C-terminal fragment of alpha1-antitrypsin activates human monocytes to a pro-inflammatory state through interactions with the CD36 scavenger receptor and LDL receptor.
Monocyte scavenger receptor, CD36 has been implicated in the pathogenesis of atherosclerosis as a major oxidised LDL receptor mediating lipid accumulation and foam cell formation. Previously, we found that treatment of monocyte cultures with the carboxyl terminal fragment of alpha1-antitrypsin (C-36) increases lipid binding and uptake, induces LDL receptor mRNA and CD36 receptor protein expression, and also significantly increases production of pro-inflammatory molecules. To assess the role of the CD36 receptor in proatherogenic monocyte activation by the C-36 fragment, we tested whether specific anti-CD36 receptor antibodies would block the effects of C-36 on monocyte activation. We find that pre-incubation of cells with anti-LDL and anti-CD36 receptor antibodies (10 microg/ml) blocks binding of 125I-C-36 by about 50%. Similarly, cells pre-incubated with oxidised LDL or native LDL at concentrations from 2.5 to 10 microg/ml showed a loss of 125I-C-36 binding (up to 49 and 57%) and uptake (up to 47 and 59.8%), respectively. In parallel experiments, monocytes were first incubated for 1 or 6 h with anti-CD36 antibodies (10 microg/ml) prior to adding C-36 peptide. Anti-CD36 antibodies suppressed C-36-induced production of gelatinase B, monocyte chemoattractant protein-1, interleukin-6 and cellular oxygen consumption to control levels, whereas levels of TNFalpha were unaffected. In contrast, saturation of LDL receptors with excess of anti-LDL (20 microg/ml) significantly inhibited C-36 induced TNFalpha levels. Results indicate that the C-36 peptide binds to both LDL and CD36 scavenger receptors which involves selective upregulation of pro-inflammatory molecules and activation of the respiratory burst in human monocytes. This also supports important roles for CD36 and LDL receptors in atherogenesis and suggests that blockade of CD36 receptor can be protective in pro-inflammatory activation of human monocytes.
Janciauskiene
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Gastroenterology-Hepatology Section, Department of Medicine, University Hospital Malmö, 20502 Malmö, Sweden. sabina.janciauskiene@medforsk.mas.lu.se
Moraga
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F
Lindgren
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D001161:Arteriosclerosis / Q000503:physiopathology; D018955:CD36 Antigens / Q000378:metabolism / Q000494:pharmacology / Q000502:physiology*; D002478:Cells, Cultured; D018932:Chemokine CCL2 / Q000378:metabolism; D006801:Humans; D018836:Inflammation Mediators / Q000378:metabolism*; D015850:Interleukin-6 / Q000378:metabolism; D008077:Lipoproteins, LDL / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D008565:Membrane Proteins; D009000:Monocytes / Q000378:metabolism / Q000502:physiology*; D010084:Oxidation-Reduction; D010101:Oxygen Consumption; D010446:Peptide Fragments / Q000494:pharmacology / Q000502:physiology*; D011971:Receptors, Immunologic; D011973:Receptors, LDL / Q000378:metabolism / Q000502:physiology*; D018110:Receptors, Lipoprotein; D051116:Receptors, Scavenger; D051122:Scavenger Receptors, Class B; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D000515:alpha 1-Antitrypsin / Q000494:pharmacology / Q000502:physiology*
D018955:CD36 Antigens; D018932:Chemokine CCL2; D018836:Inflammation Mediators; D015850:Interleukin-6; D008077:Lipoproteins, LDL; D008565:Membrane Proteins; D010446:Peptide Fragments; D011971:Receptors, Immunologic; D011973:Receptors, LDL; D018110:Receptors, Lipoprotein; D051116:Receptors, Scavenger; C454739:Scarb1 protein, mouse; D051122:Scavenger Receptors, Class B; D014409:Tumor Necrosis Factor-alpha; D000515:alpha 1-Antitrypsin; C099252:oxidized low density lipoprotein; D020780:Matrix Metalloproteinase 9