The bactericidal/permeability-increasing protein (BPI) in infection and inflammatory disease

Abstract

Gram-negative bacteria (GNB) and their endotoxin present a constant environmental challenge. Endotoxins can potently signal mobilization of host defenses against invading GNB but also potentially induce severe pathophysiology, necessitating controlled initiation and resolution of endotoxin-induced inflammation to maintain host integrity. The bactericidal/permeability-increasing protein (BPI) is a pluripotent protein expressed, in humans, mainly neutrophils. BPI exhibits strong anti-microbial activity against GNB and potent endotoxin-neutralizing activity. BPI mobilized with neutrophils in response to invading GNB can promote intracellular and extracellular bacterial killing, endotoxin neutralization and clearance, and delivery of GNB outer membrane antigens to dendritic cells. Tissue expression by dermal fibroblasts and epithelia could further amplify local levels of BPI and local interaction with GNB and endotoxin, helping to constrain local tissue infection and inflammation and prevent systemic infection and systemic inflammation. This review article focuses on the structural and functional properties of BPI with respect to its contribution to host defense during GNB infections and endotoxin-induced inflammation and the genesis of auto-antibodies against BPI that can blunt BPI activity and potentially contribute to chronic inflammatory disease.

Induction and characterization of endotoxin tolerance in equine peripheral blood mononuclear cells in vitro

“…Endotoxins (lipopolysaccharides, LPS) are unique glycolipids that constitute a major portion of the outer leaflet of the outer membrane that is unique to gram negative bacteria (Schultz and Weiss 2007). Endotoxins consist of a highly conserved lipid A region, a core polysaccharide region and a repeating tetra-or penta-saccharide that constitutes the O-antigen.…”

“…Local responses to endotoxin in tissue generally involve protective inflammatory host-defense cascades but more profound responses at the systemic level can lead to a pathologic state ranging from fever to the fulminant sepsis-syndrome with multiorgan failure and high mortality (Schultz and Weiss 2007).…”

“…Presentation of endotoxin most likely occurs with endotoxin still being an integral component of the outer membrane of gram negative bacteria. The presence of other innate immune-stimulating and antigenic components within the outer membrane makes them primary targets for clearance and resolution of gram negative bacteria/endotoxin-driven inflammation but also potentially important vehicles for delivery of antigenic material to APCs (Schultz and Weiss 2007). BPI is found in plasma in much lower concentrations than LBP.…”

Looped Host Defense Peptide CLP-19 Binds to Microtubules and Inhibits Surface Expression of TLR4 on Mouse Macrophages

“…The binding model with lowest energy was chosen for further investigation using PyMOL software to identify the active sites of the three binding partners. CLP-19 was predicted to interact with the following residues of a-tubulin: Gln 11 371 , and Lys 372 . When the interatomic threshold distance was set at 5 Å , at least 24 pairs of residues might have atomic contact between CLP-19 and a-tubulin and 18 pairs of residues might have contact between CLP-19 and b-tubulin.…”

“…This interest has led to the characterization and isolation of numerous HDPs from animals, insects, plants, and even bacteria. For example, polymyxin B (9,10), bactericidal/permeability-increasing protein (11)(12)(13), , and mastoparan peptide (18) exhibit robust LPS-neutralizing activity in vitro and protection against lethal endotoxin shock in mouse models. Another HDP, the Limulus anti-LPS factor (LALF), which is a small basic protein from the arthropods Tachypleus tridentatus and Limulus polyphemus, is particularly attractive because it inhibits the endotoxin-mediated activation of the coagulation cascade by binding to LPS (19,20).…”