/home/ikeda/eclipse/workspace/macrophage/csml/ok/csml/18031244.csml - 2009.07.01.11:10

Original Literature	Model OverView
Publication Title Toll-like receptors in atherosclerosis. Authors Tobias PS, Curtiss LK. Affiliation Department of Immunology, The Scripps Research Institute, 10550 North TorreyPines Road, La Jolla, CA 92037, USA. Abstract At one time, atherosclerosis was thought to be a simple lipid storage disease.However, it is now recognized as a chronic and progressive inflammation of thearterial wall. Gene deletion experiments in murine models of atherosclerosisthat reduce the inflammatory process also reduce disease severity. Identifyingthe initiators and mediators of that inflammation can provide promising avenuesfor prevention or therapy. Two prominent risk factors, hyperlipidaemia andinfectious disease, point to innate immune mechanisms as potential contributorsto proatherogenic inflammation. The TLRs (Toll-like receptors), pro-inflammatorysensors of pathogens, are potential links between inflammation, infectiousdisease and atherosclerosis. A mechanism for hyperlipidaemic initiation ofsterile inflammation can be postulated because oxidized lipoproteins or theircomponent oxidized lipids have been identified as TLR ligands. Moreover,infectious agents are correlated with atherosclerosis risk. We have identified arole for TLR2 in atherosclerosis in mice deficient in low-density lipoproteinreceptor. We observed that proatherogenic TLR2 responses to unknown endogenousor unknown endemic exogenous agonists are mediated by non-BMDC(bone-marrow-derived cells), which can include endothelial cells. In contrast,the proatherogenic TLR2 responses to the defined synthetic exogenous agonistPam3 CSK4 are mediated at least in part by BMDC, which can include lymphocytes,monocytes/macrophages and dendritic cells. TLR2-mediated cell activation inresponse to endogenous and exogenous agents is proatherogenic in hyperlipidaemicmice. PMID 18031244

Model Detail

334.0, 14.0

30.0, 30.0

LPS

MO000016882

cso30:c:Protein

cso30:i:CC_CellComponent

csml-variable:Double

m155666

false

infinite

unit

TRANSPATH

MO000016882

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336.0, 88.0

32.0, 32.0

TLR4

MO000019394

cso30:c:Protein

cso30:i:CC_CellComponent

csml-variable:Double

m3961

false

infinite

unit

InterPro	IPR000157
TRANSPATH	MO000019394

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817.0, 421.0

30.0, 30.0

TLR2

MO000019397

cso30:c:Protein

cso30:i:CC_CellComponent

p2 p3 p4 p5 p6

csml-variable:Double

m3964

false

infinite

unit

InterPro	IPR000157
TRANSPATH	MO000019397

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956.0, 368.0

31.0, 31.0

HMGB1

MO000044940

cso30:c:Protein

cso30:i:CC_CellComponent

csml-variable:Double

m22603

false

infinite

unit

TRANSPATH

MO000044940

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7.75, 74.99690800911759

856.2594311764528, 1243.2886940682085

cso30:c:EntityBiologicalCompartment

cso30:i:CC_PlasmaMembrane

csml-variable:Double

false

infinite

unit

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16.0, 94.0

829.9775981223105, 1167.545103664102

e10

cso30:c:EntityBiologicalCompartment

cso30:i:CC_Cytosol

csml-variable:Double

m10

false

infinite

unit

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953.5, 303.25

45.0, 25.5

biglycan

e11

cso30:c:SmallMolecule

cso30:i:CC_Extracellular

csml-variable:Double

m11

false

infinite

unit

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957.5, 543.25

45.0, 25.5

serum amyloid A

e12

cso30:c:SmallMolecule

cso30:i:CC_Extracellular

csml-variable:Double

m12

false

infinite

unit

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815.875, 361.5

32.25, 45.0

HMGB1: TLR2

e13

cso30:c:Complex

cso30:i:CC_PlasmaMembrane_IntegralToPlasmaMembrane_

csml-variable:Double

m13

false

infinite

unit

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815.875, 293.5

32.25, 45.0

biglycan: TLR2

e14

cso30:c:Complex

cso30:i:CC_PlasmaMembrane_IntegralToPlasmaMembrane_

csml-variable:Double

m14

false

infinite

unit

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815.875, 481.5

32.25, 45.0

hyaluronic acid fragments: TLR2

e15

cso30:c:Complex

cso30:i:CC_PlasmaMembrane_IntegralToPlasmaMembrane_

csml-variable:Double

m15

false

infinite

unit

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815.875, 533.5

32.25, 45.0

serum amyloid A: TLR2

e16

cso30:c:Complex

cso30:i:CC_PlasmaMembrane_IntegralToPlasmaMembrane_

csml-variable:Double

m16

false

infinite

unit

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949.5, 627.25

45.0, 25.5

Pam3CSK4

e17

cso30:c:SmallMolecule

cso30:i:CC_Extracellular

csml-variable:Double

m17

false

infinite

unit

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811.875, 617.5

32.25, 45.0

Pam3CSK4: TLR2

e18

cso30:c:Complex

cso30:i:CC_PlasmaMembrane_IntegralToPlasmaMembrane_

csml-variable:Double

m18

false

infinite

unit

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7.75, 74.99690800911759

856.2594311764528, 1243.2886940682085

cso30:c:EntityBiologicalCompartment

cso30:i:CC_PlasmaMembrane_ExternalSideOfPlasmaMembrane_

csml-variable:Double

false

infinite

unit

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24.875188623529027, 92.12209663264667

822.0090539293948, 1209.0383168211513

cso30:c:EntityBiologicalCompartment

cso30:i:CC_PlasmaMembrane_IntegralToPlasmaMembrane_

csml-variable:Double

false

infinite

unit

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56.55678757705792, 122.09117672382234

758.6458560223374, 1149.1001566387988

cso30:c:EntityBiologicalCompartment

cso30:i:CC_PlasmaMembrane_InternalSideOfPlasmaMembrane_

csml-variable:Double

false

infinite

unit

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459.625, 87.5

32.97762872854524, 40.38076987168805

LPS: TLR4

cso30:c:Complex

cso30:i:CC_Cytosol

csml-variable:Double

false

infinite

unit

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189.0, 792.0

465.6500709748862, 422.29345356567933

e50

cso30:c:EntityBiologicalCompartment

cso30:i:CC_NuclearEnvelopeLumen

csml-variable:Double

m50

false

infinite

unit

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239.29367619468036, 802.0077409313898

272.27955732982184, 409.2864683429171

e51

cso30:c:EntityBiologicalCompartment

cso30:i:CC_NuclearPore

csml-variable:Double

m51

false

infinite

unit

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195.06992643728904, 797.6363602631969

453.51021810030846, 411.0207330392853

e52

cso30:c:EntityBiologicalCompartment

cso30:i:CC_NuclearInnerMembrane

csml-variable:Double

m52

false

infinite

unit

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195.93705878547314, 798.503492611381

451.7759534039399, 409.2864683429171

e53

cso30:c:EntityBiologicalCompartment

cso30:i:CC_NuclearLumen

csml-variable:Double

m53

false

infinite

unit

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189.0, 792.0

465.6500709748862, 422.29345356567933

e54

cso30:c:EntityBiologicalCompartment

cso30:i:CC_NuclearOuterMembrane

csml-variable:Double

m54

false

infinite

unit

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189.0, 792.0

465.6500709748862, 422.29345356567933

e55

cso30:c:EntityBiologicalCompartment

cso30:i:CC_Nucleus

csml-variable:Double

m55

false

infinite

unit

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195.93705878547314, 798.503492611381

451.7759534039399, 409.2864683429171

e56

cso30:c:EntityBiologicalCompartment

cso30:i:CC_Nucleoplasm

csml-variable:Double

m56

false

infinite

unit

Go back

528.9158804881849, 965.4264696368292

29.091257918298922, 26.33524401024959

e57

cso30:c:EntityBiologicalCompartment

cso30:i:CC_NuclearBody

csml-variable:Double

m57

false

infinite

unit

Go back

452.6082338479803, 1086.8249983826097

82.37757307749382, 74.57338194383664

e58

cso30:c:EntityBiologicalCompartment

cso30:i:CC_Nucleolus

csml-variable:Double

m58

false

infinite

unit

Go back

189.0, 792.0

465.6500709748862, 422.29345356567933

e59

cso30:c:EntityBiologicalCompartment

cso30:i:CC_NuclearEnvelope

csml-variable:Double

m59

false

infinite

unit

Go back

949.5, 463.25

45.0, 25.5

hyaluronic acid fragments

cso30:c:SmallMolecule

cso30:i:CC_Extracellular

csml-variable:Double

false

infinite

unit

Go back

298.7511016961721, 979.6637213250546

14.746453546866459, 7.100144300343119

e60

cso30:c:EntityBiologicalCompartment

cso30:i:CC_Chromatin

csml-variable:Double

m60

false

infinite

unit

Go back

298.25867587120234, 958.4894108513561

50.4736470593979, 90.85256470691624

e61

cso30:c:EntityBiologicalCompartment

cso30:i:CC_NuclearChromosome

csml-variable:Double

m61

false

infinite

unit

Go back

319.43298634490145, 1017.5805098477247

7.878813199515761, 7.8788131995157675

e62

cso30:c:EntityBiologicalCompartment

cso30:i:CC_NuclearCentromere

csml-variable:Double

m62

false

infinite

unit

Go back

19.0, 80.0

839.7237354966342, 1189.8668429177399

cso30:c:EntityBiologicalCompartment

cso30:i:CC_Cell

csml-variable:Double

false

infinite

unit

Go back

22.0, 101.0

805.5569854171277, 1169.6687428256696

cso30:c:EntityBiologicalCompartment

cso30:i:CC_Cell_WithoutCellWall_

csml-variable:Double

false

infinite

unit

Go back

30.0, 122.0

801.8791759029863, 1154.3288303559784

cso30:c:EntityBiologicalCompartment

cso30:i:CC_Cytoplasm

csml-variable:Double

false

infinite

unit

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409.0, 33.0

30.0, 30.0

cso30:i:ME_Binding

cso30:i:CC_Extracellular

MO000016882 MO000019394

and

mass

coefficient1:0.1
coefficient2:1.0
stoichiometry:c1 : 1
stoichiometry:c2 : 1
stoichiometry:c3 : 1

m155666*m3961*0.1

nodelay

true

false

PMID: 18031244, 12816876 Others had shown that administration of LPS (lipopolysaccharide), an exogenous TLR4 agonist, promoted disease in rabbits and mice.

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891.0, 371.0

25.0, 25.0

cso30:i:ME_Binding

cso30:i:CC_Extracellular

MO000019397 MO000044940

e13

and

mass

coefficient1:0.1
coefficient2:1.0
stoichiometry:c4 : 1
stoichiometry:c5 : 1
stoichiometry:c6 : 1

m3964*m22603*0.1

nodelay

true

false

PMID: 18031244, 16267105, 16025156, 11781369 Other possibilities include HMGB1 (high-mobility group B1), biglycan, hyaluronic acid fragments, necrotic cells and SAA (serum amyloid A) [31?36]. All of these have been shown to be TLR2 agonists in vitro.

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891.0, 463.0

25.0, 25.0

cso30:i:ME_Binding

cso30:i:CC_Extracellular

MO000019397 e6

e15

and

mass

coefficient1:0.1
coefficient2:1.0
stoichiometry:c10 : 1
stoichiometry:c11 : 1
stoichiometry:c12 : 1

m3964*m6*0.1

nodelay

true

false

Go back

887.0, 303.0

25.0, 25.0

cso30:i:ME_Binding

cso30:i:CC_Extracellular

MO000019397 e11

e14

and

mass

coefficient1:0.1
coefficient2:1.0
stoichiometry:c7 : 1
stoichiometry:c8 : 1
stoichiometry:c9 : 1

m3964*m11*0.1

nodelay

true

false

Go back

894.0, 542.0

27.0, 27.0

cso30:i:ME_Binding

cso30:i:CC_Extracellular

MO000019397 e12

e16

and

mass

coefficient1:0.1
coefficient2:1.0
stoichiometry:c13 : 1
stoichiometry:c14 : 1
stoichiometry:c15 : 1

m3964*m12*0.1

nodelay

true

false

Go back

886.0, 626.0

27.0, 27.0

cso30:i:ME_Binding

cso30:i:CC_Extracellular

e17 MO000019397

e18

and

mass

coefficient1:0.1
coefficient2:1.0
stoichiometry:c16 : 1
stoichiometry:c17 : 1
stoichiometry:c18 : 1

m17*m3964*0.1

nodelay

true

false

PMID: 18031244 the proatherogenic TLR2 responses to the defined synthetic exogenous agonist Pam3 CSK4 are mediated at least in part by BMDC, which can include lymphocytes, monocytes/macrophages and dendritic cells.

Go back