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Gene Review

BPI  -  bactericidal/permeability-increasing protein

Homo sapiens

Synonyms: BPIFD1, Bactericidal permeability-increasing protein, CAP 57, rBPI
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Disease relevance of BPI

  • BPI may attenuate the local inflammatory response and the systemic toxicity of endotoxin release during gram-negative infections [1].
  • Under optimal conditions for potentiation, fewer than 100 BPI molecules were required to kill a single E. coli J5 bacterium [2].
  • Human bactericidal/permeability-increasing protein (BPI) from neutrophils and a recombinant amino-terminal fragment, rBPI23, bind to and are cytotoxic for gram-negative bacteria both in vitro and ex vivo in plasma or whole blood [2].
  • Due to its inhibitory activity for various LPS, BPI has therapeutic potential in endotoxic shock [3].
  • 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 [4] .

High impact information on BPI

  • We designed a multistage study in the genetically isolated population of the Central Valley of Costa Rica to identify genes that promote susceptibility to severe BP (termed BPI), and screened the genome ot two Costa Rican BPI pedigrees (McInnes et al., submitted) [5] .
  • The bactericidal/permeability-increasing protein (BPI) of polymorphonuclear leukocytes (PMN) is a potent cytotoxin, specific for Gram-negative bacteria, that also inhibits endotoxin activity by neutralizing isolated bacterial lipopolysaccharides (LPS) [6].
  • This activity is weak relative to holo-BPI and the 25 kD N-terminal fragment in the Limulus and PMN-priming assay, but is comparable for inhibition of TNF production in whole blood [6].
  • Holo-BPI and the 25 kD fragment have similar neutralizing potency (in nanomolar range) in all assays toward "smooth" LPS from Escherichia coli O111:B4 and O55:B5 (possessing long chain polysaccharide or O-antigen), and "deep rough" LPS from Salmonella minnesota Re595 mutant (possessing no O-antigen) [6].

Chemical compound and disease context of BPI


Biological context of BPI


Anatomical context of BPI


Associations of BPI with chemical compounds

  • We have previously shown that human bactericidal/permeability-increasing protein (BPI) is able to inhibit serum-dependent lipopolysaccharide (LPS)-mediated activation of human monocytes and neutrophils in vitro, and to counteract the lethal effects of LPS challenge in vivo [16].
  • We studied circulating BPI across categories of glucose tolerance [17].
  • In parallel to improved insulin sensitivity, plasma BPI significantly increased in the metformin group but not in the placebo group [17].
  • There was no correlation between serum creatinine and plasma levels of either LBP or BPI [4].
  • 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 [18].

Physical interactions of BPI


Regulatory relationships of BPI

  • We further demonstrate that purified recombinant human BPI can inhibit LBP-mediated LPS binding to cells and their subsequent activation [16].
  • BPI and LBP(N)-BPI(C) promote apparently CD14-independent LPS association to monocytes without cell activation [23].
  • Thus, BPI that is functionally active against mucoid P. aeruginosa strains is expressed in the airways of CF patients but may be hampered by autoantibodies, resulting in chronic infection [24] .
  • Added BPI in nanomolar concentrations killed each of three encapsulated strains of E. coli and in closely parallel fashion inhibited tumor necrosis factor (TNF) release [9].

Other interactions of BPI

  • 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 [1].
  • Recently, the crystal structure of one of the members of the gene family, bactericidal permeability increasing protein, was solved, providing potential insights into the mechanisms of action of CETP and PLTP [25].
  • In the present study, we used the crystallographic data available for BPI to build a three-dimensional model for PLTP [26].
  • CONCLUSION: BPI and cathepsin G are the major antigenic targets of ANCA seen in patients with SSc [27].
  • Patients with antibodies to BPI had lower skin score, whereas no patient with antibodies to MPO had renal disease [27].

Analytical, diagnostic and therapeutic context of BPI


  1. Relative concentrations of endotoxin-binding proteins in body fluids during infection. Opal, S.M., Palardy, J.E., Marra, M.N., Fisher, C.J., McKelligon, B.M., Scott, R.W. Lancet (1994) [Pubmed]
  2. Human lipopolysaccharide-binding protein potentiates bactericidal activity of human bactericidal/permeability-increasing protein. Horwitz, A.H., Williams, R.E., Nowakowski, G. Infect. Immun. (1995) [Pubmed]
  3. Competition between bactericidal/permeability-increasing protein and lipopolysaccharide-binding protein for lipopolysaccharide binding to monocytes. Heumann, D., Gallay, P., Betz-Corradin, S., Barras, C., Baumgartner, J.D., Glauser, M.P. J. Infect. Dis. (1993) [Pubmed]
  4. Plasma lipopolysaccharide binding protein and bactericidal/permeability increasing factor in CRF and HD patients. Pereira, B.J., Sundaram, S., Snodgrass, B., Hogan, P., King, A.J. J. Am. Soc. Nephrol. (1996) [Pubmed]
  5. Genetic mapping using haplotype, association and linkage methods suggests a locus for severe bipolar disorder (BPI) at 18q22-q23. Freimer, N.B., Reus, V.I., Escamilla, M.A., McInnes, L.A., Spesny, M., Leon, P., Service, S.K., Smith, L.B., Silva, S., Rojas, E., Gallegos, A., Meza, L., Fournier, E., Baharloo, S., Blankenship, K., Tyler, D.J., Batki, S., Vinogradov, S., Weissenbach, J., Barondes, S.H., Sandkuijl, L.A. Nat. Genet. (1996) [Pubmed]
  6. Endotoxin-neutralizing properties of the 25 kD N-terminal fragment and a newly isolated 30 kD C-terminal fragment of the 55-60 kD bactericidal/permeability-increasing protein of human neutrophils. Ooi, C.E., Weiss, J., Doerfler, M.E., Elsbach, P. J. Exp. Med. (1991) [Pubmed]
  7. Host defense in oral and airway epithelia: chromosome 20 contributes a new protein family. Bingle, C.D., Gorr, S.U. Int. J. Biochem. Cell Biol. (2004) [Pubmed]
  8. Heat treatment of normal human sera reveals antibodies to bactericidal permeability-inducing protein (BPI). Brownlee, A.A., Lockwood, C.M. Clin. Exp. Immunol. (1999) [Pubmed]
  9. Human bactericidal/permeability-increasing protein and a recombinant NH2-terminal fragment cause killing of serum-resistant gram-negative bacteria in whole blood and inhibit tumor necrosis factor release induced by the bacteria. Weiss, J., Elsbach, P., Shu, C., Castillo, J., Grinna, L., Horwitz, A., Theofan, G. J. Clin. Invest. (1992) [Pubmed]
  10. Oxygen-independent intracellular and oxygen-dependent extracellular killing of Escherichia coli S15 by human polymorphonuclear leukocytes. Weiss, J., Kao, L., Victor, M., Elsbach, P. J. Clin. Invest. (1985) [Pubmed]
  11. The genomic organization of the genes for human lipopolysaccharide binding protein (LBP) and bactericidal permeability increasing protein (BPI) is highly conserved. Hubacek, J.A., Büchler, C., Aslanidis, C., Schmitz, G. Biochem. Biophys. Res. Commun. (1997) [Pubmed]
  12. Four BPI (bactericidal/permeability-increasing protein)-like genes expressed in the mouse nasal, oral, airway and digestive epithelia. Leclair, E.E. Biochem. Soc. Trans. (2003) [Pubmed]
  13. Antagonistic effects of lipopolysaccharide binding protein and bactericidal/permeability-increasing protein on lipopolysaccharide-induced cytokine release by mononuclear phagocytes. Competition for binding to lipopolysaccharide. Dentener, M.A., Von Asmuth, E.J., Francot, G.J., Marra, M.N., Buurman, W.A. J. Immunol. (1993) [Pubmed]
  14. Differential regulation of lipopolysaccharide (LPS) activation pathways in mouse macrophages by LPS-binding proteins. Amura, C.R., Kamei, T., Ito, N., Soares, M.J., Morrison, D.C. J. Immunol. (1998) [Pubmed]
  15. Structural requirements for intracellular processing and sorting of bactericidal/permeability-increasing protein (BPI): comparison with lipopolysaccharide-binding protein. Bülow, E., Gullberg, U., Olsson, I. J. Leukoc. Biol. (2000) [Pubmed]
  16. Bactericidal/permeability-increasing protein and lipopolysaccharide (LPS)-binding protein. LPS binding properties and effects on LPS-mediated cell activation. Wilde, C.G., Seilhamer, J.J., McGrogan, M., Ashton, N., Snable, J.L., Lane, J.C., Leong, S.R., Thornton, M.B., Miller, K.L., Scott, R.W. J. Biol. Chem. (1994) [Pubmed]
  17. Natural antibiotics and insulin sensitivity: the role of bactericidal/permeability-increasing protein. Gubern, C., López-Bermejo, A., Biarnés, J., Vendrell, J., Ricart, W., Fernández-Real, J.M. Diabetes (2006) [Pubmed]
  18. The BPI/LBP family of proteins: a structural analysis of conserved regions. Beamer, L.J., Carroll, S.F., Eisenberg, D. Protein Sci. (1998) [Pubmed]
  19. 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. Jahr, T.G., Ryan, L., Sundan, A., Lichenstein, H.S., Skjåk-Braek, G., Espevik, T. Infect. Immun. (1997) [Pubmed]
  20. Mononuclear cell line THP-1 internalizes bactericidal/permeability-increasing protein by a non-receptor-mediated mechanism consistent with pinocytosis. Burnett, R.J., Lyden, C.A., Tindal, C.J., Cave, C.M., Marra, M.N., Solomkin, J.S. Archives of surgery (Chicago, Ill. : 1960) (1996) [Pubmed]
  21. Protein Fusions of BPI with CETP Retain Functions Inherent to Each. Lloyd, D.B., Bonnette, P., Thompson, J.F. Biochemistry (2006) [Pubmed]
  22. Preferential binding of the neutrophil cytoplasmic granule-derived bactericidal/permeability increasing protein to target bacteria. Implications and use as a means of purification. Mannion, B.A., Kalatzis, E.S., Weiss, J., Elsbach, P. J. Immunol. (1989) [Pubmed]
  23. The carboxyl-terminal domain of closely related endotoxin-binding proteins determines the target of protein-lipopolysaccharide complexes. Iovine, N., Eastvold, J., Elsbach, P., Weiss, J.P., Gioannini, T.L. J. Biol. Chem. (2002) [Pubmed]
  24. Expression and antimicrobial function of bactericidal permeability-increasing protein in cystic fibrosis patients. Aichele, D., Schnare, M., Saake, M., Röllinghoff, M., Gessner, A. Infect. Immun. (2006) [Pubmed]
  25. Plasma lipid transfer proteins, high-density lipoproteins, and reverse cholesterol transport. Bruce, C., Chouinard, R.A., Tall, A.R. Annu. Rev. Nutr. (1998) [Pubmed]
  26. A hydrophobic cluster at the surface of the human plasma phospholipid transfer protein is critical for activity on high density lipoproteins. Desrumaux, C., Labeur, C., Verhee, A., Tavernier, J., Vandekerckhove, J., Rosseneu, M., Peelman, F. J. Biol. Chem. (2001) [Pubmed]
  27. Bactericidal/permeability-increasing protein and cathepsin G are the major antigenic targets of antineutrophil cytoplasmic autoantibodies in systemic sclerosis. Khanna, D., Aggarwal, A., Bhakuni, D.S., Dayal, R., Misra, R. J. Rheumatol. (2003) [Pubmed]
  28. Peri-operative myocardial tissue injury and the release of inflammatory mediators in coronary artery bypass graft patients. Fransen, E.J., Maessen, J.G., Hermens, W.T., Glatz, J.F., Buurman, W.A. Cardiovasc. Res. (2000) [Pubmed]
  29. Characterisation of autoantibodies to neutrophil granule constituents among patients with reactive arthritis, rheumatoid arthritis, and ulcerative colitis. Locht, H., Skogh, T., Wiik, A. Ann. Rheum. Dis. (2000) [Pubmed]
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