacterial haem proteins and transported into the cell. This review describes recent work on the discovery and characterization of these systems. Reference is also made to the transport of haem in serum (via haemoglobin, haemoglobin/haptoglobin, haemopexin, albumin and lipoproteins) and to mechanisms of iron removal from the haem itself (probably via a haem oxygenase pathway in which the protoporphyrin ring is degraded). Haem protein-receptor interactions are discussed in terms of the criteria that govern protein-protein interactions in general, and connections between haem transport and the emerging field of metal transport via metallochaperones are outlined.
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PMID:Emerging strategies in microbial haem capture. 1112 83

This article describes the first autopsy case of heme oxygenase (HO)-1 deficiency. A 6-year-old boy who presented with growth retardation; anemia; leukocytosis; thrombocytosis; coagulation abnormality; elevated levels of haptoglobin, ferritin, and heme in serum; a low serum bilirubin concentration; and hyperlipidemia was diagnosed as HO-1 deficient by gene analysis several months before death. Autopsy showed amyloid deposits in the liver and adrenal glands and mesangioproliferative glomerular changes in kidneys, in addition to an irregular distribution of foamy macrophages with iron pigments. Fatty streaks and fibrous plaques were noted in the aorta. Compared with HO-1--targeted mice, the present case seems to more severely involve endothelial cells and the reticuloendothelial system, resulting in intravascular hemolysis, disseminated intravascular coagulation, and amyloidosis with a short survival. This contrasts to the predominant iron metabolic disorders of HO-1--targeted mice with a long survival.
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PMID:Heme oxygenase-1 deficiency: the first autopsy case. 1182 83

Haptoglobin (Hp), a conserved plasma glycoprotein, forms very stable soluble complexes with free plasma haemoglobin. Haemoglobin binding by haptoglobin is thought to be important in the rapid hepatic clearance of haemoglobin from the plasma and in the inhibition of glomerular filtration of haemoglobin. It is thought to reduce haemoglobin-induced renal damage during haemolysis. To evaluate these functions, Hp knockout (Hp-/-) mice were created. The Hp-/- mouse was generated by a standard gene replacement technique in mouse embryonic stem cells. These mice were evaluated with and without haemolysis using several parameters: mortality, haemoglobin clearance, renal tissue damage and function. Hp-/- mice were viable but had a small, significant reduction in postnatal viability. The lack of Hp did not impair clearance of free plasma haemoglobin. Induction of severe haemolysis by phenylhydrazine caused extensive haemoglobin precipitation in the renal tubular cells. However, haemoglobin precipitation in the kidney was not increased in Hp-/- mice. Nevertheless, Hp-/- mice were more susceptible to phenylhydrazine with a mortality rate of 55% in Hp-/- mice versus 18% in Hp+/+ mice. In general, phenylhydrazine-treated Hp-/- mice suffered greater tissue damage, as evidenced by the induction of a hepatic acute phase response, resulting in increased plasma alpha1-acidic glycoprotein (AGP) levels and higher plasma malonaldehyde (MDA) and 4-hydroxy-2(E)-nonenal (HNE) levels. Gross pathological analysis indicated that the kidney was the most affected tissue in phenylhydrazine-treated Hp-/- and Hp+/+ mice, and Hp-/- mice were more severely affected. They had lower mitotic indices in their kidneys, higher basal levels of renal lipid peroxidation, as evidenced by levels of malonaldehyde and 4-hydroxy-2(E)-nonenal (MDA/HNE) and elevated levels of 8-hydroxyguanine (but not other products of oxidative DNA damage). There also was increased induction of haem oxygenase-1. The more severe renal damage in Hp-/- mice was also evident in the delayed erythropoietin gene expression and poorer renal clearance of [3H]-inulin. The reduction in glomerular filtration function in Hp+/+ and Hp-/- mice could be restored to baseline by vasodilators (prazosin or diazoxide), implicating renal vasoconstriction as a major mechanism of acute renal failure during induced haemolysis. These data suggest that Hp plays a pivotal role in reducing renal oxidative damage during haemolysis.
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PMID:Consequences of haemolysis without haptoglobin. 1186 80

The heme-heme oxygenase system has recently been recognized to possess important regulatory properties. It is tightly involved in both physiological as well as pathophysiological processes, such as cytoprotection, apoptosis, and inflammation. Heme functions as a double-edged sword. In moderate quantities and bound to protein, it forms an essential element for various biological processes, but when unleashed in large amounts, it can become toxic by mediating oxidative stress and inflammation. The effect of this free heme on the vascular system is determined by extracellular factors, such as hemoglobin/heme-binding proteins, haptoglobin, albumin, and hemopexin, and intracellular factors, including heme oxygenases and ferritin. Heme oxygenase (HO) enzyme activity results in the degradation of heme and the production of iron, carbon monoxide, and biliverdin. All these heme-degradation products are potentially toxic, but may also provide strong cytoprotection, depending on the generated amounts and the microenvironment. Pre-induction of HO activity has been demonstrated to ameliorate inflammation and mediate potent resistance to oxidative injury. A better understanding of the complex heme-heme
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PMID:Different faces of the heme-heme oxygenase system in inflammation. 1286 63

CD163 is a hemoglobin scavenger receptor exclusively expressed in the monocyte-macrophage system. A particularly high expression is seen in macrophages of the 'alternative activation' phenotype playing a major role in dampening the inflammatory response and in scavenging components of damaged cells. CD163-mediated endocytosis of haptoglobin-hemoglobin complexes formed upon red blood cell hemolysis leads to lysosomal degradation of the ligand protein and metabolism of heme by cytosolic heme oxygenase. In accordance with a stimulated expression of haptoglobin, CD163 and heme oxygenase-1 during the acute phase response, there is evidence that this metabolic pathway regulates inflammation by at least two ways. First, CD163 is reported to directly induce intracellular signaling leading to secretion of anti-inflammatory cytokines. Second and perhaps even more important, the CD163-mediated delivery of hemoglobin to the macrophage may fuel an anti-inflammatory response because heme metabolites have potent anti-inflammatory effects. In addition to being present on the macrophage surface, continuous shedding of the extracellular domain of CD163 leads to substantial amounts of soluble receptor in plasma. An increased shedding is due to inflammatory stimuli, and a role for soluble CD163 in immune suppression has been proposed. Furthermore, recent data indicate that soluble CD163 may be a valuable diagnostic parameter for monitoring macrophage activation in inflammatory conditions.
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PMID:CD163: a regulated hemoglobin scavenger receptor with a role in the anti-inflammatory response. 1547 9

Many reports have stated that some of the pathogenic bacteria can obtain iron from ferroproteins, such as cytochrome C, ferritin, hemin, hemoglobin, and myoglobin. These reports prompted us to determine if an opportunistic pathogenic fungus, Candida albicans, can utilize ferroproteins to circumvent the iron-regulatory effect of transferrin. The following assays were carried out to measure in vitro growth stimulation by the ferroproteins: as an initial step, C. albicans was cultured in iron-free (pretreated with apotransferrin for 24 h) culture medium. Once Candida albicans yeast cell growth reached stasis from iron starvation, individual ferroproteins were added to the culture media. Results showed that hemin, hemoglobin, and myoglobin supported a partial growth recovery. Additional studies with haptoglobin, a serum protein that interacts with the globin moiety of certain ferroproteins, established that C. albicans could obtain iron from the haptoglobin-ferroprotein complexes. These data indicate that the heme part of the ferroproteins is the source of iron. This implies that heme oxygenase, CaHMX1 might be involved in bringing about dissociation of heme-containing protein for iron-acquisition. In addition, anticandidal activity of transferrin takes place not only by the process of iron regulation, but also by direct interaction with the yeast cells.
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PMID:Utilization of ferroproteins by Candida albicans during candidastasis by apotransferrin. 1617 24

Transgenic sickle mice expressing betaS hemoglobin have activated vascular endothelium that exhibits enhanced expression of NF-kappaB and adhesion molecules that promote vascular stasis in sickle, but not in normal, mice in response to hypoxia/reoxygenation. Sickle mice hemolyze rbcs in vivo as demonstrated by increased reticulocyte counts, plasma hemoglobin and bilirubin, and reduced plasma haptoglobin. The heme content is elevated in sickle organs, which promotes vascular inflammation and heme oxygenase-1 expression. Treatment of sickle mice with hemin further increases heme oxygenase-1 expression and inhibits hypoxia/reoxygenation-induced stasis, leukocyte-endothelium interactions, and NF-kappaB, VCAM-1, and ICAM-1 expression. Heme oxygenase inhibition by tin protoporphyrin exacerbates stasis in sickle mice. Furthermore, treatment of sickle mice with the heme oxygenase enzymatic product carbon monoxide or biliverdin inhibits stasis and NF-kappaB, VCAM-1, and ICAM-1 expression. Local administration of heme oxygenase-1 adenovirus to subcutaneous skin increases heme oxygenase-1 and inhibits hypoxia/reoxygenation-induced stasis in the skin of sickle mice. Heme oxygenase-1 plays a vital role in the inhibition of vaso-occlusion in transgenic sickle mice.
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PMID:Heme oxygenase-1 is a modulator of inflammation and vaso-occlusion in transgenic sickle mice. 1648 41


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