Lipopolysaccharide Binding Protein Binds to Triacylated and Diacylated Lipopeptides and Mediates Innate Immune Responses1

LPS binding protein (LBP) is an acute-phase protein synthesized predominantly in the liver of the mammalian host. It was first described to bind LPS of Gram-negative bacteria and transfer it via a CD14-enhanced mechanism to a receptor complex including TLR-4 and MD-2, initiating a signal transduction cascade leading to the release of proinflammatory cytokines. 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. Lipoproteins and lipopeptides have repeatedly been shown to act as potent cytokine inducers, interacting with TLR-2, in synergy with TLR-1 or -6. In this study, we show that these compounds also interact with LBP and CD14. We used triacylated lipopeptides, corresponding to lipoproteins of Borrelia burgdorferi, mycobacteria, and Escherichia coli, as well as diacylated lipopeptides, corresponding to, e.g., 2-kDa macrophage activating lipopeptide of Mycoplasma spp. Activation of Chinese hamster ovary cells transfected with TLR-2 by both lipopeptides was enhanced by cotransfection of CD14. Responsiveness of human mononuclear cells to these compounds was greatly enhanced in the presence of human LBP. Binding of lipopeptides to LBP as well as competitive inhibition of this interaction by LPS was demonstrated in a microplate assay. Furthermore, we were able to show that LBP transfers lipopeptides to CD14 on human monocytes using FACS analysis. These results support that LBP is a pattern recognition receptor transferring a variety of bacterial ligands including the two major types of lipopeptides to CD14 present in different receptor complexes.

[1]  S. Akira,et al.  Toll-like receptors and innate immunity , 2006, Journal of Molecular Medicine.

[2]  藤田 真理.  Involvement of leucine residues at positions 107, 112, and 115 in a leucine-rich repeat motif of human Toll-like receptor 2 in the recognition of diacylated lipoproteins and lipopeptides and Staphylococcus aureus peptidoglycans , 2005 .

[3]  L. Kremer,et al.  Lipomannans, But Not Lipoarabinomannans, Purified from Mycobacterium chelonae and Mycobacterium kansasii Induce TNF-α and IL-8 Secretion by a CD14-Toll-Like Receptor 2-Dependent Mechanism1 , 2003, The Journal of Immunology.

[4]  E. Tuomanen,et al.  Recognition of pneumococcal peptidoglycan: an expanded, pivotal role for LPS binding protein. , 2003, Immunity.

[5]  P. Tobias,et al.  Lipopolysaccharide (LPS)-binding Protein Inhibits Responses to Cell-bound LPS* , 2003, Journal of Biological Chemistry.

[6]  U. Göbel,et al.  Lipoteichoic Acid (LTA) of Streptococcus pneumoniaeand Staphylococcus aureus Activates Immune Cells via Toll-like Receptor (TLR)-2, Lipopolysaccharide-binding Protein (LBP), and CD14, whereas TLR-4 and MD-2 Are Not Involved* , 2003, The Journal of Biological Chemistry.

[7]  S. Akira,et al.  Cutting Edge: Role of Toll-Like Receptor 1 in Mediating Immune Response to Microbial Lipoproteins1 , 2002, The Journal of Immunology.

[8]  A. Nesburn,et al.  Lipopeptide vaccines--yesterday, today, and tomorrow. , 2002, The Lancet. Infectious diseases.

[9]  Thomas Hartung,et al.  Cytokine induction by purified lipoteichoic acids from various bacterial species – Role of LBP, sCD14, CD14 and failure to induce IL‐12 and subsequent IFN‐γ release , 2002, European journal of immunology.

[10]  K. Wegscheider,et al.  High concentrations of lipopolysaccharide-binding protein in serum of patients with severe sepsis or septic shock inhibit the lipopolysaccharide response in human monocytes. , 2001, Blood.

[11]  M. Arditi,et al.  Cooperation of Toll-Like Receptor 2 and 6 for Cellular Activation by Soluble Tuberculosis Factor and Borrelia burgdorferi Outer Surface Protein A Lipoprotein: Role of Toll-Interacting Protein and IL-1 Receptor Signaling Molecules in Toll-Like Receptor 2 Signaling1 , 2001, The Journal of Immunology.

[12]  S. Akira,et al.  Discrimination of bacterial lipoproteins by Toll-like receptor 6. , 2001, International immunology.

[13]  U. Göbel,et al.  Toll-like Receptor-2 Mediates Treponema Glycolipid and Lipoteichoic Acid-induced NF-κB Translocation* , 2001, The Journal of Biological Chemistry.

[14]  A. Aderem,et al.  The repertoire for pattern recognition of pathogens by the innate immune system is defined by cooperation between toll-like receptors. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[15]  U. Göbel,et al.  Involvement of Lipopolysaccharide Binding Protein, CD14, and Toll-Like Receptors in the Initiation of Innate Immune Responses by Treponema Glycolipids1 , 2000, The Journal of Immunology.

[16]  R. Tapping,et al.  Soluble CD14-mediated cellular responses to lipopolysaccharide. , 2000, Chemical immunology.

[17]  E. Wouters,et al.  Production of the acute-phase protein lipopolysaccharide-binding protein by respiratory type II epithelial cells: implications for local defense to bacterial endotoxins. , 2000, American journal of respiratory cell and molecular biology.

[18]  D. Golenbock,et al.  Toll-like Receptor 2 Functions as a Pattern Recognition Receptor for Diverse Bacterial Products* , 1999, The Journal of Biological Chemistry.

[19]  W. Buurman,et al.  Lipopolysaccharide binding protein and serum amyloid A secretion by human intestinal epithelial cells during the acute phase response. , 1999, Journal of immunology.

[20]  R. M. Wooten,et al.  Cutting edge: inflammatory signaling by Borrelia burgdorferi lipoproteins is mediated by toll-like receptor 2. , 1999, Journal of immunology.

[21]  B. Bloom,et al.  Host defense mechanisms triggered by microbial lipoproteins through toll-like receptors. , 1999, Science.

[22]  M. Rothe,et al.  Peptidoglycan- and Lipoteichoic Acid-induced Cell Activation Is Mediated by Toll-like Receptor 2* , 1999, The Journal of Biological Chemistry.

[23]  B. Monks,et al.  Cutting edge: cells that carry A null allele for toll-like receptor 2 are capable of responding to endotoxin. , 1999, Journal of immunology.

[24]  S. Akira,et al.  Cutting edge: Toll-like receptor 4 (TLR4)-deficient mice are hyporesponsive to lipopolysaccharide: evidence for TLR4 as the Lps gene product. , 1999, Journal of immunology.

[25]  S. Roman-Roman,et al.  Signal transduction pathways involved in the activation of NF-kappa B, AP-1, and c-fos by Mycoplasma fermentans membrane lipoproteins in macrophages. , 1999, Journal of immunology.

[26]  P. Ricciardi-Castagnoli,et al.  Defective LPS signaling in C3H/HeJ and C57BL/10ScCr mice: mutations in Tlr4 gene. , 1998, Science.

[27]  M. Rothe,et al.  Human Toll-like Receptor 2 Confers Responsiveness to Bacterial Lipopolysaccharide , 1998, The Journal of experimental medicine.

[28]  G. Jung,et al.  Structure and Specific Activity of Macrophage-Stimulating Lipopeptides from Mycoplasma hyorhinis , 1998, Infection and Immunity.

[29]  A. Gurney,et al.  Toll-like receptor-2 mediates lipopolysaccharide-induced cellular signalling , 1998, Nature.

[30]  C. Schmid,et al.  Vaccination against Lyme disease with recombinant Borrelia burgdorferi outer-surface lipoprotein A with adjuvant. Lyme Disease Vaccine Study Group. , 1998, The New England journal of medicine.

[31]  J. Radolf,et al.  Treponema pallidum and Borrelia burgdorferi lipoproteins and synthetic lipopeptides activate monocytic cells via a CD14-dependent pathway distinct from that used by lipopolysaccharide. , 1998, Journal of immunology.

[32]  R. Schumann,et al.  LPS-binding protein protects mice from septic shock caused by LPS or gram-negative bacteria. , 1998, The Journal of clinical investigation.

[33]  R. Tapping,et al.  Binding of Bacterial Peptidoglycan to CD14* , 1998, The Journal of Biological Chemistry.

[34]  R. Schumann,et al.  Similar organization of the lipopolysaccharide-binding protein (LBP) and phospholipid transfer protein (PLTP) genes suggests a common gene family of lipid-binding proteins. , 1997, Genomics.

[35]  A. Hoess,et al.  Interchangeable endotoxin-binding domains in proteins with opposite lipopolysaccharide-dependent activities. , 1997, Journal of immunology.

[36]  C. Janeway,et al.  Innate Immunity: The Virtues of a Nonclonal System of Recognition , 1997, Cell.

[37]  G. Rune,et al.  Lipopolysaccharide-binding protein is required to combat a murine Gram-negative bacterial infection , 1997, Nature.

[38]  K. Mittenbühler,et al.  Bacterial cell wall components as immunomodulators--I. Lipopeptides as adjuvants for parenteral and oral immunization. , 1997, International journal of immunopharmacology.

[39]  G. Jung,et al.  Isolation, Structure Elucidation, and Synthesis of a Macrophage Stimulatory Lipopeptide from Mycoplasma fermentans Acting at Picomolar Concentration , 1997, The Journal of experimental medicine.

[40]  H. Flad,et al.  Specific binding of soluble peptidoglycan and muramyldipeptide to CD14 on human monocytes , 1997, Infection and immunity.

[41]  F. Herrmann,et al.  Effects of site-directed mutagenesis of basic residues (Arg 94, Lys 95, Lys 99) of lipopolysaccharide (LPS)-binding protein on binding and transfer of LPS and subsequent immune cell activation. , 1996, Journal of immunology.

[42]  F. Herrmann,et al.  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 , 1996, Molecular and cellular biology.

[43]  P. Mühlradt,et al.  Identification of S-(2,3-dihydroxypropyl)cystein in a macrophage-activating lipopeptide from Mycoplasma fermentans. , 1996, Biochemistry.

[44]  L. Davis,et al.  Treponema pallidum and Borrelia burgdorferi lipoproteins and synthetic lipopeptides activate monocytes/macrophages. , 1995, Journal of immunology.

[45]  J. Weis,et al.  Biological activities of native and recombinant Borrelia burgdorferi outer surface protein A: dependence on lipid modification , 1994, Infection and immunity.

[46]  D. Beezhold,et al.  A 48-kilodalton Mycoplasma fermentans membrane protein induces cytokine secretion by human monocytes , 1994, Infection and immunity.

[47]  A. Tomasz,et al.  CD14 is a pattern recognition receptor. , 1994, Immunity.

[48]  F. Herrmann,et al.  Lipopolysaccharide binding protein: its role and therapeutical potential in inflammation and sepsis. , 1994, Biochemical Society transactions.

[49]  J. Weis,et al.  Borrelia burgdorferi outer surface lipoproteins OspA and OspB possess B-cell mitogenic and cytokine-stimulatory properties , 1993, Infection and immunity.

[50]  M. Glauser,et al.  Septic shock: pathogenesis , 1991, The Lancet.

[51]  R. Ulevitch,et al.  Structure and function of lipopolysaccharide binding protein. , 1990, Science.

[52]  R. Ulevitch,et al.  CD14, a receptor for complexes of lipopolysaccharide (LPS) and LPS binding protein. , 1990, Science.

[53]  J. Radolf,et al.  Immunogenic integral membrane proteins of Borrelia burgdorferi are lipoproteins , 1990, Infection and immunity.

[54]  K. Anderson,et al.  The Toll gene of drosophila, required for dorsal-ventral embryonic polarity, appears to encode a transmembrane protein , 1988, Cell.

[55]  M. L. Le Beau,et al.  The CD14 monocyte differentiation antigen maps to a region encoding growth factors and receptors. , 1988, Science.

[56]  J. Gilsdorf,et al.  Community-acquired pneumonia in children. , 1987, Seminars in respiratory infections.

[57]  J. Strominger,et al.  Biochemical characterization of a soluble form of the 53‐kDa monocyte surface antigen , 1986, European journal of immunology.

[58]  A. Schneider,et al.  Separation and purification of a potent bactericidal/permeability-increasing protein and a closely associated phospholipase A2 from rabbit polymorphonuclear leukocytes. Observations on their relationship. , 1979, The Journal of biological chemistry.

[59]  V. Braun,et al.  Chemical characterization, spatial distribution and function of a lipoprotein (murein-lipoprotein) of the E. coli cell wall. The specific effect of trypsin on the membrane structure. , 1969, European journal of biochemistry.