/home/ikeda/eclipse/workspace/macrophage/csml/ok/csml/18073395.csml - 2009.07.01.11:12

Original Literature	Model OverView
Publication Title Toll-like receptors, Notch ligands, and cytokines drive the chronicity of lunginflammation. Authors Raymond T, Schaller M, Hogaboam CM, Lukacs NW, Rochford R, Kunkel SL. Affiliation Immunology Program and Department of Pathology, University of Michigan MedicalSchool, Ann Arbor, Michigan 48109-2200, USA. Abstract Current dogma supports the concept that the expression of a disease-inducingsignature cytokine phenotype is important to the maintenance stage of chroniclung disorders. This cytokine phenotype has been characterized as a polarizationtoward type 2 cytokines, which are profibrotic and immunoregulatory. The biologyof this latter activity could mechanistically explain pathogen-inducedexacerbation of chronic lung inflammation, as a skewed cytokine profile in thelung alters dendritic cell function, activates fibroblasts, and facilitates asubsequent "second hit" by an infectious pathogen. In this setting, cytokinebiology is also linked to Toll-like receptors (TLRs) in the maintenance of lungimmunity, as the activity of this receptor-ligand system by both leukocytes andstromal cells is likely an important component of disease chronicity. Theparticipation of dendritic cells via TLRs in chronic lung disease couldfacilitate communication circuits established between antigen-presenting cellsand lymphocytes. Data suggest that TLR activation via myeloid differentiationfactor 88 adaptor protein leads to the induction of a Notch ligand known asDelta-like-4 on dendritic cells that activate the Notch receptor on T cells,promoting a helper T-cell type 1 cytokine response. It is likely that theevolution of host defense signals designed to recognize patterns emitted from ahostile microbial environment may now be superimposed on adaptive immunity andprovide the underpinning to support the maintenance of chronic lung disease. PMID 18073395

Model Detail

759.0, 946.0

32.5, 32.5

MHC class II

G010240

cso30:c:mRNA

cso30:i:CC_CellComponent

csml-variable:Double

m93228

false

infinite

unit

TRANSFAC

G010240

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433.0, 864.0

32.0, 32.0

IL-5

G010292

cso30:c:mRNA

cso30:i:CC_CellComponent

p12

csml-variable:Double

m93275

false

infinite

unit

TRANSFAC

G010292

Go back

676.0, 1075.0

30.0, 30.0

IFN-gamma

G010453

cso30:c:mRNA

cso30:i:CC_Nucleoplasm

p11

csml-variable:Double

m93423

false

infinite

unit

TRANSFAC

G010453

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437.0, 916.0

32.0, 32.0

IL-13

G010530

cso30:c:mRNA

cso30:i:CC_Nucleoplasm

p13

csml-variable:Double

m93493

false

infinite

unit

TRANSFAC

G010530

Go back

747.0, 874.0

31.0, 31.0

IL-12 p40

G010657

cso30:c:mRNA

cso30:i:CC_CellComponent

csml-variable:Double

m93589

false

infinite

unit

TRANSFAC

G010657

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756.0, 1027.0

30.0, 30.0

CD86

G010859

cso30:c:mRNA

cso30:i:CC_CellComponent

csml-variable:Double

m93745

false

infinite

unit

TRANSFAC

G010859

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803.0, 990.0

32.0, 32.0

CD80

G012224

cso30:c:mRNA

cso30:i:CC_CellComponent

csml-variable:Double

m95018

false

infinite

unit

TRANSFAC

G012224

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797.0, 848.0

28.0, 28.0

DLL4

G029064

cso30:c:mRNA

cso30:i:CC_CellComponent

csml-variable:Double

m107762

false

infinite

unit

TRANSFAC

G029064

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211.0, 830.0

40.0, 40.0

Notch

MO000000280

cso30:c:Protein

cso30:i:CC_CellComponent

p14

csml-variable:Double

m222

false

infinite

unit

TRANSPATH

MO000000280

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313.0, 992.0

36.0, 36.0

IL-13

MO000007321

cso30:c:Protein

cso30:i:CC_CellComponent

p13

csml-variable:Double

m836

false

infinite

unit

InterPro	IPR001325
TRANSPATH	MO000007321

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310.0, 245.0

33.0, 33.0

MyD88

MO000016573

cso30:c:Protein

cso30:i:CC_CellComponent

csml-variable:Double

m1572

false

infinite

unit

InterPro	IPR000157
TRANSPATH	MO000016573

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308.0, 795.0

38.0, 38.0

IL-5

MO000017013

cso30:c:Protein

cso30:i:CC_CellComponent

p12

csml-variable:Double

m1913

false

infinite

unit

InterPro	IPR000186
TRANSPATH	MO000017013

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1102.0, 873.0

34.0, 34.0

IL-12

MO000017265

cso30:c:Protein

cso30:i:CC_CellComponent

p10

csml-variable:Double

m2121

false

infinite

unit

TRANSPATH

MO000017265

Go back

212.0, 415.0

30.0, 30.0

TLRs

MO000019395

cso30:c:Protein

cso30:i:CC_CellComponent

csml-variable:Double

m3962

false

infinite

unit

TRANSPATH

MO000019395

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167.0, 546.0

32.0, 32.0

Jagged

MO000031247

cso30:c:Protein

cso30:i:CC_CellComponent

p15

csml-variable:Double

m10790

false

infinite

unit

TRANSPATH

MO000031247

Go back

1006.0, 977.0

34.0, 34.0

IL-12R

MO000033676

cso30:c:Protein

cso30:i:CC_CellComponent

p10

csml-variable:Double

m12340

false

infinite

unit

TRANSPATH

MO000033676

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160.0, 607.0

38.0, 38.0

DLL3

MO000064853

cso30:c:Protein

cso30:i:CC_CellComponent

p16

csml-variable:Double

m39723

false

infinite

unit

TRANSPATH

MO000064853

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158.0, 781.0

42.0, 42.0

DLL4

MO000068539

cso30:c:Protein

cso30:i:CC_CellComponent

p14 p19

csml-variable:Double

m43386

false

infinite

unit

TRANSPATH

MO000068539

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197.75, 32.99690800911759

856.2594311764528, 1243.2886940682085

cso30:c:EntityBiologicalCompartment

cso30:i:CC_PlasmaMembrane

csml-variable:Double

false

infinite

unit

Go back

206.0, 52.0

829.9775981223105, 1167.545103664102

e10

cso30:c:EntityBiologicalCompartment

cso30:i:CC_Cytosol

csml-variable:Double

m10

false

infinite

unit

Go back

213.25, 306.0

34.72591301156176, 48.45476234171407

TLR ligand: TLR: MyD88

e11

cso30:c:Complex

cso30:i:CC_PlasmaMembrane_IntegralToPlasmaMembrane_

csml-variable:Double

m11

false

infinite

unit

Go back

800.5, 914.0

45.0, 24.0

IL-23

e12

cso30:c:mRNA

cso30:i:CC_Nucleoplasm

csml-variable:Double

m12

false

infinite

unit

Go back

1004.625, 1067.5

36.75, 45.0

IL-12: IL-12R

e13

cso30:c:Complex

cso30:i:CC_PlasmaMembrane_IntegralToPlasmaMembrane_

p10

p11

csml-variable:Double

m13

false

infinite

unit

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208.625, 891.5

36.75, 45.0

DLL4: Notch

e14

cso30:c:Complex

cso30:i:CC_PlasmaMembrane_IntegralToPlasmaMembrane_

p14

p12 p13

csml-variable:Double

m14

false

infinite

unit

Go back

160.5, 731.125

36.088750251559674, 22.254729321795132

DLL1

e15

cso30:c:Protein

cso30:i:CC_Extracellular

p18

csml-variable:Double

m15

false

infinite

unit

Go back

160.5, 671.125

36.088750251559674, 22.254729321795132

DLL2

e16

cso30:c:Protein

cso30:i:CC_Extracellular

p17

csml-variable:Double

m16

false

infinite

unit

Go back

197.75, 32.99690800911759

856.2594311764528, 1243.2886940682085

cso30:c:EntityBiologicalCompartment

cso30:i:CC_PlasmaMembrane_ExternalSideOfPlasmaMembrane_

csml-variable:Double

false

infinite

unit

Go back

214.87518862352903, 50.122096632646674

822.0090539293948, 1209.0383168211513

cso30:c:EntityBiologicalCompartment

cso30:i:CC_PlasmaMembrane_IntegralToPlasmaMembrane_

csml-variable:Double

false

infinite

unit

Go back

246.5567875770579, 80.09117672382234

758.6458560223374, 1149.1001566387988

cso30:c:EntityBiologicalCompartment

cso30:i:CC_PlasmaMembrane_InternalSideOfPlasmaMembrane_

csml-variable:Double

false

infinite

unit

Go back

148.0, 368.25

30.0, 19.5

TLR ligand

cso30:c:Protein

cso30:i:CC_Extracellular

csml-variable:Double

false

infinite

unit

Go back

380.0, 722.0

492.1282343046551, 446.30623855934294

e50

cso30:c:EntityBiologicalCompartment

cso30:i:CC_NuclearEnvelopeLumen

csml-variable:Double

m50

false

infinite

unit

Go back

433.1535150645622, 732.5768090266413

287.76213328056184, 432.5596398357492

e51

cso30:c:EntityBiologicalCompartment

cso30:i:CC_NuclearPore

csml-variable:Double

m51

false

infinite

unit

Go back

386.4150794043437, 727.9568594468906

479.2980754959679, 434.3925196655615

e52

cso30:c:EntityBiologicalCompartment

cso30:i:CC_NuclearInnerMembrane

csml-variable:Double

m52

false

infinite

unit

Go back

387.33151931924994, 728.8732993617967

477.4651956661551, 432.5596398357492

e53

cso30:c:EntityBiologicalCompartment

cso30:i:CC_NuclearLumen

csml-variable:Double

m53

false

infinite

unit

Go back

380.0, 722.0

492.1282343046551, 446.30623855934294

e54

cso30:c:EntityBiologicalCompartment

cso30:i:CC_NuclearOuterMembrane

csml-variable:Double

m54

false

infinite

unit

Go back

380.0, 722.0

492.1282343046551, 446.30623855934294

e55

cso30:c:EntityBiologicalCompartment

cso30:i:CC_Nucleus

csml-variable:Double

m55

false

infinite

unit

Go back

387.33151931924994, 728.8732993617967

477.4651956661551, 432.5596398357492

e56

cso30:c:EntityBiologicalCompartment

cso30:i:CC_Nucleoplasm

csml-variable:Double

m56

false

infinite

unit

Go back

739.2444466432488, 905.2879829812496

30.745468078766596, 27.832739523936105

e57

cso30:c:EntityBiologicalCompartment

cso30:i:CC_NuclearBody

csml-variable:Double

m57

false

infinite

unit

Go back

658.5977341314992, 1033.589571068124

87.06179191609351, 78.81383268193741

e58

cso30:c:EntityBiologicalCompartment

cso30:i:CC_Nucleolus

csml-variable:Double

m58

false

infinite

unit

Go back

380.0, 722.0

492.1282343046551, 446.30623855934294

e59

cso30:c:EntityBiologicalCompartment

cso30:i:CC_NuclearEnvelope

csml-variable:Double

m59

false

infinite

unit

Go back

210.75, 486.0

32.37952007998667, 39.648391934677555

TLR ligand: TLR

cso30:c:Complex

cso30:i:CC_PlasmaMembrane_IntegralToPlasmaMembrane_

p2 p4 p5 p6 p7 p8

csml-variable:Double

false

infinite

unit

Go back

495.9918558106283, 920.3348045569628

15.584978073946015, 7.503878331899941

e60

cso30:c:EntityBiologicalCompartment

cso30:i:CC_Chromatin

csml-variable:Double

m60

false

infinite

unit

Go back

495.4714292781872, 897.9564636619998

53.343719575203274, 96.0186952353659

e61

cso30:c:EntityBiologicalCompartment

cso30:i:CC_NuclearChromosome

csml-variable:Double

m61

false

infinite

unit

Go back

517.849770173151, 960.4076475549209

8.326824519056112, 8.326824519056116

e62

cso30:c:EntityBiologicalCompartment

cso30:i:CC_NuclearCentromere

csml-variable:Double

m62

false

infinite

unit

Go back

209.0, 38.0

839.7237354966342, 1189.8668429177399

cso30:c:EntityBiologicalCompartment

cso30:i:CC_Cell

csml-variable:Double

false

infinite

unit

Go back

212.0, 59.0

805.5569854171277, 1169.6687428256696

cso30:c:EntityBiologicalCompartment

cso30:i:CC_Cell_WithoutCellWall_

csml-variable:Double

false

infinite

unit

Go back

220.0, 80.0

801.8791759029863, 1154.3288303559784

cso30:c:EntityBiologicalCompartment

cso30:i:CC_Cytoplasm

csml-variable:Double

false

infinite

unit

Go back

150.0, 417.0

25.0, 25.0

cso30:i:ME_Binding

cso30:i:CC_Extracellular

e5 MO000019395

and

mass

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

m5*m3962*0.1

nodelay

true

false

PMID: 18073395 Data suggest that TLR activation via myeloid differentiation factor 88 adaptor protein leads to the induction of a Notch ligand known as Delta-like-4 on dendritic cells that activate the Notch receptor on T cells, promoting a helper T-cell type 1 cytokine response.

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1104.0, 979.0

29.0, 29.0

p10

cso30:i:ME_Binding

cso30:i:CC_Extracellular

MO000017265 MO000033676

e13

and

mass

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

m2121*m12340*0.1

nodelay

true

false

PMID: 18073395 It is clear that the activation of TLRs on antigen-presenting cells can lead to the expression of IL-12 and subsequently activate the expression of IFN-gamma from Th1 cells.

Go back

735.0, 1078.0

24.0, 24.0

p11

cso30:i:ME_GeneExpression

cso30:i:CC_Nucleoplasm

e13

G010453

and

mass

coefficient1:0.1
coefficient2:1.0
stoichiometry:c19 : 1
stoichiometry:c20 : 1

m13*0.1

nodelay

true

false

PMID: 18073395 It is clear that the activation of TLRs on antigen-presenting cells can lead to the expression of IL-12 and subsequently activate the expression of IFN-gamma from Th1 cells.

Go back

312.0, 863.0

30.0, 30.0

p12

cso30:i:ME_Translation

cso30:i:CC_Cytosol

G010292 e14

MO000017013

and

mass

coefficient1:0.1
coefficient2:1.0
stoichiometry:c23 : 1
stoichiometry:c28 : 1
stoichiometry:c21 : 1

m93275*m14*0.1

nodelay

true

false

PMID: 18073395 This study showed that production of both IL-5 and IL-13 from antigen-challenged lymphocytes recovered from animals treated with antibody to DL4 was enhanced over control antibody-treated animals.

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316.0, 915.0

30.0, 30.0

p13

cso30:i:ME_Translation

cso30:i:CC_Cytosol

G010530 e14

MO000007321

and

mass

coefficient1:0.1
coefficient2:1.0
stoichiometry:c24 : 1
stoichiometry:c29 : 1
stoichiometry:c22 : 1

m93493*m14*0.1

nodelay

true

false

Go back

137.0, 900.0

27.0, 27.0

p14

cso30:i:ME_Binding

cso30:i:CC_Extracellular

MO000068539 MO000000280

e14

and

mass

coefficient1:0.1
coefficient2:1.0
stoichiometry:c25 : 1
stoichiometry:c26 : 1
stoichiometry:c27 : 1

m43386*m222*0.1

nodelay

true

false

Go back

69.0, 549.0

30.0, 30.0

p15

cso30:i:CE_CellDifferentiation

cso30:i:CC_Extracellular

MO000031247

and

mass

coefficient1:0.1
coefficient2:1.0
stoichiometry:c35 : 1

m10790*0.1

nodelay

true

false

PMID: 18073395, 15886115 Studies suggest that the Notch ligands Delta-like-1?4 and Jagged, expressed on dendritic cells, can provide novel activation signals for the development of either Th1 and Th2 cells, respectively (67).

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69.0, 613.0

30.0, 30.0

p16

cso30:i:CE_CellDifferentiation

cso30:i:CC_Extracellular

MO000064853

and

mass

coefficient1:0.1
coefficient2:1.0
stoichiometry:c36 : 1

m39723*0.1

nodelay

true

false

Go back

69.0, 669.0

30.0, 30.0

p17

cso30:i:CE_CellDifferentiation

cso30:i:CC_Extracellular

e16

and

mass

coefficient1:0.1
coefficient2:1.0
stoichiometry:c37 : 1

m16*0.1

nodelay

true

false

Go back

69.0, 729.0

30.0, 30.0

p18

cso30:i:CE_CellDifferentiation

cso30:i:CC_Extracellular

e15

and

mass

coefficient1:0.1
coefficient2:1.0
stoichiometry:c38 : 1

m15*0.1

nodelay

true

false

Go back

70.0, 790.0

27.0, 27.0

p19

cso30:i:CE_CellDifferentiation

cso30:i:CC_Extracellular

MO000068539

and

mass

coefficient1:0.1
coefficient2:1.0
stoichiometry:c39 : 1

m43386*0.1

nodelay

true

false

Go back

313.0, 316.0

27.0, 27.0

cso30:i:ME_Binding

cso30:i:CC_Cytosol

e6 MO000016573

e11

and

mass

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

m6*m1572*0.1

nodelay

true

false

Go back

736.0, 811.0

27.0, 27.0

cso30:i:ME_GeneExpression

cso30:i:CC_Nucleoplasm

e11

G029064

and

mass

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

m11*0.1

nodelay

true

false

Go back

678.0, 877.0

25.0, 25.0

cso30:i:ME_GeneExpression

cso30:i:CC_Nucleoplasm

G010657

and

mass

coefficient1:0.1
coefficient2:1.0
stoichiometry:c30 : 1
stoichiometry:c9 : 1

m6*0.1

nodelay

true

false

PMID: 18073395 For example, a pivotal role for TLR molecules in aiding the evolution of a type 1?polarized acquire immune response has been identified via the induction of IL-12 and IL-23, and the expression of both MHC class II:peptide and costimulatory molecules (CD80 and CD86).

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678.0, 913.0

23.0, 23.0

cso30:i:ME_GeneExpression

cso30:i:CC_Nucleoplasm

e12

and

mass

coefficient1:0.1
coefficient2:1.0
stoichiometry:c31 : 1
stoichiometry:c10 : 1

m6*0.1

nodelay

true

false

Go back

682.0, 993.0

25.0, 25.0

cso30:i:ME_GeneExpression

cso30:i:CC_Nucleoplasm

G012224

and

mass

coefficient1:0.1
coefficient2:1.0
stoichiometry:c33 : 1
stoichiometry:c12 : 1

m6*0.1

nodelay

true

false

Go back

682.0, 949.0

25.0, 25.0

cso30:i:ME_GeneExpression

cso30:i:CC_Nucleoplasm

G010240

and

mass

coefficient1:0.1
coefficient2:1.0
stoichiometry:c32 : 1
stoichiometry:c11 : 1

m6*0.1

nodelay

true

false

Go back

685.0, 1028.0

26.0, 26.0

cso30:i:ME_GeneExpression

cso30:i:CC_Nucleoplasm

G010859

and

mass

coefficient1:0.1
coefficient2:1.0
stoichiometry:c34 : 1
stoichiometry:c13 : 1

m6*0.1

nodelay

true

false

Go back

920.0, 875.0

27.0, 27.0

cso30:i:ME_Translation

cso30:i:CC_Cytosol

G010657

MO000017265

and

mass

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

m93589*0.1

nodelay

true

false

PMID: 18073395 It is clear that the activation of TLRs on antigen-presenting cells can lead to the expression of IL-12 and subsequently activate the expression of IFN-gamma from Th1 cells.

Go back