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PubMed1982

Serum alpha-1-acid-glycoprotein, haptoglobin and C3 in Hodgkin's disease. A comparison with other acute-phase indicators.

107 determinations of alpha 1-acid-glycoprotein (alpha 1S), haptoglobin (Hp) and complement fraction 3 (C3) were made in 85 consecutive patients with Hodgkin's disease, both in acute phase (77 measurements) and in complete remission (30 measurements). Only alpha 1S and Hp showed much higher levels in untreated disease than in remission, and elevation of alpha 1S in activity of the disease is correlated to advanced stages and - less significantly - to severe histology. The ability of alpha 1S, Hp and C3 to discriminate between activity and remission was compared with that of erythrocyte sedimentation rate (ESR), alpha 2-globinaemia (alpha 2), fibrinogenaemia (Fb), plasma copper (Cu) and iron (Fe), all data being collected at the same point in time in each patient. The well-known discrimination ability of combined Cu and Fe (75%) can be further improved by alpha 1S (81%) much more than by Hp, C3, ESR, alpha 2 and Fb singly computed and nearly up to the maximum allowed by the eight indexes together (82%).

Acute Disease↗
PubMed1975

Haptoglobin, hemopexin, hemoglobin and hematocrit in newborns with erythrocyte glucose-6-phosphate dehydrogenase deficiency.

Hemolysis was studied in 40 G-6-PD-deficient newborn infants, half of whom had bilirubin blood levels within the normal range whereas the others, who were hyperbilirubinemic, underwent exchange transfusion. Hemoglobin, hematocrit, hemopexin and haptoglobin showed no or little differences between either of the two groups and the controls. The findings confirm the authors' assumption expressed elsewhere that this form of hyperbilirubinemia is not hemolytic in nature.

Bilirubin↗
PubMed1978

Serum haptoglobin levels in mice with 7, 12-dimethylbenz[a]anthracene-induced tumors.

Serum haptoglobin (Hp) levels were determined periodically in mice treated with the carcinogen 7, 12-dimethylbenz[a]anthracene (DMBA). The magnitude and duration of the Hp response to tumors induced by DMBA were dependent on the tumor type; lymphocytic lymphomas elicted a minimal response, whereas mice bearing mammary carcinomas and stomach squamous cell carcinomas had high Hp levels which remained elevated throughout most of the period of tumor development. In the majority of mice with mammary carcinomas, the initial rise in serum Hp coincided fairly closely with the first appearance of palpable masses. Some variation in the magnitude of the Hp response was observed between individual mice bearing chemically-induced tumors of similar histological types.

9,10-Dimethyl-1,2-benzanthracene↗
PubMed1981

Reproducibility of serum haptoglobin profiles in mice with transplanted tumors.

To determine whether the elevation of serum haptoglobin (Hp) elicited by many tumors is associated with properties of the tumor, Hp levels were determined during successive passages of two transplantable fibrosarcomas and two leukemia lines in syngeneic mice. Characteristic and unique profiles were elicited by each of the four tumors and were reproducible in each of three successive transplant generations. The Hp profiles elicited by EL4 leukemia cells were similar in allogeneic and syngeneic mice, except that the Hp maxima were greater in the allogeneic mice. Preimmunization with EL4 cells or pretreatment with immune serum or spleen cells obliterated the Hp response normally elicited by EL4 cells in allogeneic mice. These results suggest that the Hp response elicited by a tumor is associated with transmissible characteristics of the tumor.

Animals↗
PubMed1983

Activation of the complement system and accumulation of hemoglobin-haptoglobin complexes in plasma during an adverse reaction to penicillin treatment.

A patient treated with penicillin intravenously developed a serum sickness-like reaction. Classical pathway complement (C) activation was indicated by quantitation of the split products C3c and C3d as well as demonstration of C4 conversion. Circulating immune complexes could, however, not be detected by the solid-phase Clq and PEG-precipitation methods. A concomitant accumulation of circulating hemoglobin-haptoglobin complexes and a marked fall in serum-fibronectin concentrations suggested saturation of the reticuloendothelial system. The plasma became a deep-red color, and a diffuse intravascular coagulation followed. The patient recovered completely upon discontinuation of penicillin administration.

Antigen-Antibody Complex↗
PubMed2006

Haptoglobin genotype is a determinant of iron, lipid peroxidation, and macrophage accumulation in the atherosclerotic plaque.

OBJECTIVE: Intraplaque hemorrhage increases the risk of plaque rupture and thrombosis. The release of hemoglobin (Hb) from extravasated erythrocytes at the site of hemorrhage leads to iron deposition, which may increase oxidation and inflammation in the atherosclerotic plaque. The haptoglobin (Hp) protein is critical for protection against Hb-induced injury. Two common alleles exist at the Hp locus and the Hp 2 allele has been associated with increased risk of myocardial infarction. We have demonstrated decreased anti-oxidative and anti-inflammatory activity for the Hp 2 protein. We tested the hypothesis that the Hp 2-2 genotype is associated with increased oxidative and macrophage accumulation in atherosclerotic plaques. METHODS AND RESULTS: The murine Hp gene is a type 1 Hp allele. We created a murine type 2 Hp allele and targeted its insertion to the Hp locus by homologous recombination. Atherosclerotic plaques from C57Bl/6 ApoE-/- Hp 2-2 mice were associated with increased iron (P=0.008), lipid peroxidation (4-hydroxynonenal and ceroid) and macrophage accumulation (P=0.03) as compared with plaques from C57Bl/6 ApoE-/- Hp 1-1 mice. CONCLUSIONS: Increased iron, lipid peroxidation and macrophage accumulation in ApoE-/- Hp 2-2 plaques suggests that the Hp genotype plays a critical role in the oxidative and inflammatory response to intraplaque hemorrhage.

Alleles↗
PubMed2006

Haptoglobin genotype is a regulator of reverse cholesterol transport in diabetes in vitro and in vivo.

Two common alleles exist at the haptoglobin (Hp) locus, and the Hp2 allele is associated with an increased incidence of cardiovascular disease, specifically in diabetes mellitus (DM). Oxidative stress is increased in Hp2 mice and humans with DM. Oxidative modification of the apolipoprotein A-I inhibits reverse cholesterol transport. We sought to test the hypothesis that reverse cholesterol transport is impaired in Hp2 DM mice and humans. In vitro, using serum from non-DM and DM individuals, we measured cholesterol efflux from (3)H-cholesterol-labeled macrophages. In vivo, we injected (3)H-cholesterol-loaded macrophages intraperitoneally into non-DM and DM mice with the Hp1-1 or Hp2-2 genotype and monitored (3)H-tracer levels in plasma, liver, and feces. In vitro, in DM individuals only, we observed significantly decreased cholesterol efflux from macrophages incubated with serum from Hp2-1 or Hp2-2 as compared with Hp1-1 individuals (P<0.01). The interaction between Hp type and DM was recapitulated using purified Hp and glycated Hb. In vivo, DM mice loaded with (3)H-cholesterol-labeled macrophages had a 40% reduction in (3)H-cholesterol in plasma, liver, and feces as compared with non-DM mice (P<0.01). The reduction in reverse cholesterol transport associated with DM was significantly greater in Hp2-2 mice as compared with Hp1-1 mice (54% versus 25% in plasma; 52% versus 27% in liver; 57% versus 32% in feces; P<0.03). reverse cholesterol transport is decreased in Hp2-2 DM. This may explain in part the increased atherosclerotic burden found in Hp2-2 DM individuals.

Alleles↗
PubMed2000

Pulmonary expression of the human haptoglobin gene.

Haptoglobin (Hp), a member of the acute-phase reactants, has long been known as a major hemoglobin-binding protein associated with hemoglobin catabolism. Recent studies indicate that another important biologic function of Hp is the modulation of the immune response. We found that Hp is expressed at high levels in specific cells, including alveolar macrophages and eosinophils in diseased or inflamed human lung tissues, but not in the normal lung. Expression of the human Hp gene was studied in two transgenic mouse lines carrying a 9-kb human Hp 2 gene. In both lines, the human Hp transgene was expressed constitutively in alveolar macrophages at a high level, whereas the endogenous mouse Hp was synthesized in airway epithelial cells. Expression of the human Hp transgene in lung cells was upregulated when the transgenic mice were treated with endotoxin. In humans and in Hp transgenic mice, human Hp messenger RNA was also detected in circulating eosinophils, but not in other blood cells. Our findings suggest that Hp is involved in a variety of lung inflammatory diseases, including respiratory allergy and asthma. The transgenic mouse line that overexpresses the human Hp gene in alveolar macrophages and eosinophils is a promising system for investigating the function of Hp in vivo during lung inflammation.

Acute-Phase Reaction↗
PubMed1968

Immunogenetics of human haptoglobins. I. The antigenic structure of normal Hp phenotypes.

The various antigenic determinants of serum haptoglobins (Hp) may be studied semiquantitatively in a radioimmunoassay system. Using three antisera of overlapping specificities, we constructed an antigenic model of the various Hp phenotypes comprising four distinct determinants. This adds a new determinant, situated near the hemoglobin binding site, to the three determinants reported in the literature. The assay system is sensitive to 0.2 mug or less of serum Hp. Furthermore, it can detect determinants that are not recognized by double diffusion studies.

Animals↗
PubMed1968

Immunogenetics of human haptoglobins. II. Hp Bellevue, a cross-reacting mutant.

Using a radioimmunoassay method in conjunction with double diffusion studies, we characterized the antigenic determinants of the three Hp Bellevue phenotypes. An antigenic model based on these data indicates that each phenotype comprises a heterogeneous group of proteins with properties depending on their content of normal (hpbeta) and of mutant (hpbeta-Bellevue) chains of haptoglobin. The loss of the hemoglobin binding capacity and of a specific Hb-sensitive antigenic determinant is a consequence of the structural alteration in hpbeta-Bellevue and is expressed to various extents by the populations of proteins containing this chain. It is suggested that those molecules with a preponderance of mutant beta-chains are without significant hemoglobin binding capacity and are degraded more slowly in vivo than the ones capable of hemoglobin binding.

Animals↗
PubMed2001

Haptoglobin and the Th1/Th2 balance: hints from in vitro and in vivo studies.

A variety of immunomodulatory effects have previously been attributed to haptoglobin (Hp). These are supposed to be partly mediated through binding of Hp to CD11b. In the present study, we assessed its effects on T-helper (Th) cytokine production following both in vitro and in vivo stimulation of T-cells. Hp exhibits a dose-dependent inhibitory effect on human T lymphocyte release of the Th2 cytokines (IL-4, IL-5, IL-10 and IL-13) in vitro, whereas it has no clear effect on Th1 cytokine (IL-2 and IFN-gamma) release. When administered an anti-CD3 monoclonal antibody, Hp knockout mice produced more IL-4 and less IFN-gamma than did their wild-type litter-mates. Our findings imply that Hp may be regarded as a regulator of the Th1/Th2 balance in both human and murine immune systems.

Animals↗
PubMed2001

Haptoglobin and malaria.

Haptoglobin gene knockout mice and wild-type controls were infected with Plasmodium berghei ANKA or Plasmodium chabaudi. The peak parasitaemia and parasite burden were higher in Hp-/- mice than in Hp+/+ mice. The increase in spleen weight following malaria infection was smaller in Hp-/- mice than in Hp+/+ animals. The occurrence of cerebral malaria in P. berghei ANKA infection was not different in Hp gene knockout mice and their controls.

Animals↗
PubMed2001

Haptoglobin in lung defence.

Haptoglobin (Hp) has been known to be associated with the host defence response to infection and inflammation. The biological functions of Hp can be related to its ability to bind haemoglobin or to modulate immune response. Hp is expressed at a high level in lung cells, yet its protective role(s) in the lung is not known. Using transgenic mice overexpressing Hp, we demonstrated that Hp can reduce blood-induced lung injury. Hp-mediated haemoglobin catabolism in lung cells appears to be linked to iron mobilization, and may be an efficient mechanism to reduce oxidative damage associated with haemolysis.

Animals↗
PubMed2001

Haptoglobin, an inflammation-inducible plasma protein.

Sterile tissue injury or infection initiates a local inflammatory response that mobilizes a systemic acute phase reaction resulting in, among other things, the induction of genes encoding the acute phase plasma proteins (APPs). In all vertebrates, a common set of APPs is increased and exerts essential protective functions. Haptoglobin (HP), one of the major APPs, acts as a high-affinity hemoglobin-binding protein and antioxidant. Liver is the major site of HP synthesis; however, regulated, low level expression is also detected in other organs. Induction of the Hp gene is mediated by interleukin-6-type cytokines and is synergistically enhanced by glucocorticoids. Growth stimulation of hepatic cells in vivo or in vitro suppresses the Hp gene-inducing effects of inflammatory cytokines. Receptors for IL-6 cytokines mediate induction of the Hp gene by the transcription factors signal transducer and activator of transcription-3 (STAT3) and CAAT/enhancer binding protein beta (C/EBPbeta), but attenuate the stimulation through co-activated STAT5 and mitogen-activated protein kinases, ERK-1 and ERK-2. The specificity by which the related cytokines, IL-6, oncostatin M, and leukemia inhibitory factor, regulate Hp gene transcription is determined by the profile of the cytokine receptor subunits expressed on the target cells and the relative extents by which these receptors activate the intracellular signaling pathways. The current hypothesis is that HP exerts an anti-inflammatory activity and that by the degree with which HP attenuates the inflammatory process, including the production of IL-6 cytokines, it determines the level and duration of acute phase expression of the Hp gene.

Animals↗
PubMed2003

The effect of supplementation with an antioxidant preparation on LDL-oxidation is determined by haptoglobin polymorphism.

The genetic polymorphism of haptoglobin (Hp) is an independent risk factor in the pathogenesis of atherosclerosis, a condition in which decreased resistance to in vitro oxidation of LDL-cholesterol is observed. We hypothesised that the Hp polymorphism is one of the factors modulating the resistance to Cu(2+)-induced oxidation of LDL during antioxidant supplementation. In this study, 74 middle-aged subjects with increased oxidative stress were allocated to either matched placebo or oral antioxidative treatment (Quatral) once daily for 16 weeks. Study parameters were increase of lag phase (DeltaLAG) and the ratio of lag phase during treatment period versus baseline (relative oxidation resistance, ROR), measured by Cu(2+)-induced oxidation of isolated LDL. Hp phenotypes were determined by starch gel electrophoresis. A significant and persistent increase of DeltaLAG (P < 0.05) and ROR (P < 0.01) were observed after 16 weeks of active treatment versus placebo. Interindividual differences in both parameters were significantly associated with the Hp polymorphism: in the active treatment group, DeltaLAG and ROR were significantly higher in Hp 1-1 subjects (P < 0.01) compared to Hp 2-1 and 2-2. Our data demonstrate that Hp phenotype is one of the modulating factors determining the increased resistance to Cu(2+)-induced oxidation of LDL during antioxidative treatment.

Aged↗
PubMed2005

The acute phase protein haptoglobin and its relation to oxidative status in piglets undergoing weaning-induced stress.

Haptoglobin (Hp) prevents the hemoglobin driven generation of hydroxyl radicals and lipid peroxides. Hp can reduce the neutrophil respiratory burst and is an antioxidative molecule in its own right. We aimed to evaluate Hp concentrations, oxidative stress and antioxidative capacity in blood during weaning and to characterise potential relationships between these parameters. Two batches of 10 piglets each (2 trials) weaned at the age of 27-30 days were fed a starter feed mix ad libitum. Blood samples were taken 1 week before weaning and at weekly intervals thereafter. Oxidative stress was monitored via the D-ROM system, antioxidative capacity was measured with the TEAC assay and Hp concentrations were measured by ELISA. Neutrophil phagocytic activity and oxidative burst were examined via flow-cytometry. Body weights were recorded weekly. Hp concentrations were increased in both trials post-weaning (P < 0.01); oxidative stress and oxidative burst were elevated in trial I (P < 0.005). In trial I, Hp and ROM values returned to baseline levels at 6 weeks post-weaning. The piglets in trial II showed respiratory symptoms and maintained elevated Hp concentrations. ROM values and Hp were related (r = 0.58; P < 0.01). Hp and body weight gain were inversely related post-weaning.

Animals↗
PubMed2005

CD163 is the macrophage scavenger receptor for native and chemically modified hemoglobins in the absence of haptoglobin.

CD163 mediates the internalization of hemoglobin-haptoglobin (Hb-Hp) complexes by macrophages. Because Hp binding capacity is exhausted during severe hemolysis, an Hp-independent Hb-clearance pathway is presumed to exist. We demonstrate that Hb interacts efficiently with CD163 in the absence of Hp. Not only is Hb internalized into an endosomal compartment by CD163 as a result of active receptor-dependent endocytosis; it also inhibits the uptake of Hb-Hp complexes, suggesting a common receptor-binding site. Free Hb further induces heme oxygenase mRNA expression in CD163+ HEK293 cells, but not in CD163- cells. Additional evidence for Hp-independent Hb-CD163 interaction is provided by the demonstration that CD163 mediates the uptake of alpha alpha-DBBF crosslinked Hb, a chemically modified Hb that forms minimal Hp complexes. Moreover, certain modifications to Hb, such as polymerization or the attachment of specific functional groups (3 lysyl residues) to the beta-Cys93 can reduce or enhance this pathway of uptake. In human macrophages, Hp-complex formation critically enhances Hb uptake at low (1 microg/mL), but not at high (greater than 100 microg/mL), ligand concentrations, lending support for a concentration-dependent biphasic model of macrophage Hb-clearance. These results identify CD163 as a scavenger receptor for native Hb and small-molecular-weight Hb-based blood substitutes after Hp depletion.

Antigens, CD↗
PubMed2006

Haptoglobin is synthesized during granulocyte differentiation, stored in specific granules, and released by neutrophils in response to activation.

Haptoglobin (Hp) is a plasma protein synthesized primarily by hepatocytes. It exerts a broad range of anti-inflammatory activities and acts indirectly as a bacteriostatic agent and an antioxidant by virtue of its ability to bind free hemoglobin (Hb) and to facilitate its immediate clearance by macrophages. We identified Hp as a novel specific granule protein of neutrophils by means of immunoelectron microscopy, subcellular fractionation, and exocytosis studies. Consistent with these findings, blood cells from a patient with specific granule deficiency (SGD) lacked neutrophil-derived Hp. Neutrophils contained a large amount of highly glycosylated Hp (beta-chain 45-65 kDa) synthesized in neutrophil precursors and stored in specific granules and a small amount of Hp (beta-chain 39 kDa) endocytosed from plasma and stored in secretory vesicles. Subsequent binding studies revealed that Hp from specific granules binds to Hb. Finally, the CCAAT enhancer binding protein-epsilon (C/EBPepsilon) induced Hp transcription in a myeloid cell line, suggesting that Hp expression in myeloid cells, as in hepatocytes, is at least partially regulated by members of the C/EBP transcription factor family. Collectively, these findings demonstrate that Hp is stored in specific granules and is released by neutrophils in response to activation. Hence, neutrophil-derived Hp might reduce tissue damage and bacterial growth at sites of infection or injury by propagating anti-inflammatory activities and Hb clearance.

Cell Differentiation↗