Apolipoprotein A-I inhibits the production of interleukin-1β and tumor necrosis factor-α by blocking contact-mediated activation of monocytes by T lymphocytes

Abstract

Tumor necrosis factor-␣ (TNF-␣) and interleukin-1␤ (IL-1␤), essential components in the pathogenesis of immunoinflammatory diseases, are strongly induced in monocytes by direct contact with stimulated T lymphocytes. This study demonstrates that adult human serum (HS) but not fetal calf or cord blood serum displays inhibitory activity toward the contact-mediated activation of monocytes by stimulated T cells, decreasing the production of both TNF-␣ and IL-1␤. Fractionation of HS and N-terminal microsequencing as well as electroelution of material subjected to preparative electrophoresis revealed that apolipoprotein A-I (apo A-I), a "negative" acute-phase protein, was the inhibitory factor. Functional assays and flow cytometry analyses show that highdensity lipoprotein (HDL)-associated apo A-I inhibits contact-mediated activation of monocytes by binding to stimulated T cells, thus inhibiting TNF-␣ and IL-1␤ production at both protein and messenger RNA levels. Furthermore, apo A-I inhibits monocyte inflammatory functions in peripheral blood mononuclear cells activated by either specific antigens or lectins without affecting cell proliferation. These results demonstrate a new antiinflammatory activity of HDL-associated apo A-I that might have modulating functions in nonseptic conditions. Therefore, because HDL has been shown to bind and neutralize lipopolysaccharide, HDL appears to play an important part in modulating both acute and chronic inflammation. IntroductionTumor necrosis factor-␣ (TNF-␣) and interleukin-1␤ (IL-1␤) are strongly induced in monocytes by direct contact with stimulated T lymphocytes, both cells involved in immunoinflammatory diseases such as rheumatoid arthritis, multiple sclerosis, systemic lupus erythematosus, and atherosclerosis. The importance of TNF-␣ and IL-1 in chronic inflammation has been well established. Based on the premise that T lymphocytes play a pivotal role in the pathogenesis of chronic inflammatory diseases, we demonstrated that direct cell-cell contact with stimulated T lymphocytes is a major stimulus triggering the production of large amounts of TNF-␣ and IL-1␤ in monocytes. [1][2][3] Various stimuli are able to induce T cells to activate monocytes by direct cellular contact: (1) mitogens, for example, a combination of phytohemagglutinin (PHA) and phorbol myristate acetate (PMA), 1,4-6 (2) cross-linking of CD3 by immobilized anti-CD3 monoclonal antibody (mAb) with or without cross-linking of the costimulatory molecule CD28, 7,8 (3) antigen-recognition on antigen-specific T-cell clones, 8 and (4) cytokines. 9 The identity of the ligands on plasma membrane of stimulated T cells that trigger the signaling of monocytemacrophages as well as that of the counter-ligands on monocytes is still elusive. However, in the human system some of the signaling may be attributed to ␤ 2 -integrins, CD69, CD23, CD40-CD40L and lymphocyte activation gene-3 (LAG-3). 1,4,5,10-14 Membrane-associated TNF-␣ and IL-1 do not play a crucial part in this cellular interaction, contrasting with their sign...

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