Apolipoprotein A-I inhibits the production of interleukin-1 beta and tumornecrosis factor-alpha by blocking contact-mediated activation of monocytesby T lymphocytes

Tumor necrosis factor-alpha (TNF-alpha) and interleukin-1 beta (IL-1 beta), essential components in the pathogenesis of immunoinflammatory diseases, a re strongly induced in monocytes by direct contact with stimulated T lympho cytes. This study demonstrates that adult human serum (HS) but not fetal ca lf or cord blood serum displays inhibitory activity toward the contact-medi ated activation of monocytes by stimulated T cells, decreasing the producti on of both TNF-alpha and IL-1 beta. Fractionation of HS and N-terminal micr osequencing as well as electroelution of material subjected to preparative electrophoresis revealed that apolipoprotein A-I (apo A-I), a "negative" ac ute-phase protein, was the inhibitory factor. Functional assays and flow cy tometry analyses show that high-density lipoprotein (HDL)-associated apo A- I inhibits contact-mediated activation of monocytes by binding to stimulate d T cells, thus inhibiting TNF-alpha and IL-1 beta production at both prote in and messenger RNA levels. Furthermore, apo A-I inhibits monocyte inflamm atory functions in peripheral blood mononuclear cells activated by either s pecific antigens or lectins without affecting cell proliferation. These res ults demonstrate a new antiinflammatory activity of HDL-associated apo A-I that might have modulating functions in nonseptic conditions. Therefore, be cause HDL has been shown to bind and neutralize lipopolysaccharide, HDL app ears to play an important part in modulating both acute and chronic inflamm ation. The novel anti-inflammatory function of apo A-I reported here might lead to new therapeutic approaches in inflammatory diseases such as rheumat oid arthritis, multiple sclerosis, systemic lupus erythematosus, and athero sclerosis. (Blood, 2001;97:2381-2389) (C) 2001 by The American Society of H ematology.