Submitted on February 7, 2006
Revised on June 15, 2006
Accepted on June 26, 2006
Autoimmune OxLDL immune-complexes activate the classical pathway of complement and induce cytokine production by mono mac 6 cells and primary human macrophages
Antonio F. Saad, Gabriel Virella, Charlyne Chassereau, Robert J. Boackle, and Maria F. Lopes-Virella
Department of Medicine, Division of Endocrinology-Metabolism-Nutrition, V.A. Strom Thurmond Research Center, Charleston, SC, Charleston, SC 29403
Corresponding Author: virellam{at}musc.edu
Oxidized LDL is immunogenic and induces autoimmune responses in humans. OxLDL antibodies are predominantly of the proinflammatory IgG1 and IgG3 isotypes. We tested the capacity of immune complexes prepared with copper-oxidized human LDL and affinity chromatography-purified human oxLDL antibodies (oxLDL-IC) to activate complement and to induce cytokine release by monomac-6 (MM6) cells and by primary human macrophages. The levels of C4d and C3a were significantly higher in human serum incubated with oxLDL-IC than after incubation with oxLDL or oxLDL antibody, indicating complement activation by the classical pathway. MM6 cells and primary human macrophages were incubated with oxLDL-IC, with or without prior conditioning with interferon-. After 18 h incubation, both MM6 cells and primary human macrophages released significantly higher levels of proinflammatory cytokines after incubation with oxLDL-IC than after incubation with oxLDL or with oxLDL antibody, both in primed and non-primed cells. OxLDL-IC were more potent activators of MM6 cells than keyhole limpet hemocyanin-IC. Blocking FcRI with monomeric IgG1 significantly depressed the response of MM6 cells to oxLDL-IC. In conclusion, human oxLDL-IC have proinflammatory properties, as reflected by their capacity to activate the classical pathway of complement and to induce pro-inflammatory cytokine release from MM6 cells and primary human macrophages.
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