Identification of haptoglobin as an alternative ligand for CD11b/CD18

Division of Clinical Immunology, Department of Medicine, University of Leuven, Belguim.
The Journal of Immunology (Impact Factor: 5.36). 05/1996; 156(7):2542-52.
Source: PubMed

ABSTRACT Haptoglobin is an acute phase protein with presumed anti-inflammatory activities. We report that purified fluorescein-labeled haptoglobin 1-1 binds to THP1 and U937 promonocytic cell lines, to monocytes, to granulocytes, and to a subset of CD8+ T cells and to NK cells. Studies with radioiodinated haptoglobin on THP1 cells were consistent with specific binding to one class of receptors with a density of 1.7 x 10(5) binding sites per cell and a low affinity of 6.5 x 10(-6) Kd. Binding was increased by Ca2+ and by Ca2+ and ADP. Binding to THP1 and U937 cells could be inhibited by preincubation with nonfluoresceinated haptoglobin and by fibrinogen, but not by albumin, transferrin, or alpha1-acid glycoprotein. Fibrinogen binds to the CD11b/CD18 integrin. We therefore examined whether haptoglobin has the same receptor. The anti-CD11b mAb44 indeed inhibited the binding of fluoresceinated haptoglobin to THP1 and U937 cell lines, and haptoglobin inhibited the binding of the anti-CD11b mAb anti-Leu15 and mAb44 to both cell lines. An anti-CD18 mAb partly inhibited the binding of fluoresceinated haptoglobin to THP1 and U937, indicating that the beta-chain of MAC-1 is also involved in haptoglobin binding. There was no interference between the binding of anti-CD4, anti-CD11a, or anti-CD11c mAb and haptoglobin binding to THP1 cells. Binding of haptoglobin to purified CD11b/CD18 indicates that it binds directly to the receptor. Haptoglobin is an alternative low affinity ligand for the CD11b/CD18 integrin, suggesting that this acute phase protein might regulate MAC-1-dependent cell function in vivo.

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    • "The exact mechanism underlying the beneficial role of Hp in ICH is not entirely clear. Even though neutralization of Hb appears to offer logical explanation for Hp benefit in ICH, Hp has also been proposed to act as extracellular chaperon (Yerbury et al., 2005), inhibitor of cathepsin B activity (Snellman and Sylven, 1967), or ligand for CD11b/CD18 and CD22 (El Ghmati et al., 1996; El-Ghmati et al., 2002). As such, it raises the possibility that Hb could protect cells by improving generalized resistance of neurons to Hb-mediated injury. "
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    ABSTRACT: After intracerebral hemorrhage (ICH), the brain parenchyma is exposed to blood containing red blood cells (RBCs) and consequently to its lysis products. Iron-rich hemoglobin (Hb) is the most abundant protein in RBCs. When released into the brain parenchyma during hemolysis, Hb becomes a central mediator of cytotoxicity. Our study indicates that haptoglobin (Hp), an acute-phase response protein primarily synthesized in the liver and known to bind and neutralize Hb in the bloodstream, is also expressed in brain in which it plays an important role in defending neurons from damage induced by hemolytic products after ICH. We demonstrate that the Hb-induced hypohaptoglobinemia aggravates ICH-induced brain damage while pharmacologic intervention with sulforaphane to induce brain Hp is linked to a reduction in brain damage. In agreement with these findings, Hp deficiency worsens whereas Hp overexpression alleviates ICH-mediated brain injury. We also identified that oligodendroglia are the primary source of brain-derived Hp among brain cells and that oligodendroglia-released Hp plays protective roles against Hb-mediated toxicity to neurons and oligodendrocytes. We conclude that Hp, particularly the brain-derived Hp, plays cytoprotective roles and represents a potential therapeutic target for ICH treatment.
    The Journal of Neuroscience : The Official Journal of the Society for Neuroscience 12/2009; 29(50):15819-27. DOI:10.1523/JNEUROSCI.3776-09.2009 · 6.75 Impact Factor
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    • "02 ) . Some families of integrin adhesion receptors such as CD11a - c and CD18 are involved in cell - to - cell viral trans - mission and contribute to variations in the survival rates af - ter HIV infection . The identification of Hp as an alternative ligand for CD11b / CD18 suggests that this protein plays an important role in HIV infection ( El Ghmati et al . , 1996 ; Quaye et al . , 2000a ) . In addition , the residual iron circulat - ing in the plasma of HIV - seropositive patients could en - hance Hb - driven oxidative stress , thereby favoring viral replication and transmission . Delanghe et al . ( 1998a ) re - ported that HIV - seropositive patients with the Hp2 - 2 phe - notype had a higher m"
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    ABSTRACT: Haptoglobin (Hp) is a plasma glycoprotein, the main biological function of which is to bind free hemoglobin (Hb) and prevent the loss of iron and subsequent kidney damage following intravascular hemolysis. Haptoglobin is also a posi-tive acute-phase protein with immunomodulatory properties. In humans, the HP locus is polymorphic, with two codominant alleles (HP1 and HP2) that yield three distinct genotypes/phenotypes (Hp1-1, Hp2-1 and Hp2-2). The corresponding proteins have structural and functional differences that may influence the susceptibility and/or out-come in several diseases. This article summarizes the available data on the structure and functions of Hp and the possible effects of Hp polymorphism in a number of important human disorders.
    Genetics and Molecular Biology 01/2008; 31(3). DOI:10.1590/S1415-47572008000400002 · 0.88 Impact Factor
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    • "This may explain why the haptoglobin level in our OLT patient was low during immunosuppressant treatment. Intriguingly, haptoglobin affinity to CD11b, which is expressed on the majority of lymph node dendritic cell (DC) subsets (myeloid and plasmacytoid DCs), could prevent the maturation of this DC subset for regulation of Langerhans cell function, resulting in T-cell skewing or in the induction of regulatory T-cells [15] [17] [19] [20]. Itano et al. also demonstrated a role of haptoglobin as a mediator in nasal tolerance induction [21], which suggests that haptoglobin may qualify as a (bio)marker for effective immunotherapy. "
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    ABSTRACT: In orthotopic liver transplantation (OLT), tolerance is induced in a certain combination of donors and a recipient in rats and, in some clinical cases, rejection has not occurred in OLT patients after weaning off immunosuppression. However, this mechanism has not yet been elucidated. Among our cases of liver transplantation (LTx), one OLT patient (Patient A) has not required immunosuppressive drugs for the last 5 years, following post-transplant lymphoproliferative disease (PTLD). This patient's serum interleukin-2 levels were undetectable following withdrawal of immunosuppressants. The same serum taken after discontinuing the immunosuppressants inhibited concanavalin A blast cultured cells and up-regulated the IL-4/IFN-gamma gene expression ratio. These results suggested that other proteins were induced following withdrawal of immunosuppressants. Proteomic assay demonstrated 12 differentiated spots exclusive to this patient where immunosuppressants have been discontinued. Haptoglobin, found to have immunosuppressive activity in vitro, may play an important role in the maintenance of drug-free tolerance as a natural immunological suppressor after cessation of immunosuppression. Proteomic analysis will allow us to develop a novel weaning protocol for patients on long-term immunosuppression to avoid major immunosuppressant-related complications.
    Transplant Immunology 03/2007; 17(2):137-46. DOI:10.1016/j.trim.2006.06.001 · 1.83 Impact Factor
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