Disease relevance of LBP

• In recent studies, we found that LBP also mediates cytokine induction caused by compounds derived from Gram-positive bacteria, including lipoteichoic acid and peptidoglycan fragments [1].
• In this study, we used an acetate auxotroph of Neisseria meningitidis serogroup B to facilitate metabolic labeling of bacterial endotoxin and compared interactions of purified endotoxin aggregates and of membrane-associated endotoxin with LBP, CD14, and endotoxin-responsive cells [2].
• Both purified endotoxin aggregates and blebs activate monocytes and endothelial cells in a LBP-, CD14-, and TLR4/MD-2-dependent fashion, but the blebs were 3-10-fold less potent when normalized for the amount of endotoxin added [2].
• Here we show that CD14 and LBP can also bind to lipoteichoic acid from the gram-positive bacterium Bacillus subtilis [3].
• OBJECTIVES: The present in vitro study aimed to investigate the possible effect of LBP and E. coli LPS interaction on the expression of cellular LPS receptors and IL-6 by human gingival fibroblast [4].
• These data suggest that transcriptional regulation of the LBP gene contributes to the risk for developing GN bacteremia and death after HCT [5].

Psychiatry related information on LBP

• METHODS: 29 morbidly obese candidates for bariatric surgery with LBP, weight 132.5+/-27 (mean+/-SD) kg and BMI 47.2+/-8.8 kg/m2 were examined for their functional status using psychometric instruments specifically designed to objectively assess the patients' complaints [6].
• SUMMARY OF BACKGROUND DATA: In chronic LBP, the interrelationship between physical impairment, pain, and disability is particularly complicated, due to the influence of various psychological factors and the lack of unequivocal methods for assessing impairment [7].
• Chronic disabling LBP commonly is confounded by chronic pain, emotional troubles, poor job satisfaction, alcohol and narcotic abuse, and compensation issues, just to identify a few [8].

High impact information on LBP

• The discovery in 1986 of a plasma protein termed LPS binding protein (LBP) led to the discovery of unanticipated mechanisms of LPS-induced cell activation [9].
• The importance of the LBP/CD14-dependent pathway has been definitively demonstrated by experiments using immunologic, biochemical, and molecular biologic approaches [10].
• LBP may control the response to LPS under physiologic conditions by forming high-affinity complexes with LPS that bind to monocytes and macrophages, which then secrete tumor necrosis factor [11].
• LBP shares sequence identity with another LPS binding protein found in granulocytes, bactericidal/permeability-increasing protein, and with cholesterol ester transport protein of the plasma [11].
• Complexes of LPS and rsCD14 formed in the absence of LBP or other serum proteins strongly stimulate integrin function on PMN and expression of E-selectin on endothelial cells, demonstrating that LBP is not necessary for CD14-dependent stimulation of cells [12].

Chemical compound and disease context of LBP

• LBP also potentiated BPI-mediated permeabilization of the E. coli outer membrane to actinomycin D by about 100-fold but had no permeabilizing activity of its own [13].
• Lipopolysaccharide binding protein (LBP) is a liver-derived acute phase protein which is implicated in modulating the host responses to lipopolysaccharide (LPS) from Gram-negative bacteria [14].
• LPS-binding protein (LBP) is a 60-kDa acute phase glycoprotein capable of binding the LPS of Gram-negative bacteria and facilitating its diffusion [15].
• Whole blood was collected in EDTA from 28 undialyzed patients with chronic renal failure (undialyzed CRF), 36 patients on chronic HD (HD) and 15 healthy controls, and plasma levels of LBP and BPI were measured by a sandwich ELISA [16].
• In human hepatoma cell lines stimulation with IL-1 beta, IL-6, TNF-alpha and dexamethasone leads to strong transcriptional activation of the LBP gene in a dose- and time-dependent manner [17].

Biological context of LBP

• LPS binding protein (LBP) is an acute-phase protein synthesized predominantly in the liver of the mammalian host [1].
• The phagocytosis is strictly dependent both on LBP and on CD14 [3].
• We have analyzed the exon-intron organization of the LBP gene and the nucleotide sequence of its approximately 20 kb spanning 5'- and 3'-untranslated regions [18].
• The LBP gene includes 15 exons, and the 2-kb promoter contains recognition elements of acute phase-typical reactants and a repetitive 12-mer motif with an as yet unknown protein-binding property [18].
• These data clearly demonstrate that LBP and CD14/TLR4 engagement is directly involved in LPS-mediated functional activation and innate immune gene expression in chicken heterophils [19].

Anatomical context of LBP

• The neutrophil granular protein bactericidal/permeability-increasing protein (BPI) competes with LBP for endotoxin binding and functions as a molecular antagonist of LBP-endotoxin interactions [20].
• Furthermore, we were able to show that LBP transfers lipopeptides to CD14 on human monocytes using FACS analysis [1].
• These data suggest that, upon NTHi infection, low numbers of bacteria binding LBP may activate TLR4-bearing cells, such as alveolar macrophages, and consequently induce an inflammatory response [21].
• CONCLUSIONS: This study suggests that LBP may down-regulate the expression of IL-6 by human gingival fibroblast [4].
• The expression of LBP was confined to the gingival epithelium, whereas mCD14 was observed around the epithelium-connective tissue interface [22].

Associations of LBP with chemical compounds

• PLTP mediates the transfer and exchange of phospholipids between lipoprotein particles, whereas LBP transfers bacterial lipopolysaccharide (LPS) either to lipoprotein particles or to CD14, a soluble and cell-surface receptor for LPS [23].
• Induction of tumor necrosis factor production from monocytes stimulated with mannuronic acid polymers and involvement of lipopolysaccharide-binding protein, CD14, and bactericidal/permeability-increasing factor [24].
• We show that induction of LBP expression is transcriptionally regulated and is dependent on stimulation with IL-1beta, IL-6, and dexamethasone [25].
• Overall differences in charge and electrostatic potential between BPI and LBP suggest that BPI's bactericidal activity is related to the high positive charge of its NH2-terminal domain [26].
• On sodium dodecyl sulphate polyacrylamide electrophoresis, bovine LBP demonstrated a single band with a molecular mass of 58 kDa [14].

Physical interactions of LBP

• The serum protein lipopolysaccharide-binding protein (LBP) binds to the lipid A component of bacterial endotoxin and facilitates its delivery to the CD14 antigen on the macrophage, where inflammatory cytokines are released and a cascade of host mediators is initiated [20].
• In contrast, LBP bound to NTHi did not promote any increased signaling mediated by TLR2, compared with NTHi without LBP [21].
• BPI inhibited the binding of poly(M) to monocytes in the presence of LBP, LBP-sCD14, or 10% human serum [24].
• BACKGROUND: This study aimed to investigate the interrelationship of in vivo expression of lipopolysaccharide-binding protein (LBP) and membrane-bound CD14 (mCD14) in human gingival tissues as well as the coexpression of Toll-like receptors (TLR) 2 and 4 in association with periodontal conditions [22].
• The TNF-alpha production triggered by reference LPS and purified fungal mannans required the presence of LPS-binding protein (LBP), and these responses were inhibited by anti-CD14 and anti-TLR4 antibodies, but not by anti-TLR2 antibody [27].

Regulatory relationships of LBP

• BPI was found to inhibit TNF production from monocytes stimulated with poly(M) in the presence of LBP, LBP-sCD14, or 10% human serum [24].
• The lipopolysaccharide-binding protein is a secretory class 1 acute-phase protein whose gene is transcriptionally activated by APRF/STAT/3 and other cytokine-inducible nuclear proteins [25].
• The COOH-terminal domain of LBP promotes delivery of LPS to CD14 on both polymorphonuclear leukocytes and monocytes resulting in cell activation [28].
• We further demonstrate that purified recombinant human BPI can inhibit LBP-mediated LPS binding to cells and their subsequent activation [29].
• These data were confirmed employing primary human hepatocytes, where TGF-beta 1 also inhibited LBP protein synthesis [30].

Other interactions of LBP

• TLR4-dependent delivery of endotoxin to human embryonic kidney (HEK) cells and cell activation at picomolar concentrations of endotoxin occurred with the purified endotoxin-MD-2 complex, but not with purified endotoxin aggregates with or without LBP and/or sCD14 [31].
• Multiple sequence alignment suggested that, in PLTP, a cluster of hydrophobic residues substitutes for a cluster of positively charged residues found on the surface of LBP and BPI, which is critical for interaction with lipopolysaccharides [32].
• PLTP shares 24% sequence similarity with LBP [23].
• Detailed sequence comparison revealed a closer relatedness of LBP with PLTP than with CETP as demonstrated by an almost identical intron positioning [18].
• Levels of LBP in serum and in SF were significantly higher in patients with RA and ReA than in the control group of degenerative arthropathies [33].

Analytical, diagnostic and therapeutic context of LBP

• Physical association of apoA-I, LBP, and FHRP in these particles was further confirmed using double immunodiffusion, and association of LBP and FHRP in plasma was confirmed by coimmunoprecipitation [34].
• Flow cytometry showed that NTHi in the stationary phase bound more LBP than did log-phase bacteria [21].
• Lipopolysaccharide-binding protein and bactericidal/permeability-increasing factor during hemodialysis: clinical determinants and role of different membranes [35].
• Furthermore, cloning of the LBP promoter revealed the presence of regulatory elements, including the common APR promoter motif APRE/STAT-3 (acute-phase response element/signal transducer and activator of transcription 3) [25].
• Isolation by gel filtration of LOS(agg):protein aggregates formed by the interaction of LOS(agg) with either LBP or sCD14 alone revealed that the sequence of LOS-protein interactions as well as the step(s) at which albumin is necessary for the production of bioactive LOS:sCD14 were specific [36].

References