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. 1997 Sep 30;94(20):10973-8.
doi: 10.1073/pnas.94.20.10973.

An opsonic function of the neutrophil bactericidal/permeability-increasing protein depends on both its N- and C-terminal domains

N M Iovine  1 , P Elsbach, J Weiss
Affiliations

An opsonic function of the neutrophil bactericidal/permeability-increasing protein depends on both its N- and C-terminal domains

N M Iovine et al. Proc Natl Acad Sci U S A. .

Abstract

The host response to Gram-negative bacterial infection is influenced by two homologous lipopolysaccharide (LPS)-interactive proteins, LPS-binding protein (LBP) and the bacteridical/permeability-increasing protein (BPI). Both proteins bind LPS via their N-terminal domains but produce profoundly different effects: BPI and a bioactive N-terminal fragment BPI-21 exert a selective and potent antibacterial effect upon Gram-negative bacteria and suppress LPS bioactivity whereas LBP is not toxic toward Gram-negative bacteria and potentiates LPS bioactivity. The latter effect of LBP requires the C-terminal domain for delivery of LPS to CD14, so we postulated that the C-terminal region of BPI may serve a similar delivery function but to distinct targets. LBP, holoBPI, BPI-21, and LBP/BPI chimeras were compared for their ability to promote uptake by human phagocytes of an encapsulated, phagocytosis-resistant strain of Escherichia coli. We show that only bacteria preincubated with holoBPI are ingested by neutrophils and monocytes. These findings suggest that, when extracellular holoBPI is bound via its N-terminal domain to Gram-negative bacteria, the C-terminal domain promotes bacterial attachment to neutrophils and monocytes, leading to phagocytosis. Therefore, analogous to the role of the C-terminal domain of LBP in delivery of LPS to CD14, the C-terminal domain of BPI may fulfill a similar function in BPI-specific disposal pathways for Gram-negative bacteria.

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Figures

Figure 1
Figure 1
Comparison of effect of increasing concentrations of various BPI and/or LBP species on (A) uptake of E. coli K1/r and (B) viability of bacteria. Bacterial uptake is expressed as number of PMN-associated E. coli/PMN (at least 100 PMN counted/sample). Bacterial viability is expressed as a percentage of viability of bacteria incubated alone. All data shown represent the mean of the same three experiments.
Figure 2
Figure 2
Thin section electron micrograph of a single PMN with three bacteria visible within two phagocytic vacuoles. E. coli were preincubated with 90 nM holoBPI before incubating with leukocytes and processing for electron microscopy, as described in Materials and Methods.
Figure 3
Figure 3
Comparison of binding of various BPI and LBP species to E. coli K1/r. The bacteria were incubated with the indicated concentrations of the various proteins under the same conditions as Fig. 1. Bound protein (associated with 8 × 106 bacteria) was detected by immunoblotting, as described in Materials and Methods. Known amounts (4, 25, and 100 ng) of each protein were run on the same immunoblot as standards to facilitate quantitation of bound protein. Data shown are representative of at least two independent experiments.
Figure 4
Figure 4
Effect of the various BPI and/or LBP species on the triggering of lucigenin- (A and C) or luminol (B and D)-enhanced leukocyte chemiluminescence by purified LPS (A and B) or E. coli K1/r (C and D). Bacteria or LPS were preincubated plus or minus the indicated protein for 30 min before addition to leukocytes plus lucigenin or luminol and measurement of chemiluminescence as described in Materials and Methods. The results shown represent the mean of four determinations using data obtained during incubation of 10 ng/ml LPS or 106/ml E. coli with leukocytes.
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