Endogenous apolipoprotein A-I stabilizes ATP-binding cassette transporter A1 and modulates Toll-like receptor 4 signaling in human macrophages.

Apolipoprotein A-I (ApoA-I) is the main functional protein component of human high-density lipoproteins. ApoA-I shows various anti-inflammatory and atheroprotective properties toward macrophages; however, endogenous apoA-I expression has not been investigated in macrophages. We have shown that endogenous apoA-I gene is expressed in human macrophages at both mRNA and protein levels. Endogenous ApoA-I is localized in intracellular vesicles and at the external side of the plasma membrane in association with ATP-binding cassette transporter A1 (ABCA1) and lipid rafts in macrophages. We have shown that endogenous ApoA-I stabilizes ABCA1, moreover, down-regulation of ApoA-I by siRNA results in an increase of Toll-like receptor 4 (TLR4) mRNA and membrane surface protein expression, as well as an enhancement of bacterial lipopolysaccharide (LPS)-induced expression of tumor necrosis factor-alpha (TNF-alpha), interleukin 1 alpha (IL-1 beta), and inducible nitric oxide synthase (NOS2) genes in human macrophages. TNF-alpha stimulates ApoA-I expression and secretion (1.2 +/- 0.2 vs. 4.3 +/- 0.9 ng/mg total protein) in macrophages. Obtained results suggest that endogenous ApoA-I has anti-inflammatory properties, presumably due to ABCA1 stabilization in macrophages; these results elucidate the cell type-specific mechanism of the TNF-alpha-mediated regulation of apoA-I gene expression in monocytes and macrophages.-Mogilenko, D. A., Orlov, S. V., Trulioff, A. S., Ivanov, A. V., Nagumanov, V. K., Kudriavtsev, I. V., Shavva, V. S., Tanyanskiy, D. A., Perevozchikov, A. P. Endogenous apolipoprotein A-I stabilizes ATP-binding cassette transporter A1 and modulates Toll-like receptor 4 signaling in human macrophages. FASEB J. 26, 2019-2030 (2012). www.fasebj.org