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PubMed1983

Undecagold labeling of a glycoprotein: STEM visualization of an undecagoldphosphine cluster labeling the carbohydrate sites of human haptoglobin-hemoglobin complex.

A new type of label for electron microscopy has been introduced recently which consists of 11 gold atoms in a compact stable cluster with an organic shell composed of primary amine-substituted phosphine ligands. The radius of the cluster is about 10 A. The (phosphine ligand) amines can be derivatized or allowed to react directly forming covalent bonds to specific sites of other molecules. This report describes the specific labeling of carbohydrate moietis on the glycoprotein human haptoglobin (Hp) in the haptoglobin-hemoglobin complex (Hp X Hb). The Hp X Hb complex is easily recognized in the EM as a barbell-shaped molecule. Only the Hp portion contains carbohydrate (eight carbohydrate chains per Hp X Hb). The carbohydrate moieties of the Hp X Hb complex were oxidized by sodium periodate to produce aldehydes. The primary amines on the undecagold cluster were allowed to react with the aldehyde residues to produce Schiff's base linkages which were subsequently reduced with sodium borohydride. Micrographs obtained on the Brookhaven National Laboratory high-resolution scanning transmission electron microscope (STEM) showed the undecagold label to be localized in a region known to be occupied by the heavy chains of haptoglobin. The amount of labeling was found to be two to four gold clusters per molecule when excess label was reacted. The variation in position of the label is discussed and may be due to flexibility of the carbohydrate chains. Control experiments ruled out nonspecific binding of the gold cluster to the Hp X Hb. The high chemical specificity of the reaction and the high resolution of the gold cluster should make this new label of widespread value in studies of other glycoproteins or carbohydrate-bearing molecules.

Affinity Labels↗
PubMed2000

The acute phase response of haptoglobin and serum amyloid A (SAA) in cattle undergoing experimental infection with bovine respiratory syncytial virus.

The ability of a pure virus infection to induce an acute phase protein response is of interest as viral infections are normally considered to be less efficient in inducing an acute phase protein response than bacterial infections. This was studied in a bovine model for infection with bovine respiratory syncytial virus (BRSV), analysing the induction of the two most dominant bovine acute phase proteins haptoglobin and serum amyloid A (SAA). Strong and reproducible acute phase responses were detected for both proteins, peaking at around 7-8 days after inoculation of BRSV, while no response was seen in mock-inoculated control animals. The serum concentrations reached for SAA and haptoglobin during the BRSV-induced acute phase response were generally the same or higher than previously reported for bacterial infections in calves. The magnitude and the duration of the haptoglobin response was found to correlate well with the severity of clinical signs (fever) and with the extent of lung consolidation while SAA responded most rapidly to infection.

Acute-Phase Reaction↗
PubMed1999

Interferon-alpha and haptoglobin in pigs selectively bred for high and low immune response and infected with Mycoplasma hyorhinis.

Pigs selected for high (H) or low (L) combined antibody and cell-mediated immune response were infected with Mycoplasma hyorhinis. Following the infection, arthritis was more severe in the H pigs, while pleuritis and peritonitis were more severe in the L pigs. Since Mycoplasma infections in pigs often cause just mild signs, indicators of the inflammatory response may aid diagnosis of such infections. In addition, data about the genetic influence on inflammatory response indicators are scanty in the pig. The objectives of the study were therefore: firstly, to determine interferon-alpha (IFNalpha) and haptoglobin in M. hyorhinis infected pigs and, secondly, to investigate if the inflammatory response as determined by these indicators was influenced by genetic selection. There was no consistent increase of IFN-alpha in serum following infection. The serum haptoglobin concentration started to increase 3 days post-infection and there was no difference between the two breeding lines. Hence, M. hyorhinis infection in pigs is reflected in increased serum haptoglobin concentration, but no effect of the magnitude of the inflammatory response on this indicator by selection for high or low immune response was observed.

Animals↗
PubMed1992

Junctions between genes in the haptoglobin gene cluster of primates.

To investigate the nature of the recombination that generated the haptoglobin three-gene cluster in Old World primates, we sequenced the region between the second gene (HPR) and the third gene (HPP) in chimpanzees (15 kb), as well as the region 3' to the cluster in humans (14 kb). Comparison to the previously sequenced human haptoglobin (HP) and HPR genes showed that the junction point between HP and HPR in humans (junction 1) was not identical to the junction point between the HPR and HPP genes of the chimpanzee (junction 2). An Alu sequence was found at each junction, but both Alu sequences lacked short direct repeats of the flanking genomic DNA. The lack of direct repeats implies that both junction Alu sequences are the products of recombination between different Alu elements. In addition, other insertion and deletion events are clustered in the regions near the junction Alu sequences. The observation that Alu sequences define the junctions between genes in the haptoglobin gene cluster emphasizes the importance of Alu sequences in the evolution of multigene families.

Animals↗
PubMed1976

Characterization of the cyanogen bromide fragments of the beta chain of human haptoglobin.

Characterization of the cyanogen bromide (CNBr) fragments of the beta chain of human haptoglobin revealed five major fragments resulting from cleavage of four methionyl residues. The fragments were isolated by gel filtration in guanidine-HCl on Sepharose 6B and Bio-Gel P10 and P60. Compositional analyses of the five cyanogen bromide fragments accounted for 248-253 amino acid residues in agreement with the number of residues determined for the intact beta chain. Most of the carbohydrate was attached to CNBr II. Automated amino-terminal sequence analysis and carboxyl-terminal hydrolysis with carboxypeptidase of the haptoglobin beta chain and cyanogen bromide fragments identified 139 residues, or about 55% of the beta-chain molecule. The placement of the fragments within the beta-chain molecule was established by sequence analysis of whole beta chain and a plasmin cleavage fragment. The position of CNBr V was confirmed by the absence of homoserine or homoserine lactone. Cyanogen bromide reaction of intact haptoglobin 1-1 resulted in the isolation of a beta-chain fragment, CNBr III, covalently attached to the intact alpha1 chain by a single disulfide bond. The beta chain was shown to have primary structural similarities to the chymotrypsin family of serin eproteases. Partial sequence analysis of CNBr V established the region which is comparable to the serine-195 active-site region: /Asp-Thr-Cys-Tyr-Gly-Asp-Ala-Gly-Ser-Ala-Phe/ (residues 189-199, chymotrypsinogen A numbering). The active-site serine-195 is replaced by alanine; however, the specificity residue of the trypsin-like enzymes, Asp-189, is preserved. Several minor cyanogen bromide cleavage products were also identified in yields of up to 15%. These minor cleavage products give evidence that tryptophanyl residues in proteins, or glycoproteins, are also susceptible to cyanogen bromide cleavage.

Amino Acid Sequence↗
PubMed1997

Oxidation of low-density lipoprotein by hemoglobin stems from a heme-initiated globin radical: antioxidant role of haptoglobin.

Hemoglobin, known as a poor peroxidase, has been recently found to be a highly reactive catalyzer of low-density lipoprotein (LDL) oxidation resulting in oxidation of LDL lipids and covalent cross-linking of the LDL protein, apo B. We evaluated three possible mechanisms that may account for hemoglobin reactivity: oxidative activation by globin-dissociated hemin following its transfer to LDL; peroxidase-like reactivity of the ferryl iron active state in intact hemoglobin; and oxidation by a globin radical formed in oxidized hemoglobin. The first mechanism was ruled out because only a minor fraction of hemin was actually transferred to LDL in the process of oxidation. The second mechanism was excluded because hemoglobin ferryl, unlike ferryl of horseradish peroxidase, was not consumed in the process of LDL oxidation. Haptoglobin completely inhibited cross-linking of globin in hemoglobin/H2O2 mixtures but not in myglobin/H2O2, as well as cross-linking of apo B and oxidation of LDL lipids. Haptoglobin could not however abolish the hemoglobin ferryl state, a finding that further supported exclusion of the second mechanism. We conclude that the active species in hemoglobin-induced LDL oxidation is the globin radical, as suggested in the third mechanism. The present findings also show that haptoglobin functions as a major antioxidant thus protecting the vascular system.

Animals↗
PubMed1990

[Distribution of serum haptoglobin groups in affective psychoses--more than a genetic marker indication?].

The haptoglobin serum group 2-2 has a preponderance in affective psychoses (p less than 0.0005). This genetic marker trait is extended on unipolar depressions (p less than 0.005) and cycloid psychoses (p less than 0.0005). In addition, it must be assumed that the serum levels of albumin (p less than 0.0001), ceruloplasmin (p less than 0.0001) and haptoglobin (p less than 0.0001) are increased in affective disorders. Besides, the transferrin serum values are decreased in cycloid psychoses (p less than 0.001). As ascertained in a supplementary study, Hp 2-2 is associated within the normal range of variation with the highest albumin serum levels already in healthy controls when compared with Hp 1-1 (p less than 0.05) and Hp 2-1 (p less than 0.001). Even after including the extreme variants, the Hp 2-2 sera display more albumin values above 40.8 g/l than the Hp 2-1 specimens and the summarized samples of Hp 1-1 and Hp 2-1 (p less than 0.02). Furthermore the Hp 2-2 sera exhibit higher ceruloplasmin levels than the samples of Hp 1-1 (p less than 0.01) and Hp 2-1 (p less than 0.005). These differences are persisting too in the same trend after including extreme high ceruloplasmin values (p less than 0.05 and p less than 0.005 respectively). Obviously there are several possibilities for Hp 2-2 to operate on the biological background of affective psychoses as a risk factor. The findings are interpreted with reference to the actual data concerning the activities of the haptoglobin genes and proteins.(ABSTRACT TRUNCATED AT 250 WORDS)

Affective Disorders, Psychotic↗
PubMed1997

Serum haptoglobin and ferritin during a competitive running and swimming season.

The purpose of the study was to examine ferritin, haptoglobin, and red cell indices during a competitive running and swimming season. Male runners (N = 8) and swimmers (N = 5) were tested four times during their respective seasons. The runners were tested before the start of organized practice (RT1), after 3 wk of increased training (RT2), 3 wk prior to the conference championship (pre-taper, RT3), and 3 d after the conference championship (post-taper, RT4). The swimmers were tested after the first 9 wk of training (ST1), after completing 2 wk of hard training (ST2), after an additional 6wk of training (pre-taper, ST3), and 1 wk following the conference championship (post-taper, ST4). For the runners, hemoglobin, hematocrit, and red blood cell number were lower (p < 0.05) at RT2 and were not accompanied by significant changes in other red cell indices or haptoglobin. Serum ferritin in the runners was lower at RT3 and RT4 compared to RT1 despite an adequate dietary iron intake. Hemoglobin and mean cell hemoglobin concentration were lower and mean cell volume was higher in the swimmers at ST3 and ST4. No significant changes were observed in other red cell indices for swimmers; however, serum haptoglobin tended (p = 0.07) to be reduced at ST2. In conclusion, collegiate male runners and swimmers do not demonstrate clinical hypoferritinemia, hypohaptoglobinemia, or alterations in red cell indices suggestive of the early stage of anemia with or without iron deficiency during their respective season.

Anemia↗
PubMed1981

Serum ferritin, transferrin, haptoglobin, and iron in middle- and long-distance runners, elite rowers, and professional racing cyclists.

Serum ferritin, transferrin, haptoglobin, and iron were measured in well-trained middle- and long-distance runners, elite rowers of the West German national team, and professional racing cyclists during the summer training and the winter rest period. None of the male athletes examined, with the exception of the racing cyclists during the summer period, received oral or parenteral iron. The runners were found to have significantly lower ferritin (P less than 0.00001), iron (P less than 0.001), and haptoglobin values (P less than 0.01) than the controls. Their transferrin levels were elevated, however not significantly. Rowers showed significantly higher ferritin levels (P less than 0.01) than the controls. The reduced haptoglobin concentrations in runners are presumed to be caused by a running-induced hemolysis. It is speculated that a recurring hemoglobinuria produced diminished iron reserves in middle- and long-distance runners.

Adult↗
PubMed1998

Characterization of the human serum trypanosome toxin, haptoglobin-related protein.

Haptoglobin-related protein (HPR) is a serum protein that is >90% homologous to the acute-phase reactant haptoglobin (Hp). Haptoglobin binds and removes free hemoglobin (Hb) from the circulation. Hpr levels are elevated with tumor progression in the serum of some cancer patients, but the relevance of this observation is not understood. HPR is an integral part of two distinct high molecular weight complexes (trypanosome lytic factor 1 (TLF1) and TLF2) that are lytic for the African parasite Trypanosoma brucei brucei. Previous data indicate that HPR represents the toxic component of both trypanosome lytic factors. It has been proposed that after uptake by the parasite, Hb bound to HPR causes lysis in a peroxidase-dependent process. We report that the molecular architecture of HPR in normal human serum is different from that of Hp and that HPR does not bind Hb in normal human serum. Immunodepletion of all detectable Hb from TLF1 does not deplete TLF1 of HPR or trypanolytic activity, suggesting that the mechanism of parasite lysis is Hb-independent.

Animals↗
PubMed2001

Smad proteins suppress CCAAT/enhancer-binding protein (C/EBP) beta- and STAT3-mediated transcriptional activation of the haptoglobin promoter.

Activin A, a member of the transforming growth factor beta (TGFbeta) superfamily, blocks interleukin (IL)-6 biological functions. The molecular basis of the influence of this TGFbeta signaling on the IL-6 receptor triggered cascade is unknown. We studied IL-6-induced secretion of the acute phase protein haptoglobin by hepatoma cells. Overexpression of the C/EBPbeta gene, a downstream effector in the IL-6 pathway, activated transcription from the haptoglobin promoter. This was abolished by either a constitutively active form of activin A type IB receptor (CAactRIB) or by a combination of Smad3 and Smad4. Similarly, Smads abolished transcriptional activation by co-stimulation with IL-6 and STAT3. The transcription co-activator p300 partially overcame the suppressive effect of Smads. Electrophoretic mobility shift assays indicated that C/EBPbeta binding to haptoglobin promoter DNA was reduced by over-expression of CAactRIB and Smad4. We thus show that Smad proteins operate as transcription inhibitors on target genes of the IL-6 induced pathway. The effect of Smads is exerted on components of the transcription activation complex and may also involve interference with DNA binding. This study thus depicts molecular sites of interaction between the TGFbeta superfamily and the IL-6 signaling cascades.

Activins↗
PubMed2001

Haptoglobin-related protein mediates trypanosome lytic factor binding to trypanosomes.

Trypanosome lytic factor (TLF-1) is an unusual high density lipoprotein (HDL) found in human serum that is toxic to Trypanosoma brucei brucei and may be critical in preventing human infections by this parasite. TLF-1 is composed of four major apolipoproteins: apolipoprotein AI, apolipoprotein AII, paraoxonase, and the primate-specific haptoglobin-related protein (Hpr). Hpr is greater than 90% homologous to haptoglobin (Hp), an abundant acute phase serum protein. Killing of trypanosomes by TLF-1 requires cell surface binding, endocytosis, and subsequent lysosomal targeting. Low temperature binding studies reveal two receptors for TLF-1: one that is high affinity/low capacity (K(d) approximately 12 nm, 350 receptors per cell) and another that binds with low affinity/high capacity (K(d) approximately 1 microm, 60,000 receptors per cell). The low affinity binding is competed by nonlytic human HDL and is likely to be apolipoprotein AI-mediated. Purified human Hpr and human Hp bind to trypanosomes, are internalized, and are targeted to the lysosome. Furthermore, Hpr shows competition for TLF-1 binding, and a monoclonal antibody against Hpr prevents both TLF-1 uptake and trypanosome killing. Based on these results, we propose that Hpr mediates the high affinity binding of TLF-1 to T. b. brucei through a haptoglobin-like receptor.

Animals↗
PubMed1983

Leucocyte-associated plasma proteins. Association of prealbumin, albumin, orosomucoid, alpha 1-antitrypsin, transferrin and haptoglobin with human lymphocytes, monocytes, granulocytes and a promyelocytic leukaemic cell line (HL-60).

The distribution of prealbumin, albumin, orosomucoid, alpha 1-antitrypsin, haptoglobin and transferrin, including their electrophoretic heterogeneous variants, was studied in isolated lymphocytes, monocytes and granulocytes and in a human promyelocytic cell line (HL-60) by crossed immunoelectrophoresis. Prealbumin, albumin and transferrin were present in lymphocytes, monocytes and granulocytes, whereas the cellular variants of orosomucoid and haptoglobin were present only in granulocytes. alpha 1-Antitrypsin was present in four electrophoretic variants which were differently distributed among the various cell types. Synthesis of alpha 1-antitrypsin by monocytes, granulocytes and HL-60 cells was demonstrated by 14C-leucine incorporation. The six plasma proteins could not be removed from intact cells by incubation with the respective antibodies at 0 degrees C, or iodinated by lactoperoxidase catalysed iodination at 23 degrees C. They were, however, readily solubilized by freeze-lysis of the cells, suggesting an intracellular localization. Compared to their plasma counterparts none of the proteins differed in their hydrophobic properties but the carbohydrate residues of orosomucoid, alpha 1-antitrypsin and haptoglobin were different. The pattern of disappearance of the proteins from the cells during incubation suggested that the localization of albumin and transferrin in relation to the cells differed from that of the other proteins.

Blood Proteins↗
PubMedDate not supplied

Haptoglobin polymorphism in Egyptians.

In 505 random serum samples from unrelated healthy genuine Egyptians, haptoglobin 2-2 phenotypes were most prevalent, though statistically were as common as haptoglobin 2-1 phenotypes. High inbreeding with average inbreeding coefficient of 0.0145 explains the deviation of Egyptian haptoglobin phenotypes from the Hardy-Weinberg equilibrium.

Adult↗
PubMed1998

The haptoglobin-gene deletion responsible for anhaptoglobinemia.

We have found an allelic deletion of the haptoglobin (Hp) gene from an individual with anhaptoglobinemia. The Hp gene cluster consists of coding regions of the alpha chain and beta chain of the haptoglobin gene (Hp) and of the alpha chain and beta chain of the haptoglobin-related gene (Hpr), in tandem from the 5' side. Southern blot and PCR analyses have indicated that the individual with anhaptoglobinemia was homozygous for the gene deletion and that the gene deletion was included at least from the promoter region of Hp to Hpr alpha but not to Hpr beta (Hpdel). In addition, we found seven individuals with hypohaptoglobinemia in three families, and the genotypes of six of the seven individuals were found to be Hp2/Hpdel. The phenotypes and genotypes in one of these three families showed the father to be hypohaptoglobinemic (Hp2) and Hp2/Hpdel, the mother to be Hp2-1 and Hp1/Hp2, one of the two children to be hypohaptoglobinemic (Hp2) and Hp2/Hpdel, and the other child to be Hp1 and Hp1/Hpdel, showing an anomalous inheritance of Hp phenotypes in the child with Hp1. The Hp2/Hpdel individuals had an extremely low level of Hp (mean+/-SD = 0.049+/-0. 043 mg/ml; n=6), compared with the level (1.64+/-1.07 mg/ml) obtained from 52 healthy volunteers having phenotype Hp2, whereas the serum Hp level of an individual with Hp1/Hpdel was 0.50 mg/ml, which was approximately half the level of Hp in control sera from the Hp1 phenotype (1.26+/-0.33 mg/ml; n=9), showing a gene-dosage effect. The other allele (Hp2) of individuals with Hp2/Hpdel was found to have, in all exons, no mutation, by DNA sequencing. On the basis of the present study, the mechanism of anhaptoglobinemia and the mechanism of anomalous inheritance of Hp phenotypes were well explained. However, the mechanism of hypohaptoglobinemia remains unknown.

Adult↗
PubMed1990

Interference with immune response at the level of generating effector cells by tumor-associated haptoglobin.

Most of the immune response regulators identified to date proved to be products of tumor, of an immune system or of combinations of such systems or to be tumor-induced host products. We have described how the haptoglobin isolated from cancer patients can impose serious hindrance to cell-mediated immune functions in vivo and in vitro under the pathophysiologic concentrations seen in these patients. Because the tumor-associated haptoglobin interferes with the innate and adaptive immune functions, elimination of the haptoglobin by passive removal or by active therapy could be an important adjunct for immunotherapy in cancer patients.

Animals↗
PubMed1983

Sequence of human haptoglobin cDNA: evidence that the alpha and beta subunits are coded by the same mRNA.

We have isolated and sequenced a cDNA clone coding for human haptoglobin. Our sequence shows that haptoglobin is very likely synthesized as a single polypeptide chain which is then cleaved at an Arg residue to generate its two characteristic alpha and beta subunit. Southern blot analysis suggests that there are at least two copies of the haptoglobin gene per haploid genome.

Amino Acid Sequence↗