Inhibition of Lipopolysaccharide-Induced Inflammatory Responses by an Apolipoprotein AI Mimetic Peptide

Abstract

Abstract-Previous studies suggest that high-density lipoprotein and apoAI inhibit lipopolysaccharide (LPS)-induced inflammatory responses. The goal of the current study was to test the hypothesis that the apoAI mimetic peptide L-4F exerts antiinflammatory effects similar to apoAI. Pretreatment of human umbilical vein endothelial cells (HUVECs) with LPS induced the adhesion of THP-1 monocytes. Incubation of cells with LPS and L-4F (1 to 50 g/mL) reduced THP-1 adhesion in a concentration-dependent manner. This response was associated with a significant reduction in the synthesis of cytokines, chemokines, and adhesion molecules. L-4F reduced vascular cell adhesion molecule-1 expression induced by LPS or lipid A, whereas a control peptide (Sc-4F) showed no effect. In contrast to LPS treatment, L-4F did not inhibit IL-1␤-or tumor necrosis factor-␣-induced vascular cell adhesion molecule-1 expression. 1 Approximately 50% of patients in intensive care units develop severe sepsis, and the overall mortality rate of all affected patients is 29%. 1 Mortality is attributable, in large part, to the cytotoxic actions of lipopolysaccharide (LPS) (endotoxin), a component of the outer membrane of Gram-negative bacteria. LPS is composed of a core oligosaccharide, a repeating polysaccharide side chain, and the glycolipid moiety lipid A. 2 Proinflammatory and cytotoxic effects of LPS are mediated by lipid A. 3 LPS is released from bacterial membranes into the circulation where it interacts with lipopolysaccharide binding protein (LBP), a member of the superfamily of phospholipid binding proteins. LBP binds to lipid A and mediates the disaggregation of LPS to form an LBP-LPS complex. 4 LBP directs LPS to membrane-associated CD14 receptors (mCD14) on myeloid cells 5 including monocytes and neutrophils. mCD14 is a cell surface-anchored protein that facilitates the binding of LPS and activation of Toll-like receptor (TLR) 4 which acts as the cellular transducer of LPS action. 2,6 Plasma LPS-LBP may also interact with soluble CD14 to form a complex that activates TLRs on endothelial, epithelial, Kuppfer, and other cells. 7 By activating nuclear factor B-dependent signaling mechanisms, LPS stimulates the synthesis/release of inflammatory cytokines, which play an important role in the innate immune response. 8,9 Dysregulation of this response leads to the development of endothelial dysfunction, intravascular coagulation, pulmonary injury, multiple organ failure, and death.The acute-phase response to bacterial infection induces changes in plasma lipoprotein levels that are characterized by Original

HDL in Infectious Diseases and Sepsis

“…Parker et al (1995), Pajkrt et al (1996) ApoA-I mimetics Gupta et al (2005) Parasites infections Trypanosoma Leishmania…”

“…Apolipoprotein mimetic peptides represent an emerging area of HDL therapy; the most effective apoA-I mimetic peptide is 4F, which has been shown to improve HDL quality/function (Sherman et al 2010;White et al 2009). 4F mimics also anti-inflammatory properties of HDL: in vitro, 4F inhibits the expression of pro-inflammatory mediators in LPS-treated cells by directly binding to LPS, thus resulting in the inhibition of LPS binding to LBP (Gupta et al 2005). In endotoxemic rats, the administration of 4F after LPS injection results in the attenuation of acute lung injury and increased survival, probably due to the preservation of circulating HDL-C and the downregulation of inflammatory pathways (Kwon et al 2012); 4F also prevents defects in vascular functions and is associated with a decrease in plasma endotoxin activity in rats (Dai et al 2010) and improved cardiac performance in LPS-treated rats (Datta et al 2011).…”

The Effect of Apolipoprotein Mimetic Peptides in Inflammatory Disorders Other Than Atherosclerosis

“…Treatment of human umbilical vein endothelial cells with bacterial lipopolysaccharide (LPS) induced the adhesion of THP-1 monocytes (Gupta 2005). Incubation of the endothelial cells with the apoA-I mimetic peptide L-4F (L-4F is identical to D-4F except that it is synthesized from all L-amino acids instead of D-amino acids as is the case for D-4F) dose dependently reduced THP-1 adhesion.…”

“…The ability of L-4F to prevent the binding of LPS to its binding protein was shown to result from a physical interaction between the apoA-I mimetic peptide and LPS. The authors concluded that apoA-I mimetic peptides might be useful in the treatment of endotoxemia (Gupta 2005).…”

Albumina modificada por glicação avançada sensibiliza macrófagos à inflamação prejudicando o transporte reverso de colesterol e a atividade anti-inflamatória da HDL

“…Redução na secreção de citocinas inflamatórias em macrófagos expostos à albumina-AGE foi obeservada apenas quando a HDL foi incubada juntamente com o S100B ou LPS. Porém, a diminuição na secreção de mediadores inflamatórios nessa situação pode estar relacionado à capacidade da HDL se ligar a porção lipídio A do LPS e, dessa forma, inibir seu efeito inflamatório (Brandenburg et al, 2002;Gupta et al,2005).…”