Human lipoproteins have divergent neutralizing effects on E. coli LPS, N. meningitidis LPS, and complete Gram-negative bacteria

The use of lipoproteins has been suggested as a treatment for Gram-negative sepsis because they inhibit lipopolysaccharide (LPS)-mediated cytokine production. However, little is known about the neutralizing effects of lipoproteins on cytokine production by meningococcal LPS or whole Gram-negative bacteria. We assessed the neutralizing effect of LDLs, HDLs, and VLDLs on LPS- or whole bacteria-induced cytokines in human mononuclear cells. A strong inhibition of Escherichia coli LPS-induced interleukin-1β (IL-1β), tumor necrosis factor-α, and IL-10 by LDL and HDL was seen, whereas VLDL had a less pronounced effect. In contrast, Neisseria meningitidis LPS, in similar concentrations, was neutralized much less effectively than E. coli LPS. Effective neutralization of meningococcal LPS required a longer interaction time, a lower concentration of LPS, or higher concentrations of lipoproteins. The difference in neutralization was independent of the saccharide tail, suggesting that the lipid A moiety accounted for the difference. Minimal neutralizing effects of the lipoproteins were observed on whole E. coli or N. meningitidis bacteria under all conditions tested.These results indicate that efficient neutralization of LPS depends on the type of LPS, but a sufficiently long interaction time, a low LPS concentration, or high lipoprotein concentration also inhibited cytokines by the less efficiently neutralized N. meningitidis LPS. Irrespective of these differences, whole bacteria showed no neutralization by lipoproteins. The use of lipoproteins has been suggested as a treatment for Gram-negative sepsis because they inhibit lipopolysaccharide (LPS)-mediated cytokine production. However, little is known about the neutralizing effects of lipoproteins on cytokine production by meningococcal LPS or whole Gram-negative bacteria. We assessed the neutralizing effect of LDLs, HDLs, and VLDLs on LPS- or whole bacteria-induced cytokines in human mononuclear cells. A strong inhibition of Escherichia coli LPS-induced interleukin-1β (IL-1β), tumor necrosis factor-α, and IL-10 by LDL and HDL was seen, whereas VLDL had a less pronounced effect. In contrast, Neisseria meningitidis LPS, in similar concentrations, was neutralized much less effectively than E. coli LPS. Effective neutralization of meningococcal LPS required a longer interaction time, a lower concentration of LPS, or higher concentrations of lipoproteins. The difference in neutralization was independent of the saccharide tail, suggesting that the lipid A moiety accounted for the difference. Minimal neutralizing effects of the lipoproteins were observed on whole E. coli or N. meningitidis bacteria under all conditions tested. These results indicate that efficient neutralization of LPS depends on the type of LPS, but a sufficiently long interaction time, a low LPS concentration, or high lipoprotein concentration also inhibited cytokines by the less efficiently neutralized N. meningitidis LPS. Irrespective of these differences, whole bacteria showed no neutralization by lipoproteins. Lipopolysaccharide (LPS), a major structural and functional component of the outer membrane of Gram-negative bacteria, is considered to be a major pathogenic element in Gram-negative septicemia (1Hurley J.C. Endotoxemia: methods of detection and clinical correlates.Clin. Microbiol. Rev. 1995; 8: 268-292Crossref PubMed Google Scholar). LPS interacts with a variety of cells to induce a wide array of inflammatory mediators. Among these, the proinflammatory cytokines interleukin-1β (IL-1β) and tumor necrosis factor-α (TNF-α) and the antiinflammatory cytokine IL-10 are key factors in the development of shock and disseminated intravascular coagulation (2Morrison D.C. Ryan J.L. Endotoxins and disease mechanisms.Annu. Rev. Med. 1987; 38: 417-432Crossref PubMed Google Scholar). Fulminant meningococcal sepsis (FMS) is an important cause of morbidity and mortality worldwide, especially in children and young adults. In addition, it is the prototypical Gram-negative sepsis syndrome, in which LPS concentrations may become extremely high and correlate with cytokine levels, morbidity, and mortality (3Van Deuren M. Brandtzaeg P. Van der Meer J.W.M. Update on meningococcal disease with emphasis on pathogenesis and clinical management.Clin. Microbiol. Rev. 2000; 13: 144-166Crossref PubMed Scopus (488) Google Scholar, 4Brandtzaeg P. Bjerre A. Ovstebo R. Brusletto B. Joo G.B. Kierulf P. Neisseria meningitidis lipopolysaccharides in human pathology.J. Endotoxin Res. 2001; 7: 401-420PubMed Google Scholar). LPS is composed of a polysaccharide tail to which the lipid portion (lipid A) is attached via 2-keto-3-deoxyoctanate (KDO). Lipid A, a glucosamine-derived phospholipid, is considered to be the toxic moiety of LPS and is responsible for many of the biological effects of LPS (5Luderitz O. Tanamoto K. Galanos C. McKenzie G.R. Brade H. Zahringer U. Rietschel E.T. Kusumoto S. Shiba T. Lipopolysaccharides: structural principles and biologic activities.Rev. Infect. Dis. 1984; 6: 428-431Crossref PubMed Scopus (63) Google Scholar). In the past, various strategies have been explored to combat the deleterious effects of LPS during sepsis. However, none of these anti-LPS strategies has shown a benefit on outcome (6McCloskey R.V. Straube R.C. Sanders C. Smith S.M. Smith C.R. Treatment of septic shock with human monoclonal antibody HA/1A. 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Recombinant bactericidal/permeability-increasing protein (rBPI21) as adjunctive treatment for children with severe meningococcal sepsis: a randomised trial. rBPI21 Meningococcal Sepsis Study Group.Lancet. 2000; 356: 961-967Abstract Full Text Full Text PDF PubMed Scopus (348) Google Scholar); thus, the search for a LPS-neutralizing treatment modality continues. Lipoproteins have been shown to bind LPS and to neutralize LPS-induced cytokine production (10Flegel W.A. Wolpl A. Mannel D.N. Northoff H. Inhibition of endotoxin-induced activation of human monocytes by human lipoproteins.Infect. Immun. 1989; 57: 2237-2245Crossref PubMed Google Scholar). Also, in animal models of sepsis, the administration of lipoproteins was found to be beneficial (11Netea M.G. Demacker P.N. Kullberg B.J. Boerman O.C. Verschueren I. Stalenhoef A.F. van der Meer J.W.M. Low-density lipoprotein receptor-deficient mice are protected against lethal endotoxemia and severe Gram-negative infections.J. Clin. Invest. 1996; 97: 1366-1372Crossref PubMed Scopus (187) Google Scholar, 12Levine D.M. Parker T.S. Donnely T.M. Walsh A. Rubin A.L. In vivo protection against endotoxin by plasma high density lipoprotein.Proc. Natl. Acad. Sci. USA. 1993; 90: 12040-12044Crossref PubMed Scopus (427) Google Scholar), and LPS infusion experiments in humans showed that the inflammatory response is inhibited by infusion of lipoproteins (13Pajkrt D. Doran J.E. Koster F. Lerch P.G. Arnet B. van der Poll T. ten Cate J.W. van Deventer S.J.H. Antiinflammatory effects of reconstituted high-density lipoprotein during human endotoxemia.J. Exp. Med. 1996; 184: 1601-1608Crossref PubMed Scopus (343) Google Scholar, 14Harris H.W. Johnson J.A. Wigmore S.J. Endogenous lipoproteins impact the response to endotoxin in humans.Crit. Care Med. 2002; 30: 23-31Crossref PubMed Scopus (48) Google Scholar). For these reasons, lipoprotein infusion during septicemia has been advocated as an adjunctive therapy. FMS especially, being the prototypical LPS-mediated disease, has been suggested as a candidate disease for treatment with lipoproteins. To date, most investigators assessing the effect of lipoproteins have used LPS derived from Enterobacteriaceae species (Escherichia coli or Salmonella typhimurium). However, the LPSs are a heterogeneous group of molecules with interspecies differences in the length and position of the acyl chains in the lipid A portion of the LPS, the length and polarity of the polysaccharide tail, and the formation of supramolecular structures (5Luderitz O. Tanamoto K. Galanos C. McKenzie G.R. Brade H. Zahringer U. Rietschel E.T. Kusumoto S. Shiba T. Lipopolysaccharides: structural principles and biologic activities.Rev. Infect. Dis. 1984; 6: 428-431Crossref PubMed Scopus (63) Google Scholar, 15Seydel U. Schromm A.B. Blunck R. Brandenburg K. Chemical structure, molecular conformation, and bioactivity of endotoxins.Chem. Immunol. 2000; 74: 5-24Crossref PubMed Scopus (73) Google Scholar, 16Brandenburg K. Fourier transform infrared spectroscopy characterization of the lamellar and nonlamellar structures of free lipid A and Re lipopolysaccharides from Salmonella minnesota and Escherichia coli.Biophys. J. 1993; 64: 1215-1231Abstract Full Text PDF PubMed Scopus (52) Google Scholar). These differences in LPS have been shown to the to induce cytokines N. A. S.M. Lipopolysaccharide the response via and Infect. Dis. PubMed Scopus Google Scholar, M. D.C. N. S.M. by and results in in murine Immun. 2001; PubMed Scopus Google Scholar, M.G. van Deuren M. Kullberg B.J. van der Meer J.W.M. the of lipid A the interaction of LPS with Immunol. 2002; Full Text Full Text PDF PubMed Scopus Google Scholar), and it is that these differences also the interaction with lipoproteins. In addition, LPS is the component of Gram-negative bacteria that cytokines T. N. van der P. van N. M.G. van der Meer J.W.M. van Deuren M. of Neisseria meningitidis LPS and to proinflammatory cytokine 2001; Google Scholar, H. Van der P. Van Deuren M. N. Gram-negative bacteria induce proinflammatory cytokine production by monocytes in the of lipopolysaccharide Exp. Immunol. 2000; Scopus Google Scholar, E. of a of Neisseria meningitidis the inflammatory response Immun. 2001; PubMed Scopus Google Scholar). the is to an adjunctive that LPS, as inhibit cytokine production by bacteria. In the these by the effect of lipoproteins on cytokine by LPS of E. coli and Neisseria meningitidis in human mononuclear cells. In addition, assessed the of lipoproteins on whole E. coli and N. meningitidis bacteria. E. coli and LPS were from Chemical E. coli LPS of lipid and the polysaccharide tail was from The lipid A of E. coli LPS is a with the acyl and of lipid A of Escherichia Escherichia coli and Salmonella and of Scholar). Meningococcal LPS was by the as by and O. lipopolysaccharide with and of the Scholar). LPS was from E. of Neisseria meningitidis from in during the of Clin. Microbiol. Google Scholar). Meningococcal LPS was from the of as by I. J. M. and characterization of the Neisseria meningitidis Microbiol. PubMed Scopus Google Scholar). to E. coli LPS, meningococcal LPS has a lipid in the lipid A of the meningococcal LPS, the are Zahringer U. B. Rietschel E.T. characterization of the lipid A component of pathogenic Neisseria 1992; PubMed Google Scholar). E. coli LPS has a polysaccharide tail, meningococcal LPS has an tail of the lipopolysaccharide A, A, coli coli meningitidis meningitidis from in a from The E. coli LPS was with protein by and by The meningococcal LPS was with and the was LPS was in E. coli is an N. meningitidis was from a with disease E. of Neisseria meningitidis from in during the of Clin. Microbiol. Google Scholar). bacteria in were and bacteria were of was used to the of the LPS was by as by and A. B. The formation of in of Escherichia coli B.J. Full Text PDF PubMed Google Scholar). Lipoproteins and and plasma were from plasma by as A. of the by with the methods for the of lipoproteins in PubMed Scopus Google under conditions Lipoproteins in were shown to be by Lipoproteins were for against with of the is the of plasma that is the lipid Lipoproteins were from The concentration of lipid in the lipoprotein was on as a in the lipoprotein was by a and a The the lipoproteins were in concentrations of lipoprotein in which the LPS or bacteria were were for for and for For experiments a higher concentration of the lipoproteins were by of the lipoprotein for the of mononuclear cells was in from human was and the of the were in the of these were by density The cells from the were in and in with and of the lipoprotein in or was with the for a the was to of on and and for The was by and required for the cytokine LPS or whole bacteria-induced cytokine production in with of and were by as by Van Van Deuren M. Van der J. Van der Meer J.W.M. and but vivo and 1995; PubMed Scopus Google Scholar). The lower of detection was for IL-10 was by a The was an was considered was to concentration To the inhibition of cytokines by the cytokine production in the of the lipoprotein in was as a of production in the of A of cytokine by N. meningitidis and E. coli LPS in on for showed that meningococcal LPS is in the of and than is E. coli LPS, especially concentrations of less than The concentrations to induce and production were for meningococcal LPS and for E. coli LPS. E. coli LPS was as in the of and as LPS on these in experiments LPS was used concentrations of to meningococcal LPS and E. coli The effect of the of concentrations of E. coli or N. meningitidis LPS with the lipoproteins and VLDL for on and IL-10 production in is shown in Lipoproteins induce cytokine production in the of suggesting of the lipoprotein with LPS. E. coli LPS-induced cytokine production was by LDL to of of production in HDL was less in the inhibition of cytokine whereas VLDL had a effect. meningococcal LPS-induced cytokine production was inhibited to a by LDL and HDL than cytokine production by E. coli LPS. LDL the N. meningitidis LPS-induced cytokine production to of production for and whereas production was inhibited HDL inhibited N. cytokines less efficiently than and the effect of VLDL was the of LPS neutralization by LDL or HDL of lipoprotein with LPS and lipoprotein concentrations We found that inhibition of E. coli LPS-induced by LDL was on the and that for of was the inhibition of N. meningitidis LPS-induced production by with E. coli LPS, required much longer to and inhibition was of The results for and HDL showed a similar inhibition by HDL was less For the of LPS concentration on lipoprotein neutralization The experiments showed that production was inhibited by E. coli LPS than by N. meningitidis LPS by However, the of inhibition by LDL is on the concentration of high concentrations, LPS showed whereas the concentration LPS were inhibited to a for showed a similar In addition, the of with lipoproteins concentrations in conditions was lipid concentrations of for for and for HDL were LDL and HDL inhibited by LPS effectively and to the whereas VLDL also inhibited but to a than LDL or HDL for showed a similar To the observed differences in inhibition of E. coli and N. meningitidis LPS-induced cytokines were on the lipid A or the saccharide tail of the LPS of the LPS the polysaccharide tail were E. coli Re LPS was to E. coli LPS, and N. meningitidis LPS was to N. meningitidis LPS. and IL-10 by E. coli Re LPS were inhibited by LDL HDL to a similar as that by E. coli LPS. difference was found in the effect of LDL on cytokine production N. meningitidis and N. meningitidis LPS. these that the differences in inhibition of cytokine production E. coli LPS and meningococcal LPS are by the of the saccharide of the LPS but by differences in the lipid A of the LPS LPS is the moiety of Gram-negative bacteria, assessed the lipoprotein were of the cytokine response by to Gram-negative bacteria. In these the E. coli LPS-induced cytokine response was inhibited by LDL or In contrast, and IL-10 by E. coli and N. meningitidis bacteria were or were inhibited by the lipoproteins or VLDL the of cytokines by these whole bacteria was higher than the with LPS, the of lipoproteins to inhibit a lower concentration of bacteria or the of a higher concentration of LDL to inhibit cytokine production. the concentration of bacteria no effect of or HDL was on or IL-10 production the results for LDL and In addition, LDL to inhibition of bacteria-induced cytokines of LPS-induced production in human mononuclear cells by LDL with a concentration to of whole E. coli or N. meningitidis bacteria. LDL was with the bacteria for are as of production in effect of LDL on production by E. coli or N. meningitidis bacteria was and are of lipoproteins on whole bacteria-induced cytokine production. of of E. coli or N. meningitidis LPS for with LDL on cytokine in human mononuclear cells. LDL was the LDL concentration which the LPS was was LDL LDL and LDL and are In the showed that concentrations of E. coli or N. meningitidis LPS, the in neutralizing effect of lipoproteins on cytokine production by N. meningitidis LPS was in with that by E. coli LPS. The neutralizing effect on E. coli LPS was shown to be and the interaction the lipoproteins and LPS, the lipoprotein concentration, or the LPS concentration, the in the neutralizing effect of the lipoproteins The difference in the of inhibition of LDL and HDL on of LPS is to be by the difference in the lipid A portion of the LPS cytokine by whole E. coli or N. meningitidis bacteria was by lipoproteins. A of the biological effects of LPS on a may results because LPS from bacteria have molecular because of the length of the saccharide To assessed the concentration of the E. coli LPS and meningococcal LPS by of a of LPS (5Luderitz O. Tanamoto K. Galanos C. McKenzie G.R. Brade H. Zahringer U. Rietschel E.T. Kusumoto S. Shiba T. Lipopolysaccharides: structural principles and biologic activities.Rev. Infect. Dis. 1984; 6: 428-431Crossref PubMed Scopus (63) Google Scholar, A. B. The formation of in of Escherichia coli B.J. Full Text PDF PubMed Google Scholar), and used concentrations of LPS in all In with on the bioactivity of LPS M. J. C. G.R. G.R. of on shock from meningococcal and Escherichia coli Infect. Dis. PubMed Scopus (48) Google Scholar, N. inhibition of LPS-induced by human monocytes is the LPS Immunol. PubMed Scopus Google Scholar), the showed that concentrations of less than meningococcal LPS is in the of and than is E. coli LPS. The effect of the lipoproteins LDL and HDL in models of Gram-negative and lethal endotoxemia is and the inhibition of LPS-induced proinflammatory cytokine of LPS by the is to be a key element in (10Flegel W.A. Wolpl A. Mannel D.N. Northoff H. Inhibition of endotoxin-induced activation of human monocytes by human lipoproteins.Infect. Immun. 1989; 57: 2237-2245Crossref PubMed Google Scholar, M.G. Demacker P.N. Kullberg B.J. Boerman O.C. Verschueren I. Stalenhoef A.F. van der Meer J.W.M. Low-density lipoprotein receptor-deficient mice are protected against lethal endotoxemia and severe Gram-negative infections.J. Clin. Invest. 1996; 97: 1366-1372Crossref PubMed Scopus (187) Google Scholar, 12Levine D.M. Parker T.S. Donnely T.M. Walsh A. Rubin A.L. In vivo protection against endotoxin by plasma high density lipoprotein.Proc. Natl. Acad. Sci. USA. 1993; 90: 12040-12044Crossref PubMed Scopus (427) Google Scholar, D. Doran J.E. Koster F. Lerch P.G. Arnet B. van der Poll T. ten Cate J.W. van Deventer S.J.H. Antiinflammatory effects of reconstituted high-density lipoprotein during human endotoxemia.J. Exp. Med. 1996; 184: 1601-1608Crossref PubMed Scopus (343) Google Scholar, 14Harris H.W. Johnson J.A. Wigmore S.J. Endogenous lipoproteins impact the response to endotoxin in humans.Crit. Care Med. 2002; 30: 23-31Crossref PubMed Scopus (48) Google Scholar). In the cytokine by the LPS from N. the that the prototypical Gram-negative sepsis syndrome, is inhibited by lipoproteins in a similar as the prototypical LPS from E. The concentrations of LPS used in the in experiments or were to be in the of concentrations of LPS by in the during meningococcal sepsis, which from to than P. Bjerre A. Ovstebo R. Brusletto B. Joo G.B. Kierulf P. Neisseria meningitidis lipopolysaccharides in human pathology.J. Endotoxin Res. 2001; 7: 401-420PubMed Google Scholar). In E. coli sepsis, LPS are lower Deventer S.J. Cate J.W. A. an of in Scopus Google Scholar, Balk R.A. R.C. cytokine and endotoxin correlate with in with the sepsis Intern. Med. 1993; PubMed Scopus Google Scholar). showed that bacteria in the outer membrane T. N. van der P. van N. M.G. van der Meer J.W.M. van Deuren M. of Neisseria meningitidis LPS and to proinflammatory cytokine 2001; Google Scholar), the concentration of bacteria was to the concentrations of LPS concentration is in with the of bacteria found during meningococcal sepsis to S.J. M. J. J.A. Meningococcal with disease Dis. 2002; PubMed Scopus Google Scholar). plasma concentrations are during sepsis or LDL and HDL for LDL and for whereas VLDL was to a concentration of M. P. E. in children with 1993; PubMed Scopus Google Scholar, van J.A. J. van in with severe Care Med. PubMed Scopus Google Scholar). the concentrations of LDL and HDL used for are in with the concentrations of these lipoproteins as they in septic For the lipoproteins were to also concentrations that are under VLDL during sepsis, lipoprotein concentrations that are in M.G. Demacker Kullberg B.J. Boerman O.C. Stalenhoef Van der Meer J.W.M. lipopolysaccharide and cells neutralization by lipoproteins PubMed Scopus Google Scholar), found that of E. coli LPS with LDL as as HDL inhibited the cytokine whereas VLDL had a less pronounced effect. However, concentrations and N. meningitidis LPS was neutralized much less efficiently than E. coli LPS. The neutralizing effect of LDL and HDL was on the of the LPS with the lipoproteins and the concentration of LPS or lipoproteins. E. coli was inhibited of for meningococcal LPS, inhibition was of a and a concentration of the of inhibition was by the concentration of LPS. the of concentrations E. coli LPS was neutralized by LDL than was N. meningitidis LPS assessed by However, the concentration E. coli LPS also showed whereas the concentration LPS were neutralized to a To the impact of higher concentrations of lipoproteins on LPS the lipoprotein by In lipoprotein were and the concentration of lipoprotein in the concentrations under these higher concentrations of LPS were inhibited and to a by LDL and HDL of of the difference in neutralization low concentrations of that concentrations E. coli and N. meningitidis LPSs are neutralized by the lipoproteins VLDL had a less pronounced neutralizing effect on it be that higher concentrations, as during sepsis, the effect of VLDL is also these results indicate that the efficient neutralization of LPS depends on the type of LPS, but a sufficiently long interaction time, a low concentration of LPS, and a high concentration of lipoproteins also inhibit cytokines by a less efficiently neutralized LPS. results the that lipoproteins be important for E. coli LPS-mediated However, because during severe meningococcal sepsis, LPS concentrations are much the from the of disease to is P. Bjerre A. Ovstebo R. Brusletto B. Joo G.B. Kierulf P. Neisseria meningitidis lipopolysaccharides in human pathology.J. Endotoxin Res. 2001; 7: 401-420PubMed Google Scholar), and concentrations of LDL and HDL are it is that lipoproteins an important in neutralizing LPS during type of The molecular differences E. coli LPS and N. meningitidis LPS are the and of the saccharide tail and the position and of the acyl chains on the To which of these differences the neutralization by the effect of lipoproteins on cytokine by of E. coli and N. meningitidis LPS that are of a saccharide tail, E. coli Re LPS and N. meningitidis LPS. showed that the neutralizing of lipoproteins is independent of the of the saccharide the lipid A with in E. coli LPS and of the acyl chains in N. meningitidis LPS, for the effect. The bioactivity and of an LPS is suggested to be by the of the lipid A, the bioactivity and of the LPS M.G. van Deuren M. Kullberg B.J. van der Meer J.W.M. the of lipid A the interaction of LPS with Immunol. 2002; Full Text Full Text PDF PubMed Scopus Google Scholar). For and D.M. Parker T.S. Donnely T.M. Walsh A. Rubin A.L. In vivo protection against endotoxin by plasma high density lipoprotein.Proc. Natl. Acad. Sci. USA. 1993; 90: 12040-12044Crossref PubMed Scopus (427) Google have the in which the acyl of the lipid A portion of LPS are the lipid of the the of LPS. We that the lower of neutralization of meningococcal LPS by lipoproteins is by the lipid A with the lipoprotein lipid LPS is considered to be the pathogenic component of Gram-negative bacteria (1Hurley J.C. Endotoxemia: methods of detection and clinical correlates.Clin. Microbiol. Rev. 1995; 8: 268-292Crossref PubMed Google Scholar). However, it has been shown that of Gram-negative bacteria also cytokine production T. N. van der P. van N. M.G. van der Meer J.W.M. van Deuren M. of Neisseria meningitidis LPS and to proinflammatory cytokine 2001; Google Scholar, H. Van der P. Van Deuren M. N. Gram-negative bacteria induce proinflammatory cytokine production by monocytes in the of lipopolysaccharide Exp. Immunol. 2000; Scopus Google Scholar, E. of a of Neisseria meningitidis the inflammatory response Immun. 2001; PubMed Scopus Google Scholar). lipoproteins cytokine production with whole bacteria, low concentrations or high lipoprotein was the that whole bacteria, in to LPS, in which neutralization by lipoproteins depends on the interaction and concentration of LPS or are to neutralization by lipoproteins. We that LPS, in the outer membrane of the Gram-negative interacts less with the lipoproteins than LPS. In addition, it be that than LPS, of E. coli or N. meningitidis that are inhibited by lipoproteins may for the effect of lipoproteins on whole Gram-negative bacteria. The the in animal in which lipoprotein administration cytokines and outcome the administration of whole E. coli or and Doran J.E. effect of reconstituted high density lipoprotein in Gram-negative Clin. Med. 1995; Google Scholar, C. M.C. lipoproteins septic in Exp. Med. 1995; PubMed Scopus Google Scholar). is on the of lipoproteins during Gram-negative sepsis. In LDL and HDL inhibit cytokines by E. coli LPS, but N. meningitidis LPS neutralization by human lipoproteins. However, a sufficiently long interaction time, a low LPS concentration, or higher lipoprotein concentration also cytokines by less efficiently neutralized LPS. In contrast, lipoproteins have a neutralizing effect on whole E. coli or N. meningitidis bacteria. about the for treatment of meningococcal and of Gram-negative sepsis with lipoproteins. The P. Demacker for on lipoprotein