Lipopolysaccharide——a Target for the Development of Novel Drugs Being Aimed at Gram-Negative Bacteria_Journal of Biomedical Engineering

Authors：

WANGJiarong , LIYan ,  SUNHongbin

High Magnetic Field Laboratory, Chinese Academy of Sciences, Hefei 230031, China;

Corresponding author：

SUNHongbin, Email: hbsun@hmfl.ac.cn

Keywords：

lipopolysaccharide; lipopolysaccharide signal transduction; lipopolysaccharide-binding protein; lipopolysaccharide receptors

DOI：

10.7507/1001-5515.20150162

Video：

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Abstract Full text Figures/Tables Video References Cited by

Lipopolysaccharide (LPS), the important component of the outer membrane of Gram-negative bacteria, contributes to the integrity of the outer membrane, and protects the cell against bactericidal agents. LPS, also called endotoxin synonymously, is well known as a potent inducer of the innate immune system that often causes septic shock in the intensive cares. Chemically, the amphiphilic LPS is made up of three parts, i.e. hydrophobic lipid A, hydrophilic core oligosaccharide chain, and hydrophilic O-antigenic polysaccharide side chain. Specially, the lipid A is known to be responsible for a variety of biological effects during Gram-negative sepsis. LPS can elicit a strong response from innate immune system and result in local or systemic adverse reactions. LPS can trigger massive inflammatory responses and may result in immunopathology, for which the molecular basis is mediated by the signal pathway of LPS. In recent years, a tremendous progress has been made in determining the associated proteins and receptors in the LPS signaling that leads to the disease. This review gives a summary of recent progresses of research on LPS and LPS receptors.

Citation： WANGJiarong, LIYan, SUNHongbin. Lipopolysaccharide——a Target for the Development of Novel Drugs Being Aimed at Gram-Negative Bacteria. Journal of Biomedical Engineering, 2015, 32(4): 910-913. doi: 10.7507/1001-5515.20150162 Copy

1.	BRUEGEL M,LUDWIG U,KLEINHEMPEL A,et al.Sepsis-associated changes of the arachidonic acid metabolism and their diagnostic potential in septic patients[J].Crit Care Med,2012,40(5):1478-1486.
2.	GENTILE L F,CUENCA A G,VANZANT E L,et al.Is there value in plasma cytokine measurements in patients with severe trauma and sepsis?[J].Methods,2013,61(1):3-9.
3.	SCHULTE W,BERNHAGEN J,BUCALA R.Cytokines in sepsis:potent immunoregulators and potential therapeutic targets——an updated view[J].Mediators Inflamm,2013,2013:165974.
4.	DING P H,JIN L J.The role of lipopolysaccharide-binding protein in innate immunity:a revisit and its relevance to oral/periodontal health[J].J Periodontal Res,2014,49(1):1-9.
5.	KAGAN J C.Immunology.Sensing endotoxins from within[J].Science,2013,341(6165):1184-1185.
6.	NEEDHAM B D,TRENT M S.Fortifying the barrier:the impact of lipid A remodelling on bacterial pathogenesis[J].Nat Rev Microbiol,2013,11(7):467-481.
7.	PUPO E,LINDNER B,BRADE H,et al.Intact rough-and smooth-form lipopolysaccharides from Escherichia coli separated by preparative gel electrophoresis exhibit differential biologic activity in human macrophages[J].FEBS J,2013,280(4):1095-1111.
8.	NETEA M G,VAN DEUREN M,KULLBERG B J,et al.Does the shape of lipid A determine the interaction of LPS with Toll-like receptors?[J].Trends Immunol,2002,23(3):135-139.
9.	LI Y,WANG Z,CHEN J,et al.Influence of lipid A acylation pattern on membrane permeability and innate immune stimulation[J].Mar Drugs,2013,11(9):3197-3208.
10.	LEE C C,AVALOS A M,PLOEGH H L.Accessory molecules for Toll-like receptors and their function[J].Nat Rev Immunol,2012,12(3):168-179.
11.	ZANONI I,GRANUCCI F.Role of CD14 in host protection against infections and in metabolism regulation[J].Front Cell Infect Microbiol,2013,3:32.
12.	ZANONI I,OSTUNI R,MAREK L R,et al.CD14 controls the LPS-induced endocytosis of Toll-like receptor 4[J].Cell,2011,147(4):868-880.
13.	PARK S H,KIM N D,JUNG J K,et al.Myeloid differentiation 2 as a therapeutic target of inflammatory disorders[J].Pharmacol Ther,2012,133(3):291-298.
14.	KANG J Y,LEE J O.Structural biology of the Toll-like receptor family[J].Annu Rev Biochem,2011,80:917-941.
15.	RATHINAM V A,FITZGERALD K A.Immunology:lipopolysaccharide sensing on the inside[J].Nature,2013,501(7466):173-175.
16.	JIN L,DONG G Z,LEI C L,et al.Effects of dietary supplementation of glutamine and mannan oligosaccharides on plasma endotoxin and acute phase protein concentrations and nutrient digestibility in finishing steers[J].Journal of Applied Animal Research,2014,41(2):160-165.
17.	GONZALEZ-QUINTELA A,ALONSO M,CAMPOS J,et al.Determinants of serum concentrations of lipopolysaccharide-binding protein (LBP) in the adult population:the role of obesity[J].PLoS One,2013,8(1):e54600.
18.	BASHIR A,BANDAY M Z,LIPOPOLYSACCHARIDE H E.Mediator of sepsis enigma:recognition and signaling[J].Int J Biochem Res Rev,2011,1(1):1-13.
19.	HAZIOT A,CHEN S,FERRERO E,et al.The monocyte differentiation antigen,CD14,is anchored to the cell membrane by a phosphatidylinositol linkage[J].J Immunol,1988,141(2):547-552.
20.	KIM J I,LEE C J,JIN M S,et al.Crystal structure of CD14 and its implications for lipopolysaccharide signaling[J].J Biol Chem,2005,280(12):11347-11351.
21.	KELLEY S L,LUKK T,NAIR S K,et al.The crystal structure of human soluble CD14 reveals a bent solenoid with a hydrophobic amino-terminal pocket[J].J Immunol,2013,190(3):1304-1311.
22.	CUNNINGHAM M D,SHAPIRO R A,SEACHORD C,et al.CD14 employs hydrophilic regions to "capture" lipopolysaccharides[J].J Immunol,2000,164(6):3255-3263.
23.	WATANABE S,KUMAZAWA Y,INOUE J.Liposomal lipopolysaccharide initiates TRIF-dependent signaling pathway Independent of CD14[J].PLoS One,2013,8(4):e60078.
24.	VISINTIN A,LATZ E,MONKS B G,et al.Lysines 128 and 132 enable lipopolysaccharide binding to MD-2,leading to Toll-like receptor-4 aggregation and signal transduction[J].J Biol Chem,2003,278(48):48313-48320.
25.	DA SILVA CORREIA J,ULEVITCH R J.MD-2 and TLR4 N-linked glycosylations are important for a functional lipopolysaccharide receptor[J].J Biol Chem,2002,277(3):1845-1854.
26.	GRAY P,DAGVADORJ J,MICHELSEN K S,et al.Myeloid differentiation factor-2 interacts with Lyn kinase and is tyrosine phosphorylated following lipopolysaccharide-induced activation of the TLR4 signaling pathway[J].J Immunol,2011,187(8):4331-4337.
27.	PARK B S,SONG D H,KIM H M,et al.The structural basis of lipopolysaccharide recognition by the TLR4-MD-2 complex[J].Nature,2009,458(7242):1191-1195.
28.	MENG J,GONG M,BJÖRKBACKA H,et al.Genome-wide expression profiling and mutagenesis studies reveal that lipopolysaccharide responsiveness appears to be absolutely dependent on TLR4 and MD-2 expression and is dependent upon intermolecular Ionic interactions[J].J Immunol,2011,187(7):3683-3693.
29.	KONDO T,KAWAI T,AKIRA S.Dissecting negative regulation of Toll-like receptor signaling[J].Trends Immunol,2012,33(9):449-458.
30.	TSUKAMOTO H,FUKUDOME K,TAKAO S,et al.Multiple potential regulatory sites of TLR4 activation induced by LPS as revealed by novel inhibitory human TLR4 mAbs[J].Int Immunol,2012,24(8):495-506.
31.	HAZIOT A,HIJIYA N,GANGLOFF S C,et al.Induction of a novel mechanism of accelerated bacterial clearance by lipopolysaccharide in CD14-deficient and Toll-like receptor 4-deficient mice[J].J Immunol,2001,166(2):1075-1078.
32.	KAYAGAKI N,WONG M T,STOWE I B,et al.Noncanonical inflammasome activation by intracellular LPS Independent of TLR4[J].Science,2013,341(6151):1246-1249.
33.	HAGAR J A,POWELL D A,AACHOUI Y,et al.Cytoplasmic LPS activates caspase-11:implications in TLR4-independent endotoxic shock[J].Science,2013,341(6151):1250-1253.
34.	徐智,李昆霖,陈锐,等.LPS/CD14结合位点模拟肽对内毒素性大鼠急性肺损伤的治疗作用[J].第三军医大学学报,2012,34(24):2469-2473.
35.	IBRAHIM H,BARROW P,FOSTER N.VIP as a potential therapeutic agent in gram negative sepsis[J].Endocr Metab Immune Disord Drug Targets,2012,12(4):308-315.
36.	SCHMIDTCHEN A,MALMSTEN M.Peptide interactions with bacterial lipopolysaccharides[J].Curr Opin Colloid Interface Sci,2013,18(5):381-392.

1. BRUEGEL M,LUDWIG U,KLEINHEMPEL A,et al.Sepsis-associated changes of the arachidonic acid metabolism and their diagnostic potential in septic patients[J].Crit Care Med,2012,40(5):1478-1486.
2. GENTILE L F,CUENCA A G,VANZANT E L,et al.Is there value in plasma cytokine measurements in patients with severe trauma and sepsis?[J].Methods,2013,61(1):3-9.
3. SCHULTE W,BERNHAGEN J,BUCALA R.Cytokines in sepsis:potent immunoregulators and potential therapeutic targets——an updated view[J].Mediators Inflamm,2013,2013:165974.
4. DING P H,JIN L J.The role of lipopolysaccharide-binding protein in innate immunity:a revisit and its relevance to oral/periodontal health[J].J Periodontal Res,2014,49(1):1-9.
5. KAGAN J C.Immunology.Sensing endotoxins from within[J].Science,2013,341(6165):1184-1185.
6. NEEDHAM B D,TRENT M S.Fortifying the barrier:the impact of lipid A remodelling on bacterial pathogenesis[J].Nat Rev Microbiol,2013,11(7):467-481.
7. PUPO E,LINDNER B,BRADE H,et al.Intact rough-and smooth-form lipopolysaccharides from Escherichia coli separated by preparative gel electrophoresis exhibit differential biologic activity in human macrophages[J].FEBS J,2013,280(4):1095-1111.
8. NETEA M G,VAN DEUREN M,KULLBERG B J,et al.Does the shape of lipid A determine the interaction of LPS with Toll-like receptors?[J].Trends Immunol,2002,23(3):135-139.
9. LI Y,WANG Z,CHEN J,et al.Influence of lipid A acylation pattern on membrane permeability and innate immune stimulation[J].Mar Drugs,2013,11(9):3197-3208.
10. LEE C C,AVALOS A M,PLOEGH H L.Accessory molecules for Toll-like receptors and their function[J].Nat Rev Immunol,2012,12(3):168-179.
11. ZANONI I,GRANUCCI F.Role of CD14 in host protection against infections and in metabolism regulation[J].Front Cell Infect Microbiol,2013,3:32.
12. ZANONI I,OSTUNI R,MAREK L R,et al.CD14 controls the LPS-induced endocytosis of Toll-like receptor 4[J].Cell,2011,147(4):868-880.
13. PARK S H,KIM N D,JUNG J K,et al.Myeloid differentiation 2 as a therapeutic target of inflammatory disorders[J].Pharmacol Ther,2012,133(3):291-298.
14. KANG J Y,LEE J O.Structural biology of the Toll-like receptor family[J].Annu Rev Biochem,2011,80:917-941.
15. RATHINAM V A,FITZGERALD K A.Immunology:lipopolysaccharide sensing on the inside[J].Nature,2013,501(7466):173-175.
16. JIN L,DONG G Z,LEI C L,et al.Effects of dietary supplementation of glutamine and mannan oligosaccharides on plasma endotoxin and acute phase protein concentrations and nutrient digestibility in finishing steers[J].Journal of Applied Animal Research,2014,41(2):160-165.
17. GONZALEZ-QUINTELA A,ALONSO M,CAMPOS J,et al.Determinants of serum concentrations of lipopolysaccharide-binding protein (LBP) in the adult population:the role of obesity[J].PLoS One,2013,8(1):e54600.
18. BASHIR A,BANDAY M Z,LIPOPOLYSACCHARIDE H E.Mediator of sepsis enigma:recognition and signaling[J].Int J Biochem Res Rev,2011,1(1):1-13.
19. HAZIOT A,CHEN S,FERRERO E,et al.The monocyte differentiation antigen,CD14,is anchored to the cell membrane by a phosphatidylinositol linkage[J].J Immunol,1988,141(2):547-552.
20. KIM J I,LEE C J,JIN M S,et al.Crystal structure of CD14 and its implications for lipopolysaccharide signaling[J].J Biol Chem,2005,280(12):11347-11351.
21. KELLEY S L,LUKK T,NAIR S K,et al.The crystal structure of human soluble CD14 reveals a bent solenoid with a hydrophobic amino-terminal pocket[J].J Immunol,2013,190(3):1304-1311.
22. CUNNINGHAM M D,SHAPIRO R A,SEACHORD C,et al.CD14 employs hydrophilic regions to "capture" lipopolysaccharides[J].J Immunol,2000,164(6):3255-3263.
23. WATANABE S,KUMAZAWA Y,INOUE J.Liposomal lipopolysaccharide initiates TRIF-dependent signaling pathway Independent of CD14[J].PLoS One,2013,8(4):e60078.
24. VISINTIN A,LATZ E,MONKS B G,et al.Lysines 128 and 132 enable lipopolysaccharide binding to MD-2,leading to Toll-like receptor-4 aggregation and signal transduction[J].J Biol Chem,2003,278(48):48313-48320.
25. DA SILVA CORREIA J,ULEVITCH R J.MD-2 and TLR4 N-linked glycosylations are important for a functional lipopolysaccharide receptor[J].J Biol Chem,2002,277(3):1845-1854.
26. GRAY P,DAGVADORJ J,MICHELSEN K S,et al.Myeloid differentiation factor-2 interacts with Lyn kinase and is tyrosine phosphorylated following lipopolysaccharide-induced activation of the TLR4 signaling pathway[J].J Immunol,2011,187(8):4331-4337.
27. PARK B S,SONG D H,KIM H M,et al.The structural basis of lipopolysaccharide recognition by the TLR4-MD-2 complex[J].Nature,2009,458(7242):1191-1195.
28. MENG J,GONG M,BJÖRKBACKA H,et al.Genome-wide expression profiling and mutagenesis studies reveal that lipopolysaccharide responsiveness appears to be absolutely dependent on TLR4 and MD-2 expression and is dependent upon intermolecular Ionic interactions[J].J Immunol,2011,187(7):3683-3693.
29. KONDO T,KAWAI T,AKIRA S.Dissecting negative regulation of Toll-like receptor signaling[J].Trends Immunol,2012,33(9):449-458.
30. TSUKAMOTO H,FUKUDOME K,TAKAO S,et al.Multiple potential regulatory sites of TLR4 activation induced by LPS as revealed by novel inhibitory human TLR4 mAbs[J].Int Immunol,2012,24(8):495-506.
31. HAZIOT A,HIJIYA N,GANGLOFF S C,et al.Induction of a novel mechanism of accelerated bacterial clearance by lipopolysaccharide in CD14-deficient and Toll-like receptor 4-deficient mice[J].J Immunol,2001,166(2):1075-1078.
32. KAYAGAKI N,WONG M T,STOWE I B,et al.Noncanonical inflammasome activation by intracellular LPS Independent of TLR4[J].Science,2013,341(6151):1246-1249.
33. HAGAR J A,POWELL D A,AACHOUI Y,et al.Cytoplasmic LPS activates caspase-11:implications in TLR4-independent endotoxic shock[J].Science,2013,341(6151):1250-1253.
34. 徐智,李昆霖,陈锐,等.LPS/CD14结合位点模拟肽对内毒素性大鼠急性肺损伤的治疗作用[J].第三军医大学学报,2012,34(24):2469-2473.
35. IBRAHIM H,BARROW P,FOSTER N.VIP as a potential therapeutic agent in gram negative sepsis[J].Endocr Metab Immune Disord Drug Targets,2012,12(4):308-315.
36. SCHMIDTCHEN A,MALMSTEN M.Peptide interactions with bacterial lipopolysaccharides[J].Curr Opin Colloid Interface Sci,2013,18(5):381-392.

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