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PubMed1996

Quantitative determination of bovine serum haptoglobin in experimentally induced Escherichia coli mastitis.

A high performance liquid chromatography (HPLC) method was developed, validated and used to analyse haptoglobin concentrations in serum samples taken from eight cows which had been challenged twice intramammarily with Escherichia coli. The results of the HPLC were compared with those from a photometric assay. The kinetics of the haptoglobin response were analysed with pharmacokinetic computer software. In contrast with the photometric assay, the HPLC was sufficiently sensitive to detect normal background levels of bovine serum haptoglobin. The serum haptoglobin concentrations of healthy cows ranged from 22 to 47 mg litre-1. As the concentration of haptoglobin increased, the results of the two methods correlated well (r = 0.96). A 52-fold increase in serum haptoglobin was detected after the first challenge with E coli. The mean pharmacokinetic parameters of the response after the first challenge were: lag phase 12 hours, t2/1increase 20 hours, tmax 72 hours, t1/2decrease 46 hours, and mean residence time 112 hours. The second challenge three weeks later resulted in a significantly lower haptoglobin response, the area under curve being 35 per cent of that after the first challenge. The clinical signs and inflammatory changes in the milk did not differ significantly between the challenges.

Animals↗
PubMed1997

Tissue, temporal and inducible expression pattern of haptoglobin in mice.

Haptoglobin (Hp) is a member of the acute phase plasma proteins previously thought to be synthesized solely by the adult liver. The present study analyzes the tissue and temporal expression pattern of endogenous haptoglobin in the mouse and acute phase inducibility in various tissues. The liver is found to be the major site of haptoglobin expression but significant expression levels were also observed in the lung and skin. Acute phase induction by bacterial lipopolysaccharide (LPS) demonstrated that haptoglobin was induced not only in the liver but also in other tissues, including lung, skin, spleen, and kidney. Temporal analyses demonstrated that haptoglobin is expressed during embryogenesis in the liver and is inducible in various tissues surveyed throughout development. Transgenic mice that harbored a 1.05-kilobase (kb) region of the human haptoglobin promoter linked to two different reporter genes gave rise to lung-specific expression in the majority of transgenic lines with minimal liver expression. However, when induced with lipopolysaccharide, the 1.05-kb fragment contained the necessary elements for a response comparable to endogenous expression levels. In conclusion, these studies demonstrate that haptoglobin is not an adult liver specific gene, and its role as an acute phase reactant may well be more diverse than previously suspected.

Acute-Phase Reaction↗
PubMed2004

A circulating ligand for galectin-3 is a haptoglobin-related glycoprotein elevated in individuals with colon cancer.

BACKGROUND & AIMS: Galectin-3 is a beta-galactoside-binding protein implicated in tumor progression and metastasis of colorectal cancers. To determine whether circulating galectin-3 ligands are related to the presence of colon cancer, we sought to identify and quantify ligands in serum that bind to galectin-3. METHODS: Sera from patients with colon cancer, adenomas, and normal individuals were desialylated, reduced, and separated by sodium dodecyl sulfate/polyacrylamide gel electrophoresis (SDS-PAGE) and blots probed with biotinylated galectin-3. RESULTS: In colon cancer sera, the major galectin-3 ligand was a 40-kilodalton band distinct from mucin, carcinoembryonic antigen, and Mac-2 binding protein. Serum 40-kilodalton ligand was 10- to 30-fold higher in patients with colon cancer than in healthy subjects. Ligand was purified by gel filtration, affinity precipitation on galectin-3/agarose, and SDS-PAGE. When tryptic peptides were analyzed by matrix-assisted laser-desorption ionization mass spectrometry and protein database searching, the 40-kilodalton ligand was identified as haptoglobin beta subunit. In confirmation of this finding, depletion of haptoglobin by immunoprecipitation also eliminated the 40-kilodalton ligand. Colon cancer sera had only a modest increase in total haptoglobin as compared with healthy subjects, suggesting that the structure rather than the amount of haptoglobin is altered in patients with colon cancer. Immunohistochemical staining confirmed the absence of haptoglobin in normal colon and the ectopic expression of haptoglobin in colon cancers and adenomatous polyps. CONCLUSIONS: A major circulating ligand for galectin-3, which is elevated in the sera of patients with colon cancer, is a cancer-associated glycoform of haptoglobin.

Adenoma↗
PubMed1983

Regulation of mouse haptoglobin synthesis.

A cloned line of mouse hepatoma cells (Hepa-1) responded to treatment with dexamethasone by a 30-80-fold increase in synthesis and secretion of functional haptoglobin. Under the same conditions, the production of albumin was only slightly elevated whereas that of alpha 1-fetoprotein was reduced by 50%. The hormone concentration for half-maximal stimulation of haptoglobin synthesis was between 1 and 2 X 10(-8) M. The time course of induction is characteristic for a glucocorticoid-regulated protein. Cell-free translation of RNA indicated an increase in the amount of functional haptoglobin mRNA that can account for the change in the protein production. To correlate our findings on Hepa-1 cells with those on nontransformed liver cells, we tested the hormonal response of isolated hepatocytes in tissue culture. Haptoglobin was first synthesized and secreted by hepatocytes from 17-19-d-old fetuses. But neither prenatal nor adult hepatocytes showed a dexamethasone-dependent increase in haptoglobin synthesis. However, when several independent clones of hybrid cells formed from adult mouse hepatocytes and rat hepatoma cells were treated with dexamethasone, the synthesis of mouse haptoglobin was in all cases elevated. It appears that haptoglobin expression in mouse liver cells is potentially sensitive to glucocorticoids, but this modulation is manifested only in transformed cells and their derivatives.

Animals↗
PubMed1959

Comparative studies on the physical characteristics of the heritable haptoglobin groups of human serum.

Ultracentrifugal studies of the alpha(2)-proteins of normal human serum before and after the addition of hemoglobin have revealed three separate and clearly distinguishable patterns based on the three major serum haptoglobin groups. Isolation of the three haptoglobin hemoglobin complexes disclosed characteristic patterns for each group. The heterozygote was found to possess electrophoretic and ultracentrifugal components not seen in either homozygote. Separation of normal human serum, to which hemoglobin had been added, by conventional starch zone electrophoresis resulted in three characteristic patterns which also permitted the ready identification of the serum haptoglobin group. The haptoglobin hemoglobin complex from Group 1-1 had the fastest mobility and that of Group 2-2 the slowest. The heterozygote Group 2-1 had an intermediate mobility. Immunologic differences between the haptoglobin hemoglobin complexes of the three groups could not be detected. Some of the variations in the reported electrophoretic and ultracentrifugal patterns of normal human serum could be reasonably ascribed to the group variation of the haptoglobins in man. The physical studies imply that the proteins characteristic of the heterozygote differ in size and charge from those present in either of the two homozygotes and indicate that the genetic control of the synthesis of the serum haptoglobins is probably exceedingly complex.

Blood Proteins↗
PubMed2001

Haptoglobin is present in human endometrium and shows elevated levels in the decidua during pregnancy.

Assuming that haptoglobin, by virtue of its immunomodulatory properties, could be a regulatory factor during reproduction, its presence in the human uterus was determined. Protein extracts from endometrial tissue samples of pregnant and non-pregnant women were analysed by the immunoblot technique and the intensities of specific bands were quantified. Bands corresponding to haptoglobin were identified in tissue samples obtained from both sources. Protein, purified by high-performance liquid chromatography and monitored by Western blot analysis for its haptoglobin identity, was used for amino-terminal sequencing. Sequencing of the 42 kDa protein identified it as the beta chain of haptoglobin. Immunohistochemistry was used to corroborate the findings and to visualize the distribution of haptoglobin in the tissue. The intensity of the 42 kDa band derived from decidua graviditatis was significantly higher than the intensity of bands derived from non-pregnant endometrium in the proliferative phase (P < 0.01) and in the secretory phase (P < 0.05). Immunohistochemical staining with anti-human haptoglobin antibody elicited strong signals in the decidua graviditatis and weaker signals in the normal endometrium, with the latter showing menstrual cycle-dependent variation. Moderate staining of stroma and a lack of staining of epithelium in the proliferative phase contrasted with the strong staining of stroma and moderate level of staining of epithelium observed in the secretory phase. Haptoglobin in the uterus may exert several functions such as the known binding of haemoglobin, but could also be involved in the multi-factorial mechanism protecting the fetus from a maternal allograft-like immune response.

Blotting, Western↗
PubMed1977

Studies on hemoglobin tryptophanyl contact residues in the haptoglobin-hemoglobin complex.

Hemoglobin and apohemoglobin bind heptoglobin in the same molar ratio. Structural studies on haptoglobin-hemoglobin complex do not suggest any important structural changes in either protein upon binding. However, when apohemoglobin is bound to haptoglobin, a marked reduction in secondary structure, attributed to unfolding of globin chains, has been observed. Here we describe some properties of the haptoglobin-apohemoglobin (Hp-apoHb) complex, prepared by isoelectric focusing in the presence of an excess of haptoglobin. This complex does not exhibit the irreversibility of complexes obtained with hemoglobin in identical experimental conditions. The 'freezing' of the conformation of apohemoglobin upon binding to haptoglobin has been studied by fluorescence quenching experiments carried out in the presence of 8 M acrylamide. Changes in conformation of haptoglobin upon binding to apohemoglobin have been detected by titration of the exposed tryptophans using N-bromosuccinimide. Comparison of the additivity of exposed tryptophans in the complexes reveal that two tryptophans become inaccessible in the complex formation of haptoglobin with hemoglobin but not with apohemoglobin. These tryptophans, probably located on the alpha1beta2 contact interface of hemoglobin, have been tentatively identified as Trp-C3(37)beta.

Apoproteins↗
PubMed1996

Comparison of haptoglobin and apolipoprotein A-I on biliary lipid particles involved in cholesterol crystallization.

Several proteins are known to modulate cholesterol crystallization. We recently demonstrated that haptoglobin has cholesterol crystallization promoting activity. However, this effect is still not well understood mechanistically. The current study examined the distribution of haptoglobin compared to apolipoprotein A-I (apo A-I) to micelles, vesicles and crystals as an initial step in providing a focus for further studies of the mechanism of cholesterol crystallization activity. Specific protein purification was accomplished by immunoaffinity chromatography. The crystallization-promoting activity of biliary haptoglobin, albumin and commercial apo A-I was measured by a photometric crystal growth assay. The distribution of micelles, vesicles and proteins in model bile was determined by Sepharose CL-6B column chromatography. Detection of the presence of test proteins in cholesterol crystals was determined using specific 125I-radiolabelled proteins. Haptoglobin (20 micrograms/mL) showed a significant crystallization promoting-activity, whereas apo A-I (30 micrograms/mL) only tended to show a slight inhibitory activity. The cholesterol crystal-bound protein in each case was found to be less than 1% of the total concentration of that protein that had been added to the model bile system. The elution profile of commercial apo A-I from a Sepharose CL-6B column was strikingly altered when it was added to model bile prior to elution. In contrast, the column elution profiles for both haptoglobin and albumin were unchanged when model bile was similarly added to the sample. Haptoglobin increased the amount of cholesterol found in the vesicular fraction when compared to apo A-I. Haptoglobin does not bind tightly to either biliary lipid particles or to cholesterol crystals but does increase the amount of cholesterol in vesicles by inducing a shift from micellar cholesterol (P = 0.046). This shift appears to explain in part its promoting effect on cholesterol crystallization.

Apolipoprotein A-I↗
PubMed1995

Identification of an iron-regulated outer membrane protein of Neisseria meningitidis involved in the utilization of hemoglobin complexed to haptoglobin.

Hemoglobin complexed to the plasma protein haptoglobin can be used by Neisseria meningitidis as a source of iron to support growth in vitro. An N meningitidis mutant, DNM2E4, was generated by insertion of the mini-Tn3erm transposon into the gene coding for an 85-kDa iron-regulated outer membrane protein. Membrane proteins prepared from DNM2E4 were identical to those of the wild-type strain except that the 85-kDa protein was not produced. This mutant was unable to use hemoglobin-haptoglobin complexes as an iron source to support growth and was also impaired in the utilization of free hemoglobin. The mutant failed to bind free hemoglobin, hemoglobin-haptoglobin complexes, or apo-haptoglobin in a solid-phase dot blot assay. The 85-kDa protein was affinity purified when hemoglobin-haptoglobin complexes were used as a ligand but was not purified when free hemoglobin was used. We hypothesize that the 85-kDa iron-regulated protein is the hemoglobin-haptoglobin receptor and designate this protein Hpu (for hemoglobin-haptoglobin utilization).

Amino Acid Sequence↗
PubMed1993

Identification of haptoglobin as an angiogenic factor in sera from patients with systemic vasculitis.

Angiogenesis is an important process in chronic inflammatory diseases. We observed that sera from patients with systemic vasculitis stimulated angiogenesis in an in vitro model using human umbilical vein endothelial cells cultured on a basement membrane (Matrigel) substrate. After 40% ammonium sulfate precipitation, angiogenic activity remained in the low molecular weight fraction and could be inactivated by heat. SDS-page of serum FPLC fractions exhibiting maximal angiogenic activity demonstrated two prominent species of 45 and 16-20 kD in patients' sera. These bands were much less apparent in sera obtained from control subjects. Amino-terminal sequencing of the 45-kD protein demonstrated that it was haptoglobin. Purified haptoglobin stimulated angiogenesis in a dose-dependent manner. The angiogenic activity of vasculitis patients' sera was partially inhibited by an antihaptoglobin antibody. Furthermore, serum haptoglobin levels in vasculitis patients correlated both with disease and angiogenic activity. Haptoglobin angiogenic activity was confirmed in two in vivo models using an implanted disc and a subcutaneous injection of basement membrane. Stimulation of angiogenesis is a newly recognized biological function of haptoglobin. The increased levels of haptoglobin found in chronic inflammatory conditions may play an important role in tissue repair. In systemic vasculitis, haptoglobin might also compensate for ischemia by promoting development of collateral vessels.

Amino Acid Sequence↗
PubMed2000

Distribution of haptoglobin phenotypes in a Korean population, using the semi-automated PhastSystem.

We have established a new phenotyping method for haptoglobin, based on sodium dodecyl sulphate-polyacrylamide gel electrophoresis using the PhastSystem (Pharmacia Biotech, Uppsala, Sweden), followed by immunoblotting for detection. We measured haptoglobin concentrations and determined the haptoglobin phenotypes of 316 healthy Koreans using this method: 31 (9.8%) were of Hp 1-1 type, 140 (44.3%) of Hp 2-1 type and 145 (45.9%) of Hp 2-2 type. The haptoglobin allele frequencies were calculated to be 0.32 for Hp1 and 0.68 for Hp2. We were able to visualize up to 12 bands from the human Hp 2-2 polymeric series, with molecular weights in the range 171.9 x 10(3) to 802.2 x 10(3). The reference range of serum haptoglobin concentrations obtained by the IFCC (International Federation of Clinical Chemistry) standard method was 0.27-2.14 g/L. The serum haptoglobin concentration in Koreans was similar to that of Caucasians, but the Hp1 allele frequency was lower in Koreans. Our method could be used in clinical laboratories as a simple and practical method of haptoglobin phenotyping. In addition, the Hp 2-2 polymeric series could be used as high molecular weight standards.

Alleles↗
PubMed2004

Haptoglobin phenotypes in health and disorders.

Haptoglobin is a positive acute phase protein that binds free hemoglobin and removes it from the circulation to prevent kidney injury, and iron lossfollowing hemolysis. Also, by bindingfree hemoglobin, haptoglobin functions as an antioxidant. In addition, haptoglobin acts as a potent immunosuppressor of lymphocyte function and modulates the helper T-cell type 1 and type 2 (Th1/Th2) balance within the body. Three major haptoglobin phenotypes are known to exist (Hp 1-1, Hp 2-1, and Hp 2-2). Hp 1-1 is biologically the most effective in binding free hemoglobin and suppressing inflammatory responses associated with free hemoglobin. Hp 2-2 is biologically the least active, and Hp 2-1 is moderately active. The possible association of allelic polymorphism of haptoglobin with various pathologic conditions such as coronary artery disease has been studied. This article reviews the known functions of haptoglobin and the present understanding of a possible association of haptoglobin phenotypes with pathogenesis of a number of human disorders.

Brain Diseases↗
PubMedDate not supplied

Carbohydrate structures of haptoglobin in sera of healthy people and a patient with congenital disorder of glycosylation.

Haptoglobin is one of acute phase glycoproteins often used as markers in glycopathology studies. In this work the oligosaccharide structures of haptoglobin from 'healthy' subjects have been studied in detail, taking into consideration the possible dependence of glycosylation on the phenotype. About 75% of charged haptoglobin glycans were of biantennary complex structure, and some of them lacked one terminal sialic acid molecule. Triantennary structures made up almost 25% of the charged glycans pool, and highly branched tetrasialylated oligosaccharides did not exceed 1%. The main difference between haptoglobin derived from the sample of pooled 44 sera and from the 2-2 phenotype individual concerned the relative content of trisialylated oligosaccharide with one 2-3 linked sialic acid residue. The oligosaccharide profile of haptoglobin derived from serum of a patient suffering from congenital disorder of glycosylation was compared to 'healthy' controls. It was shown, that four main glycans are identical in patient and 'normal' haptoglobins. Some alterations were found in the relative content of mono-, bi-, and trisialylated glycans as well as in the appearance of some tracely abundant oligosaccharides in haptoglobin of the patient with congenital disorder of glycosylation.

Adult↗
PubMed2004

The effect of vitamin therapy on the progression of coronary artery atherosclerosis varies by haptoglobin type in postmenopausal women.

OBJECTIVE: Antioxidant trials have not demonstrated efficacy in slowing cardiovascular disease but could not rule out benefit for specific patient subgroups. Antioxidant therapy reduces LDL oxidizability in haptoglobin 1 allele homozygotes (Hp 1-1), but not in individuals with the haptoglobin 2 allele (Hp 2-1 or Hp 2-2). We therefore hypothesized that haptoglobin type would be predictive of the effect of vitamin therapy on coronary atherosclerosis as assessed by angiography. RESEARCH DESIGN AND METHODS: We tested this hypothesis in the Women's Angiographic Vitamin and Estrogen (WAVE) trial, a prospective angiographic study of vitamins C and E with or without hormone replacement therapy (HRT) in postmenopausal women. Haptoglobin type was determined in 299 women who underwent baseline and follow-up angiography. The annualized change in the minimum luminal diameter (MLD) was examined in analyses stratified by vitamin use, haptoglobin type, and diabetes status. RESULTS: We found a significant benefit on the change in MLD with vitamin therapy as compared with placebo in Hp 1-1 subjects (0.079 +/- 0.040 mm, P = 0.049). This benefit was more marked in diabetic subjects (0.149 +/- 0.064 mm, P = 0.021). On the other hand, there was a trend toward a more rapid decrease in MLD with vitamin therapy in Hp 2-2 subjects, which was more marked in diabetic subjects (0.128 +/- 0.057 mm, P = 0.027). HRT had no effect on these outcomes. CONCLUSIONS: The relative benefit or harm of vitamin therapy on the progression of coronary artery stenoses in women in the WAVE study was dependent on haptoglobin type. This influence of haptoglobin type seemed to be stronger in women with diabetes.

Aged↗
PubMed1997

[Identification of the properties of haptoglobin-like substance in burn serum].

In our previous study, a haptoglobin-like substance possessing immunosuppressive activity was found in the sera of burned patients. However, its properties have not yet been clarified. In the present study, we mainly investigated the properties of the haptoglobin-like substance. The results showed that the abnormal protein bands identified by SDS-PAGE were the different subunits of haptoglobin, i.e., beta, alpha 2 and alpha 1 chains. The haptoglobin in burned sera was identical to that in normal sera in molecular weight, isoelectric point, hemoglobin-binding capacity and immunochemical properties as analyzed by SDS-PAGE, isoelectric focusing, immunochemical and biochemical methods. According to our results, it is suggested that the haptoglobin-like substance reported in the past is probably the haptoglobin, and that there may be no alteration in the properties of haptoglobin following burns.

Animals↗
PubMedDate not supplied

[Haptoglobin in cerebrospinal fluid as a marker of infectious process in central nervous system].

INTRODUCTION: Haptoglobin is a transport protein and protects organism against iron loss and it should be involved in central nervous system infectious process. PATIENTS AND METHODS: Simultaneous serum and cerebrospinal fluid were obtained of 39 pediatric patients, 14 suffering from viral meningoencephalitis and 25 from bacterial meningoencephalitis. Five control cases were examined too. Haptoglobin, IgG and albumin were quantified in both fluids by radial immunodiffusion. Haptoglobin cerebrospinal fluid/serum ratio, haptoglobin index and haptoglobin/IgG index were calculated. Local IgG intrathecal synthesis was determined by reibergram. RESULTS: Haptoglobin index was higher not statistically significant in viral meningoencephalitis in comparison with bacterial disease but both were statistically significant with respect to control group. Increased haptoglobin/IgG index were statistically significant in bacterial meningoencephalitis in relation with viral meningoencephalitis. There were no association between haptoglobin and polymorphonuclear cells count and globular sediment speed. CONCLUSION: Haptoglobin should be considered a relevant marker of central nervous system infectious process.

Biomarkers↗
PubMed1975

Serum haptoglobins in pregnancy.

Serum haptoglobin types and levels were determined by starch gel electrophoresis and a colorimetric method based on the peroxidase activity of the haptoglobin-methaemoglobin complex in 220 pregnant women and 120 normal female subjects. The frequency distributions of haptoglobin types in the 2 groups of subjects were similar. No correlation between the number of gravida or duration of pregnancy and serum haptoglobin levels were observed in pregnant subjects. Haptoglobin values were found to be low in 39% of pregnant women and a direct relationship between these low haptoglobin levels and the haemoglobin concentrations was observed. The cause of low haptoglobin values was probably haemodilution and increased blood estrogen concentrations during pregnancy.

Blood Donors↗
PubMed1992

[Haptoglobin polymorphism--not only a genetic marker].

The biological activities of the haptoglobin polymorphism are controlled by continuous DNA sequences coding for the HP alpha and Hp beta polypeptide chains and forming with a linked Hp related gene the haptoglobin gene complex on chromosome 16. Probably, this DNA domain originates from the gene family of the serine proteases after having lost the informations for the proteolytic functions. Instead of this, the haptoglobins have acquired other qualities, among them the hemoglobin binding capacity, inserted into the Hp beta chain. The Hp polymorphism is constituted by the evolutionary progressive DNA sequences for the Hp alpha chains, which probably have activation functions. The haptoglobins display immunoregulative abilities, which can be immunosuppressive by inhibition of the lymphocyte reactivity or immunoinductive by influencing the IgM biosynthesis, adapted to the functional requirements. In this field, Hp 2-2 has a stronger effect than the two other Hp types. Moreover, the haptoglobins inhibit the prostaglandin synthesis and protect against harmful oxidation processes. These qualities are based on the hemoglobin binding ability and can be realized by Hp 1-1 with the comparatively highest efficacy. Further on, the haptoglobins are protease inhibitors. Finally, Hp 2-2 is associated with higher albumin and ceruloplasmin serum levels than Hp 2-1 and Hp 1-1. Evidently, the haptoglobins are inserted into a widely ramified network of biological functions. The selective advantages and disadvantages of the Hp polymorphism are noticeable under pathological conditions in case of malignant tumors, inflammations, autoimmune diseases, allergic illness, affective psychoses and affective lability favouring addiction.

Blood Proteins↗