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Haptoglobin inducing activity
Eph receptor A5
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abbr. Hp. A tetrameric plasma glycoprotein produced primarily by hepatocytes. Haptoglobulin is polymorphic due to the existence of two allelic forms of the alpha chains (alpha-1, 9 kDa, 83 amino acids; and alpha-2, 17.3 kDa, 142 amino acids).
There are three different phenotypic haptoglobulins: Haptoglobin type 1-1 (2 alpha-1/2 beta), Haptoglobin type 2-2 (2 alpha-2/2 beta), Haptoglobin type 1-2 (alpha-1 alpha-2/2 beta). The glycosylated beta chain (40 kDa, 245 amino acids unglycosylated 35 kDa) is the same in all Haptoglobin types (Bowman et al, 1988). Haptoglobin is homologous to serine proteases of the chymotrypsinogen family but has no serine prote3ase activity and has different functions (Kurosky et al, 1980).
Type 1-1 haptoglobulin is monomeric but the other two types occur in several polymeric forms with molecular masses up to 1 million. Cloning of the human haptoglobin cDNA shows that haptoglobin is synthesized as a single polypeptide chain, which is then cleaved at an arginine residue to generate its two subunits, alpha-2 and beta (van der Straten et al, 1983; Raugei et al, 1983). The genes encoding the haptoglobin alpha and beta chains have been mapped to human chromosome 16q22 (McGill et al, 1984). A closely linked haptoglobin-related (Hpr) gene pair has been identified 2.2 kb downstream of the haptoglobin locus (Maeda and Smithies, 1986).
Haptoglobin is synthesized at hepatic and extrahepatic sites. Haptoglobin is one of the acute phase proteins produced during the acute phase reaction. Its synthesis is induced by various cytokines, including IL1 (previously identified as Haptoglobin inducing activity), IL6, CNTF (ciliary neurotrophic factor). The increased synthesis of haptoglobin mediated by IL6 is suppressed by TNF-alpha. The gene encoding Haptoglobin contains an IL6-responsive element (see: IL6RE) (Marinkovic and Baumann, 1990; Baumann et al, 1990; Oliviero and Cortese, 1989; Raynes et al, 1991). TGF-beta has been shown to attenuate glucocorticoid-dependent increases in haptoglobin expression (Yu et al, 1999).
The haptoglobin gene is transcribed actively in adult but not in fetal liver. Serum haptoglobulin levels are increased greatly when there is extensive tissue damage (see also: inflammation, wound healing) or necrosis. One of the major functions appears to prevent loss of body iron from intravascular hemolysis. Haptoglobulin forms complexes with free plasma oxyhemoglobulin that cannot be filtered by the kidneys (Kazim and Atassi, 1981). The heme porphyrin ring is enzymatically removed in the liver and the globin is subsequently degraded. Human haptoglobin probably also binds human myoglobin, albeit with a much lower affinity than that for hemoglobin (Sakata et al, 1986).
Haptoglobin can modulate the functions of lymphocytes and macrophages. Haptoglobin is taken up by neutrophils and is secreted from cytoplasmic granular stores during phagocytosis by those cells. This release can be triggered by TNF-alpha or fMLP (Berkova et al, 1999). Haptoglobin inhibits mitogenic responses of polyclonal lymphocytes to phytohemagglutinin or concanavalin and inhibits or enhances mitogenesis in B-cells in response to bacterial endotoxins, depending on its concentration (Murata and Miyamoto, 1993).
Haptoglobin inhibits respiratory burst activity in neutrophils stimulated with fMLP, arachidonic acid, and opsonized zymosan (Oh et al, 1990). Haptoglobin inhibits the chemotactic response of human granulocytes and differentiated HL-60 cells to fMLP, but does not affect chemotaxis induced by IL8. Haptoglobin also inhibits phagocytosis and reduces intracellular bactericidal activities of granulocytes (Rossbacher et al, 1999).
Haptoglobin has been identified as one of the proteins in the synovial fluids of patients with rheumatoid arthritis that complexes hyaluronic acid and protects it from depolymerisation by activated phagocytes (Hutadilok et al, 1988). Haptoglobin may have immunosuppressive activities (see: SER (suppressive E receptor). Haptoglobin-hamoglobin complexes in human plasma inhibit endothelium dependent relaxation (Edwards et al, 1986).
Haptoglobin stimulates the formation of prostaglandin E2 in osteoblast-like cells isolated from neonatal mouse calvarial bones and potentiates the stimulatory effect of Bradykinin and thrombin on PGE2 formation (Frohlander et al, 1991). Enhanced production of haptoglobin seen in different inflammatory processes may contribute, therefore, to the destruction of bone by inducing the formation of prostanoids capable of stimulating bone resorption (Lerner and Frohlander, 1992).
Haptoglobin has been shown to support angiogenesis. It is found in sera from patients with systemic vasculitis and serum haptoglobin levels in vasculitis patients correlate both with disease and angiogenic activity (Cid et al, 1993). It has been suggested that the increased levels of haptoglobin found in chronic inflammatory conditions may play an important role in tissue repair (see also: inflammation, wound healing). In systemic vasculitis, haptoglobin might compensate also for ischemia by promoting development of collateral vessels.
Haptoglobin has been suggested to be a sensitive parameter for early detection of moderate hemolysis in pregnant women with HELLP syndrome, an extremely progressive form of gestosis characterized by hemolysis, elevated liver enzymes, and low platelet counts (Wilke et al, 1992).
See also: Angiogenesis Dictionary section of this encyclopedia for other entries directly bearing on factors and processes involved in the generation of new blood vessels.
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ENTRY LAST MODIFIED: January 2002
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