C-terminal fragment of alpha 1-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 o f atherosclerosis as a major oxidised LDL receptor mediating lipid accumula tion and foam cell formation. Previously, we found that treatment of monocy te cultures with the carboxyl terminal fragment of al-antitrypsin (C-36) in creases lipid binding and uptake, induces LDL receptor mRNA and CD36 recept or protein expression, and also significantly increases production of pro-i nflammatory molecules. To assess the role of the CD36 receptor in proathero genic monocyte activation by the C-36 fragment, we tested whether specific anti-CD36 receptor antibodies would block the effects of C-36 on monocyte a ctivation. We find that pre-incubation of cells with anti-LDL and anti-CD36 receptor antibodies (10 mug/ml) blocks binding of I-125-C-36 by about 50%. Similarly, cells pre-incubated with oxidised LDL or native LDL at concentr ations from 2.5 to 10 mug/ml showed a loss Of I-125-C-36 binding (up to 49 and 57%) and uptake (up to 47 and 59.8%), respectively. In parallel experim ents, monocytes were first incubated for 1 or 6 h with anti-CD36 antibodies (10 mug/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 TNF alpha were unaffected. In contrast, saturation of LDL recepto rs with excess of anti-LDL (20 mug/ml) significantly inhibited C-36 induced TNF alpha 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 mon ocytes. This also supports important roles for CD36 and LDL receptors in at herogenesis and suggests that blockade of CD36 receptor can be protective i n pro-inflammatory activation of human monocytes. (C) 2001 Elsevier Science Ireland Ltd. All rights reserved.