LPS-binding protein protects mice from septic shock caused by LPS or gram-negative bacteria.

Lamping, Norbert; Dettmer, Rabea; Schröder, Nicolas W.J.; Pfeil, D; Hallatschek, Werner; Burger, Roger A.; Schumann, Ralf R.

doi:10.1172/jci2338

Cited by 317 publications

(266 citation statements)

References 51 publications

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“…Whereas LBP can promote LPS signaling at all LBP concentrations, the inhibitory mechanisms require relatively high LBP concentrations to have a significant impact. In the same experiments, high concentrations of LBP were inhibitory only when the LPS concentration was low (Յ1 ng/ml), whereas at higher LPS concentrations, much higher concentrations of LBP were required to inhibit responses to the LPS (27,28). LBP concentrations often increase to very high levels in the blood of septic patients, and progressive immunodepletion of LBP from the serum of these patients revealed that the LBP can have a strong inhibitory effect on the activity of LPS (28).…”

Section: Table I Lbp Does Not Inhibit Cell Responses To Il-1␤mentioning

confidence: 86%

“…When LBP and LPS were coincubated with macrophages in serum-free medium, concentrations of LBP that are much lower than those found in normal plasma (0.1 g of LBP/ml) promoted maximal cell stimulation, whereas higher concentrations (1-10 g/ml) were less stimulatory, suggesting that LBP was exerting a significant inhibitory effect at the higher concentrations (27,39). Whereas LBP can promote LPS signaling at all LBP concentrations, the inhibitory mechanisms require relatively high LBP concentrations to have a significant impact.…”

Section: Table I Lbp Does Not Inhibit Cell Responses To Il-1␤mentioning

confidence: 89%

“…LBP can prevent lethal shock caused by LPS or Gram-negative bacteria when administered intraperitoneally in mice (27). High acute phase concentrations of LBP in the plasma of septic humans decrease monocyte responses to LPS (28).…”

mentioning

confidence: 99%

“…The inhibitory mechanism of LBP can be explained in part by its ability to neutralize the bioactivity of LPS by transferring it to plasma lipoproteins (6,29). Other inhibitory mechanisms are suggested by the ability of LBP to inhibit cell responses to LPS in serum-free medium (27,28). Possible mechanisms might include the formation of large LPS⅐LBP complexes that are internalized by mCD14 but that contribute little to LPS signaling (30).…”

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confidence: 99%

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Lipopolysaccharide (LPS)-binding Protein Inhibits Responses to Cell-bound LPS

Thompson

Tobias

Viriyakosol

et al. 2003

Journal of Biological Chemistry

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Lipopolysaccharide (LPS)-binding protein (LBP) is an acute phase reactant that may play a dual role in vivo,both potentiating and decreasing cell responses to bacterial LPS. Whereas low concentrations of LBP potentiate cell stimulation by transferring LPS to CD14, high LBP concentrations inhibit cell responses to LPS. One inhibitory mechanism involves the ability of LBP to neutralize LPS by transferring it to plasma lipoproteins, whereas other inhibitory mechanisms, such as the one described here, do not require exogenous lipoproteins. Here we show that LBP can inhibit monocyte responses to LPS that has already bound to membrane-bound CD14 (mCD14) on the cell surface. LBP caused rapid dissociation of LPS from mCD14 as measured by the ability of LBP to inhibit cross-linking of a radioiodinated, photoactivatable LPS derivative to mCD14. Whereas LBP removed up to 75% of the mCD14-bound LPS in 10 min, this was not accompanied by extensive release of the LPS from the cells. The cross-linking data suggest that much of the LPS that remained bound to the cells was associated with LBP. The ability of LBP to inhibit cell responses could not be explained by its effect on LPS internalization, because LBP did not significantly increase the internalization of the cell-bound LPS. In cell-free LPS cross-linking experiments, LBP inhibited the transfer of LPS from soluble CD14 to soluble MD-2. Our data support the hypothesis that LBP can inhibit cell responses to LPS by inhibiting LPS transfer from mCD14 to the Toll-like receptor 4-MD-2 signaling receptor.Lipopolysaccharide (LPS 1 ; endotoxin), an abundant component of the outer membrane of Gram-negative bacteria, is one of the most potent of the known bacterial agonists in animal host cells. Whereas LPS recognition benefits the host by sensing the presence of bacteria and mobilizing defense mechanisms, an exaggerated response to LPS may contribute to the harmful sequelae of severe sepsis, which include coagulation disorders, organ failure, shock, and death. The host, therefore, has numerous mechanisms that down-regulate responses to LPS and remove it from the circulation and tissues (1-7).The potency of LPS is due to the sensitivity of the host recognition system, which requires the Toll-like receptor 4 (Tlr4) (8) signaling receptor. At least three LPS-binding proteins (LBP (9), CD14 (10), and MD-2 (11)) are required for sensitive Tlr4-mediated LPS recognition. Plasma LBP potentiates LPS recognition by transferring it from bacterial membranes (6) to CD14 (12, 13), which is expressed as a glycosylphosphatidylinositol-anchored protein on the surfaces of myeloid lineage cells (mCD14) and as an anchorless plasma protein, soluble CD14 (sCD14) (14, 15). CD14 presents LPS to Tlr4, presumably by transferring the LPS to MD-2, an accessory protein that is constitutively associated with the extracellular domain of Tlr4 (16). MD-2 binds LPS with high affinity (17), and it is required for Tlr4 signaling (11). Although normal expression of the Tlr4 and MD-2 are too low for direct measurements...

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Section: Table I Lbp Does Not Inhibit Cell Responses To Il-1␤mentioning

confidence: 86%

Section: Table I Lbp Does Not Inhibit Cell Responses To Il-1␤mentioning

confidence: 89%

mentioning

confidence: 99%

mentioning

confidence: 99%

See 2 more Smart Citations

Lipopolysaccharide (LPS)-binding Protein Inhibits Responses to Cell-bound LPS

Thompson

Tobias

Viriyakosol

et al. 2003

Journal of Biological Chemistry

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“…At low concentrations (up to 1 µg/ml, corresponding to constitutive LBP levels), recombinant murine LBP induced TNF-α synthesis in a murine macrophage (RAW 264.7) culture with LPS, but clearly decreased the TNF-α response at a high concentration (10 µg/ml, simulating the acute phase rise of LBP) 35 . Moreover, LBP also reduced the mortality of mice after LPS challenge in vivo.…”

Section: Discussionmentioning

confidence: 98%

Aggravation of Galactosamine Hepatotoxicity by Albumin in Rats

et al. 2008

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Abstract:The effect of rat albumin (RALB) on D-galactosamine (GalN) hepatotoxicity was investigated in male Crl:CD(SD) rats aged 6 weeks. The animals were divided into control, RALB, GalN, and RALB + GalN groups. GalN (800 mg/kg) was intraperitoneally administered immediately after an intravenous injection of RALB (100 mg/kg). The animals were euthanized 6 or 24 h later and subjected to laboratory investigations and histological examinations of the liver. Furthermore, in order to determine the contributing factors of the effect on the hepatotoxicity, intra-and intergroup comparisons were made between liver-injured and normal animals for parameters showing marked fluctuations at 6 h post-dosing. As a result, RALB induced fluctuations in many parameters, but no histological changes were observed in the liver at both 6 and 24 h. GalN induced mild or moderate hepatocyte necrosis (necrosis and/or apoptosis of hepatocytes) at 6 and 24 h, respectively, accompanied by increases in the serum ALT and AST levels. Concurrent administration of RALB with GalN markedly aggravated the GalN-induced hepatotoxicity, as shown by severe hepatocyte necrosis accompanied by further increases in the serum ALT, AST, and T-BIL levels in the surviving animals at 6 and 24 h, and by very severe hepatocyte necrosis with congestion in the dead animals. Moreover, serum tumor necrosis factor-α (TNF-α) level was also increased at 6 h in the RALB + GalN group, but not in the RALB or GalN alone groups. In conclusion, RALB was shown to aggravate GalN hepatotoxicity in rats, and the increased serum TNF-α level is considered to be a contributing factor of the aggravation. (J Toxicol Pathol 2008; 21: 175-183)

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