Genomes and Genes
lymphocyte antigen 96
Summary: A secreted protein that associates with TOLL-LIKE RECEPTOR 4 and is essential for receptor recognition of LIPOPOLYSACCHARIDES.
- Vasl J, Prohinar P, Gioannini T, Weiss J, Jerala R. Functional activity of MD-2 polymorphic variant is significantly different in soluble and TLR4-bound forms: decreased endotoxin binding by G56R MD-2 and its rescue by TLR4 ectodomain. J Immunol. 2008;180:6107-15 pubmed..Coexpression of wild-type and G56R MD-2 yielded an intermediate phenotype with responses to LPS diminished to a greater extent than that resulting from expression of the D299G TLR4 polymorphic variant. ..
- Visintin A, Iliev D, Monks B, Halmen K, Golenbock D. MD-2. Immunobiology. 2006;211:437-47 pubmed..In silico analysis suggests that MD-2 and MD-1 are paralogs derived from a common predecessor at the level of early vertebrates. In this review, we summarize the current state of knowledge concerning MD-2. ..
- Akashi S, Saitoh S, Wakabayashi Y, Kikuchi T, Takamura N, Nagai Y, et al. Lipopolysaccharide interaction with cell surface Toll-like receptor 4-MD-2: higher affinity than that with MD-2 or CD14. J Exp Med. 2003;198:1035-42 pubmed..These results reveal direct LPS interaction with cell surface TLR4-MD-2 that is distinct from that with MD-2 or CD14. ..
- Miyake K. Endotoxin recognition molecules, Toll-like receptor 4-MD-2. Semin Immunol. 2004;16:11-6 pubmed..MD-2 has a role in cell surface expression of TLR4 and interaction with LPS. TLR4-MD-2 contributes to containment of infections by Gram-negative bacteria by activating immune responses. ..
- Gioannini T, Teghanemt A, Zhang D, Coussens N, Dockstader W, Ramaswamy S, et al. Isolation of an endotoxin-MD-2 complex that produces Toll-like receptor 4-dependent cell activation at picomolar concentrations. Proc Natl Acad Sci U S A. 2004;101:4186-91 pubmed
- Gruber A, Mancek M, Wagner H, Kirschning C, Jerala R. Structural model of MD-2 and functional role of its basic amino acid clusters involved in cellular lipopolysaccharide recognition. J Biol Chem. 2004;279:28475-82 pubmed..Our structural model of MD-2 is corroborated by biochemical analysis and contributes to the unraveling of molecular interactions in LPS recognition. ..
- Blais D, Vascotto S, Griffith M, Altosaar I. LBP and CD14 secreted in tears by the lacrimal glands modulate the LPS response of corneal epithelial cells. Invest Ophthalmol Vis Sci. 2005;46:4235-44 pubmed..The complementation of these tear and corneal immune proteins could play an important role in LPS recognition and signaling and, therefore, could modulate ocular innate immunity. ..
- Prohinar P, Re F, Widstrom R, Zhang D, Teghanemt A, Weiss J, et al. Specific high affinity interactions of monomeric endotoxin.protein complexes with Toll-like receptor 4 ectodomain. J Biol Chem. 2007;282:1010-7 pubmed..MD-2/TLR4 complex. The ability to assay specific high affinity interactions of monomeric endotoxin.protein complexes with TLR4ECD should allow better definition of the structural requirements for endotoxin-induced TLR4 activation. ..
- Jia H, Kline J, Penisten A, Apicella M, Gioannini T, Weiss J, et al. Endotoxin responsiveness of human airway epithelia is limited by low expression of MD-2. Am J Physiol Lung Cell Mol Physiol. 2004;287:L428-37 pubmed..The regulation of MD-2 expression in airway epithelia and pulmonary macrophages may serve as a means to modify endotoxin responsiveness in the airway. ..
- Visintin A, Latz E, Monks B, Espevik T, Golenbock D. Lysines 128 and 132 enable lipopolysaccharide binding to MD-2, leading to Toll-like receptor-4 aggregation and signal transduction. J Biol Chem. 2003;278:48313-20 pubmed..These findings help clarify the earliest events of TLR4 triggering by LPS and identify MD-2 as an attractive target for pharmacological intervention in endotoxin-mediated diseases. ..
- Marr N, Hajjar A, Shah N, Novikov A, Yam C, Caroff M, et al. Substitution of the Bordetella pertussis lipid A phosphate groups with glucosamine is required for robust NF-kappaB activation and release of proinflammatory cytokines in cells expressing human but not murine Toll-like receptor 4-MD-2-CD14. Infect Immun. 2010;78:2060-9 pubmed publisher..We speculate that in B. pertussis, lipid A modification has evolved to benefit the bacteria during human infection by modulating immune defenses rather than to evade innate immune recognition...
- Meng J, Drolet J, Monks B, Golenbock D. MD-2 residues tyrosine 42, arginine 69, aspartic acid 122, and leucine 125 provide species specificity for lipid IVA. J Biol Chem. 2010;285:27935-43 pubmed publisher..Thus, surface charge differences at the two MD-2/TLR4 interfaces determine the species-specific activation of lipid IV(A). ..
- Miyake K, Ogata H, Nagai Y, Akashi S, Kimoto M. Innate recognition of lipopolysaccharide by Toll-like receptor 4/MD-2 and RP105/MD-1. J Endotoxin Res. 2000;6:389-91 pubmed..RP105/MD-1 thus constitutes an LPS-signaling complex on B-cells. These results suggest that a variety of cell surface molecules regulate LPS recognition/signaling by TLR4. ..
- Divanovic S, Trompette A, Atabani S, Madan R, Golenbock D, Visintin A, et al. Negative regulation of Toll-like receptor 4 signaling by the Toll-like receptor homolog RP105. Nat Immunol. 2005;6:571-8 pubmed..Finally, RP105 regulated TLR4 signaling in dendritic cells as well as endotoxin responses in vivo. Thus, our results identify RP105 as a physiological negative regulator of TLR4 responses. ..
- da Silva Correia J, Soldau K, Christen U, Tobias P, Ulevitch R. Lipopolysaccharide is in close proximity to each of the proteins in its membrane receptor complex. transfer from CD14 to TLR4 and MD-2. J Biol Chem. 2001;276:21129-35 pubmed..These data support the contention that LPS is in close proximity to the three known proteins of its membrane receptor complex. Thus, LPS binds directly to each of the members of the tripartite LPS receptor complex. ..
- Schromm A, Lien E, Henneke P, Chow J, Yoshimura A, Heine H, et al. Molecular genetic analysis of an endotoxin nonresponder mutant cell line: a point mutation in a conserved region of MD-2 abolishes endotoxin-induced signaling. J Exp Med. 2001;194:79-88 pubmed..We hypothesize that MD-2 conformationally affects the extracellular domain of TLR4, perhaps resulting in a change in affinity for LPS or functioning as a portion of the true ligand for TLR4...
- Ohto U, Fukase K, Miyake K, Satow Y. Crystal structures of human MD-2 and its complex with antiendotoxic lipid IVa. Science. 2007;316:1632-4 pubmed..The phosphorylated glucosamine moieties are located at the entrance to the cavity. These structures suggest that MD-2 plays a principal role in endotoxin recognition and provide a basis for antiseptic drug development. ..
- Akashi S, Shimazu R, Ogata H, Nagai Y, Takeda K, Kimoto M, et al. Cutting edge: cell surface expression and lipopolysaccharide signaling via the toll-like receptor 4-MD-2 complex on mouse peritoneal macrophages. J Immunol. 2000;164:3471-5 pubmed..Moreover, LPS-induced TNF-alpha production by peritoneal macrophages was inhibited by MTS510. Collectively, the TLR4-MD-2 complex is expressed on macrophages in vivo and senses and signals the presence of LPS. ..
- Divanovic S, Trompette A, Atabani S, Madan R, Golenbock D, Visintin A, et al. Inhibition of TLR-4/MD-2 signaling by RP105/MD-1. J Endotoxin Res. 2005;11:363-8 pubmed
- Yu L, Phillips R, Zhang D, Teghanemt A, Weiss J, Gioannini T. NMR studies of hexaacylated endotoxin bound to wild-type and F126A mutant MD-2 and MD-2·TLR4 ectodomain complexes. J Biol Chem. 2012;287:16346-55 pubmed publisher..This re-arrangement of Phe(126) may act as a "hydrophobic switch," driving agonist-dependent contacts needed for TLR4 dimerization and activation. ..
- Teghanemt A, Prohinar P, Gioannini T, Weiss J. Transfer of monomeric endotoxin from MD-2 to CD14: characterization and functional consequences. J Biol Chem. 2007;282:36250-6 pubmed..TLR4. These findings describe a novel pathway of endotoxin transfer that provides an additional layer of regulation of cell activation by endotoxin. ..
- Lenoir C, Sapin C, Broquet A, Jouniaux A, Bardin S, Gasnereau I, et al. MD-2 controls bacterial lipopolysaccharide hyporesponsiveness in human intestinal epithelial cells. Life Sci. 2008;82:519-28 pubmed publisher..Our data contradict previous opinion that both TLR4 and MD-2 limit IEC response to LPS, and emphasize the prominent role of MD-2 in intestinal immune responses to Gram-negative bacteria. ..
- Vasl J, Oblak A, Gioannini T, Weiss J, Jerala R. Novel roles of lysines 122, 125, and 58 in functional differences between human and murine MD-2. J Immunol. 2009;183:5138-45 pubmed publisher..These findings reveal novel roles of lysines 122, 125, and 58 in human MD-2 that contribute to the functional differences between human and murine MD-2 and, potentially, to differences in the sensitivity of humans and mice to endotoxin. ..
- Walsh C, Gangloff M, Monie T, Smyth T, Wei B, McKinley T, et al. Elucidation of the MD-2/TLR4 interface required for signaling by lipid IVa. J Immunol. 2008;181:1245-54 pubmed
- Gross P, Brandl K, Dierkes C, Scholmerich J, Salzberger B, Gluck T, et al. Lipopolysaccharide-trap-Fc, a multifunctional agent to battle gram-negative bacteria. Infect Immun. 2009;77:2925-31 pubmed publisher..Therefore, LPS-Trap-Fc not only neutralizes LPS but also, after binding to bacteria, enhances phagocytosis and complement-mediated killing and could thus act as a multifunctional agent to fight gram-negative bacteria in vivo. ..
- Kobayashi M, Saitoh S, Tanimura N, Takahashi K, Kawasaki K, Nishijima M, et al. Regulatory roles for MD-2 and TLR4 in ligand-induced receptor clustering. J Immunol. 2006;176:6211-8 pubmed..These results support a principal role for MD-2 in LPS recognition. ..
- Mullen G, Kennedy M, Visintin A, Mazzoni A, Leifer C, Davies D, et al. The role of disulfide bonds in the assembly and function of MD-2. Proc Natl Acad Sci U S A. 2003;100:3919-24 pubmed..These disulfide bonds produce a heterogeneous array of oligomers, including some species that can form an active complex with TLR4. ..
- Rallabhandi P, Bell J, Boukhvalova M, Medvedev A, Lorenz E, Arditi M, et al. Analysis of TLR4 polymorphic variants: new insights into TLR4/MD-2/CD14 stoichiometry, structure, and signaling. J Immunol. 2006;177:322-32 pubmed..A structural model that accounts for the diminished responsiveness of mutant TLR4 polymorphisms to structurally unrelated TLR4 agonists is proposed. ..
- Muroi M, Tanamoto K. Structural regions of MD-2 that determine the agonist-antagonist activity of lipid IVa. J Biol Chem. 2006;281:5484-91 pubmed
- Tsuneyoshi N, Fukudome K, Kohara J, Tomimasu R, Gauchat J, Nakatake H, et al. The functional and structural properties of MD-2 required for lipopolysaccharide binding are absent in MD-1. J Immunol. 2005;174:340-4 pubmed..The Phe residues are present in MD-2 and absent in MD-1. Therefore, the LPS recognition mechanism by RP105/MD-1 is distinct from that of TLR4/MD-2. ..
- Palsson McDermott E, O Neill L. Signal transduction by the lipopolysaccharide receptor, Toll-like receptor-4. Immunology. 2004;113:153-62 pubmed
- Uehara A, Sugawara S, Takada H. Priming of human oral epithelial cells by interferon-gamma to secrete cytokines in response to lipopolysaccharides, lipoteichoic acids and peptidoglycans. J Med Microbiol. 2002;51:626-34 pubmed..These findings suggested that IFN-gamma primed oral epithelial cells to produce cytokines upon stimulation with various bacterial components by up-regulation of the TLR system. ..
- Re F, Strominger J. Monomeric recombinant MD-2 binds toll-like receptor 4 tightly and confers lipopolysaccharide responsiveness. J Biol Chem. 2002;277:23427-32 pubmed..Remarkably, although the majority of recombinant MD-2 exists in multimeric form, monomeric MD-2 was found to preferentially bind TLR4 and to confer LPS responsiveness more efficiently than MD-2 multimers. ..
- Miyake K. Roles for accessory molecules in microbial recognition by Toll-like receptors. J Endotoxin Res. 2006;12:195-204 pubmed..TLR2 is also reported to require similar accessory molecules. Innate immune responses to microbial products driven by TLRs are controlled by accessory molecules working upstream of TLRs. ..
- Dunzendorfer S, Lee H, Soldau K, Tobias P. Toll-like receptor 4 functions intracellularly in human coronary artery endothelial cells: roles of LBP and sCD14 in mediating LPS responses. FASEB J. 2004;18:1117-9 pubmed..Results further suggest that LBP levels, which vary as LBP is an acute phase reactant, could be relevant to initiating inflammatory responses in the vasculature in response to chronic or recurring low LPS. ..
- Yoon S, Hong M, Han G, Wilson I. Crystal structure of soluble MD-1 and its interaction with lipid IVa. Proc Natl Acad Sci U S A. 2010;107:10990-5 pubmed publisher..These findings suggest that soluble MD-1 alone, in addition to its complex with RP105, can regulate host LPS sensitivity. ..
- Pugin J, Stern Voeffray S, Daubeuf B, Matthay M, Elson G, Dunn Siegrist I. Soluble MD-2 activity in plasma from patients with severe sepsis and septic shock. Blood. 2004;104:4071-9 pubmed..We therefore propose that soluble MD-2 is an important mediator of organ inflammation during sepsis. ..
- Saitoh S, Akashi S, Yamada T, Tanimura N, Matsumoto F, Fukase K, et al. Ligand-dependent Toll-like receptor 4 (TLR4)-oligomerization is directly linked with TLR4-signaling. J Endotoxin Res. 2004;10:257-60 pubmed..These results demonstrate that ligand-induced TLR4-oligomerization is directly linked with TLR4-signaling and suggest that MD-2 has an important role in regulating TLR4-oligomerization. ..
- Mitsuzawa H, Nishitani C, Hyakushima N, Shimizu T, Sano H, Matsushima N, et al. Recombinant soluble forms of extracellular TLR4 domain and MD-2 inhibit lipopolysaccharide binding on cell surface and dampen lipopolysaccharide-induced pulmonary inflammation in mice. J Immunol. 2006;177:8133-9 pubmed..This study provides novel usage of sTLR4 and sMD-2 as an antagonist against endotoxin-induced pulmonary inflammation. ..
- Visintin A, Mazzoni A, Spitzer J, Segal D. Secreted MD-2 is a large polymeric protein that efficiently confers lipopolysaccharide sensitivity to Toll-like receptor 4. Proc Natl Acad Sci U S A. 2001;98:12156-61 pubmed..We conclude that normal and transfected cells secrete a soluble form of MD-2 that binds with high affinity to TLR4 and that could play a role in regulating responses to LPS and other pathogen-derived substances in vivo. ..
- Latz E, Visintin A, Lien E, Fitzgerald K, Monks B, Kurt Jones E, et al. Lipopolysaccharide rapidly traffics to and from the Golgi apparatus with the toll-like receptor 4-MD-2-CD14 complex in a process that is distinct from the initiation of signal transduction. J Biol Chem. 2002;277:47834-43 pubmed..Golgi-associated TLR4 expression was disrupted by brefeldin A, yet LPS signaling was preserved. We conclude that LPS signaling may be initiated by surface aggregation of TLR4 and is not dependent upon LPS trafficking to the Golgi. ..
- Wang X, Loram L, RAMOS K, de Jesus A, Thomas J, Cheng K, et al. Morphine activates neuroinflammation in a manner parallel to endotoxin. Proc Natl Acad Sci U S A. 2012;109:6325-30 pubmed publisher..These results provide an exciting, nonconventional avenue to improving the clinical efficacy of opioids. ..
- Tsukamoto H, Fukudome K, Takao S, Tsuneyoshi N, Kimoto M. Lipopolysaccharide-binding protein-mediated Toll-like receptor 4 dimerization enables rapid signal transduction against lipopolysaccharide stimulation on membrane-associated CD14-expressing cells. Int Immunol. 2010;22:271-80 pubmed publisher..This early activation was blocked by inhibitory anti-CD14 mAb. These studies suggest that LPS-induced TLR4/MD-2 receptor dimerization is not essential for signaling but prompts rapid signaling during innate immune responses. ..
- Lewis S, Hutchinson M, Rezvani N, Loram L, Zhang Y, Maier S, et al. Evidence that intrathecal morphine-3-glucuronide may cause pain enhancement via toll-like receptor 4/MD-2 and interleukin-1beta. Neuroscience. 2010;165:569-83 pubmed publisher..These data provide the first evidence for a TLR4 and IL-1 mediated component to M3G-induced effects, likely of at least microglial origin. ..
- Miyake K, Nagai Y, Akashi S, Nagafuku M, Ogata M, Kosugi A. Essential role of MD-2 in B-cell responses to lipopolysaccharide and Toll-like receptor 4 distribution. J Endotoxin Res. 2002;8:449-52 pubmed..Here, we further show that B cells lacking MD-2 do not up-regulate CD23 in response to LPS. TLR4 predominantly resides in the Golgi apparatus without MD-2. MD-2 is essential for LPS responses in vivo. ..
- Kennedy M, Mullen G, Leifer C, Lee C, Mazzoni A, Dileepan K, et al. A complex of soluble MD-2 and lipopolysaccharide serves as an activating ligand for Toll-like receptor 4. J Biol Chem. 2004;279:34698-704 pubmed..We propose that the soluble MD-2.LPS complex plays a crucial role in the LPS response by activating epithelial and other TLR4(+)/MD-2(-) cells in the inflammatory microenvironment. ..
- Jin M, Lee J. Structures of the toll-like receptor family and its ligand complexes. Immunity. 2008;29:182-91 pubmed publisher..This observation suggests the hypothesis that dimerization of the extracellular domains forces the intracellular TIR domains to dimerize, and this initiates signaling by recruiting intracellular adaptor proteins. ..
- Kim H, Park B, Kim J, Kim S, Lee J, Oh S, et al. Crystal structure of the TLR4-MD-2 complex with bound endotoxin antagonist Eritoran. Cell. 2007;130:906-17 pubmed..The interaction with Eritoran is mediated by a hydrophobic internal pocket in MD-2. Based on structural analysis and mutagenesis experiments on MD-2 and TLR4, we propose a model of TLR4-MD-2 dimerization induced by LPS. ..
- Gon Y, Asai Y, Hashimoto S, Mizumura K, Jibiki I, Machino T, et al. A20 inhibits toll-like receptor 2- and 4-mediated interleukin-8 synthesis in airway epithelial cells. Am J Respir Cell Mol Biol. 2004;31:330-6 pubmed..Taken together, our results suggest that A20 may function as a negative regulator of TLR-mediated inflammatory responses in the airway, thereby protecting the host against harmful overresponses to pathogens. ..
- Zimmer S, Liu J, Clayton J, Stephens D, Snyder J. Paclitaxel binding to human and murine MD-2. J Biol Chem. 2008;283:27916-26 pubmed publisher..In particular, Phe(126) appears to operate as a bridge for TLR4.MD-2 dimerization in the mouse but not the human protein. ..
- Jiang Z, Georgel P, Du X, Shamel L, Sovath S, Mudd S, et al. CD14 is required for MyD88-independent LPS signaling. Nat Immunol. 2005;6:565-70 pubmed..Thus, the TLR4-MD-2 complex receptor can function in two separate modes: one in which full signaling occurs and one limited to MyD88-dependent signaling. ..