1. Information
    majorVersion:3 minorVersion:0 projectID:local projectVersionID:undef fileName:/home/ikeda/eclipse/workspace/macrophage/csml/ok/csml/18336664.csml convertedTime:2009.07.01.11:17

  2. Original Literature
  3. Model OverView
  4. Model Abstracts
  5. Model Detail
  6. Download
Original Literature Model OverView
Publication
Title Mechanisms for the anti-inflammatory effects of adiponectin in macrophages.
Authors Huang H, Park PH, McMullen MR, Nagy LE.
Affiliation Department of Pathobiology, Cleveland Clinic, Cleveland, OH 44195, USA.
Abstract Adiponectin is an adipokine with potent anti-inflammatory properties. Thedevelopment of alcoholic liver disease is thought to involve increasedpro-inflammatory activity, mediated in part by the activation of hepaticmacrophages (Kupffer cells). Chronic ethanol feeding sensitizes hepaticmacrophages to activation by lipopolysaccharide (LPS), leading to increasedproduction of reactive oxygen species and tumor necrosis factor-alpha(TNF-alpha). Adiponectin can normalize Toll-like receptor-4 (TLR-4) mediatedsignaling in hepatic macrophages after ethanol feeding, likely contributing tothe hepatoprotective effect of adiponectin in the progression of alcoholic liverdisease. However, the mechanisms by which adiponectin suppress TLR-4 mediatedresponses are not well understood. Using the macrophage-like cell line,RAW264.7, we have investigated the molecular mechanisms by which adiponectinsuppresses LPS-stimulated TNF-alpha production. Globular adiponectin(gAcrp)-mediated desensitization of LPS-stimulated responses in RAW264.7macrophages was dependent on the production of the anti-inflammatory cytokineinterleukin (IL)-10. gAcrp initially increased TNF-alpha expression in RAW264.7macrophages; this TNF-alpha then contributed to increased expression of IL-10.This initial gAcrp-mediated increase in TNF-alpha production by macrophages wasmediated via activation of ERK1/2-->Egr-1 and nuclear factor(NF)-kappaB-dependent mechanisms. gAcrp-stimulated IL-10 expression was alsodependent on the phosphorylation of cAMP response element-binding protein andthe cAMP response element in the IL-10 promoter. In summary, these studiesreveal a complex, integrated response of macrophages to gAcrp. gAcrp initiallyactivated signaling pathways considered to be pro-inflammatory, with asubsequent increase in the expression of the potent, anti-inflammatory cytokine,IL-10. Increased IL-10 expression was ultimately required for the suppression ofTLR4-mediated signaling by gAcrp.
PMID 18336664
Model Abstract

Entity

G010329:TNF-alpha G010389:IL-1beta G011345:IL10 MO000000001:PKAc MO000000011:ERK MO000000022:p38 MO000000058:NF-kappaB MO000000289:TNF-alpha MO000008272:ROS MO000016597:IL-1beta MO000016882:LPS MO000017189:CREB MO000017190:Egr-1 MO000017247:IL-10 MO000019387:cytokines MO000022523:adiponectin MO000033598:fatty acids MO000038306:ERK{p} e1: e10: e11:fatty acids{oxidated} e12:NF-kappaB{activated} e13:p38{p} e14:ethanol e15:PKAc{activated} e16:CREB{p} e17:CREB{p} e18:IL-10: CREB{p} e19:IL-10 e2: e20:Egr-1{activated} e3: e4: e5:ROS e50: e51: e52: e53: e54: e55: e56: e57: e58: e59: e6:cytokines e60: e61: e62: e7: e8: e9:

Process

p1 p10 p11 p12 p13 p14 p15 p16 p17 p18 p19 p2 p20 p21 p22 p23 p24 p3 p4 p5 p6 p7 p8 p9
Model Detail
593.0, 729.0
29.5, 29.5

TNF-alpha

--

G010329

cso30:c:mRNA

cso30:i:CC_CellComponent

--

true true true true

csml-variable:Double

m93309

10

false

infinite

0

unit false false false
TRANSFACG010329

--

Go back
757.0, 805.0
29.0, 29.0

IL-1beta

--

G010389

cso30:c:mRNA

cso30:i:CC_CellComponent

--

--

p12

true true true true

csml-variable:Double

m93364

10

false

infinite

0

unit false false false
TRANSFACG010389

--

Go back
712.0, 608.0
32.0, 32.0

IL10

--

G011345

cso30:c:mRNA

cso30:i:CC_CellComponent

--

true true true true

csml-variable:Double

m94230

10

false

infinite

0

unit false false false
TRANSFACG011345

--

Go back
600.0, 364.0
32.0, 32.0

PKAc

--

MO000000001

cso30:c:Protein

cso30:i:CC_CellComponent

--

--

p16

true true true true

csml-variable:Double

m17

10

false

infinite

0

unit false false false
TRANSPATHMO000000001

--

Go back
453.0, 275.0
30.0, 30.0

ERK

--

MO000000011

cso30:c:Protein

cso30:i:CC_CellComponent

--

--

p7 p15

true true true true

csml-variable:Double

m14

10

false

infinite

0

unit false false false
TRANSPATHMO000000011

--

Go back
457.0, 352.0
28.0, 28.0

p38

--

MO000000022

cso30:c:Protein

cso30:i:CC_CellComponent

--

--

p8

true true true true

csml-variable:Double

m20

10

false

infinite

0

unit false false false
TRANSPATHMO000000022

--

Go back
460.0, 189.0
33.0, 33.0

NF-kappaB

--

MO000000058

cso30:c:Protein

cso30:i:CC_CellComponent

--

--

p6 p21

true true true true

csml-variable:Double

m12

10

false

infinite

0

unit false false false
TRANSPATHMO000000058

--

Go back
368.0, 728.0
32.0, 32.0

TNF-alpha

--

MO000000289

cso30:c:Protein

cso30:i:CC_CellComponent

--

true true true true

csml-variable:Double

m230

10

false

infinite

0

unit false false false
InterProIPR003636
TRANSPATHMO000000289

--

Go back
361.0, 627.0
30.0, 30.0

ROS

--

MO000008272

cso30:c:Protein

cso30:i:CC_CellComponent

--

p1

--

true true true true

csml-variable:Double

m1063

10

false

infinite

0

unit false false false
TRANSPATHMO000008272

--

Go back
843.0, 932.0
32.0, 32.0

IL-1beta

--

MO000016597

cso30:c:Protein

cso30:i:CC_CellComponent

--

p12

--

true true true true

csml-variable:Double

m1591

10

false

infinite

0

unit false false false
TRANSPATHMO000016597

--

Go back
216.0, 373.0
29.5, 29.5

LPS

--

MO000016882

cso30:c:Protein

cso30:i:CC_CellComponent

--

--

p1 p2 p3 p6 p8 p7 p9

true true true true

csml-variable:Double

m155666

10

false

infinite

0

unit false false false
TRANSPATHMO000016882

--

Go back
725.0, 333.0
30.0, 30.0

CREB

--

MO000017189

cso30:c:Protein

cso30:i:CC_CellComponent

--

--

p17

true true true true

csml-variable:Double

m2057

10

false

infinite

0

unit false false false
InterProIPR003102
TRANSPATHMO000017189

--

Go back
657.0, 249.0
29.0, 29.0

Egr-1

--

MO000017190

cso30:c:Protein

cso30:i:CC_CellComponent

--

--

p22

true true true true

csml-variable:Double

m2058

10

false

infinite

0

unit false false false
InterProIPR007087
TRANSPATHMO000017190

--

Go back
628.0, 920.0
28.0, 28.0

IL-10

--

MO000017247

cso30:c:Protein

cso30:i:CC_CellComponent

--

true true true true

csml-variable:Double

m2103

10

false

infinite

0

unit false false false
InterProIPR000098
TRANSPATHMO000017247

--

Go back
366.0, 676.0
28.0, 28.0

cytokines

--

MO000019387

cso30:c:Protein

cso30:i:CC_CellComponent

--

p2

--

true true true true

csml-variable:Double

m3957

10

false

infinite

0

unit false false false
TRANSPATHMO000019387

--

Go back
240.0, 636.0
31.0, 31.0

adiponectin

--

MO000022523

cso30:c:Protein

cso30:i:CC_CellComponent

--

true true true true

csml-variable:Double

m6806

10

false

infinite

0

unit false false false
InterProIPR008161
TRANSPATHMO000022523

--

Go back
434.0, 820.0
31.0, 31.0

fatty acids

--

MO000033598

cso30:c:Protein

cso30:i:CC_CellComponent

--

--

p4

true true true true

csml-variable:Double

m12273

10

false

infinite

0

unit false false false
TRANSPATHMO000033598

--

Go back
454.0, 311.0
34.5, 34.5

ERK{p}

--

MO000038306

cso30:c:Protein

cso30:i:CC_CellComponent

--

true true true true

csml-variable:Double

m16522

10

false

infinite

0

unit false false false
TRANSPATHMO000038306

--

Go back
303.74693271595356, 35.42839392056544
648.9020465781829, 995.9339563602422

--

e1

cso30:c:EntityBiologicalCompartment

cso30:i:CC_PlasmaMembrane

--

--

--

true true true true

csml-variable:Double

m1

0

false

infinite

0

unit false true false

--

Go back
309.9990587531695, 57.00061699551716
628.9847941244175, 935.2597026490982

--

e10

cso30:c:EntityBiologicalCompartment

cso30:i:CC_Cytosol

--

--

--

true true true true

csml-variable:Double

m10

0

false

infinite

0

unit false true false

--

Go back
438.0, 868.0
31.0, 31.0

fatty acids{oxidated}

--

e11

cso30:c:Protein

cso30:i:CC_CellComponent

--

p4

--

true true true true

csml-variable:Double

m11

10

false

infinite

0

unit false false false
TRANSPATHMO000033598

--

Go back
463.0, 233.0
33.0, 33.0

NF-kappaB{activated}

--

e12

cso30:c:Protein

cso30:i:CC_CellComponent

--

true true true true

csml-variable:Double

m13

10

false

infinite

0

unit false false false
TRANSPATHMO000000058

--

Go back
452.5, 397.125
29.64, 22.229999999999997

p38{p}

--

e13

cso30:c:Protein

cso30:i:CC_Cytosol

--

p8

--

true true true true

csml-variable:Double

m15

0

false

infinite

0

unit false false false

--

Go back
138.5, 507.25
43.81412952060555, 24.828006728343144

ethanol

--

e14

cso30:c:SmallMolecule

cso30:i:CC_Extracellular

--

--

p1 p3 p5 p6 p8 p7

true true true true

csml-variable:Double

m16

0

false

infinite

0

unit false false false

--

Go back
600.0, 416.0
32.0, 32.0

PKAc{activated}

--

e15

cso30:c:Protein

cso30:i:CC_CellComponent

--

true true true true

csml-variable:Double

m18

10

false

infinite

0

unit false false false
TRANSPATHMO000000001

--

Go back
726.0, 378.5
36.959999999999994, 27.72

CREB{p}

--

e16

cso30:c:Protein

cso30:i:CC_Cytosol

--

true true true true

csml-variable:Double

m19

0

false

infinite

0

unit false false false

--

Go back
726.0, 550.5
36.959999999999994, 27.72

CREB{p}

--

e17

cso30:c:Protein

cso30:i:CC_Cytosol

--

true true true true

csml-variable:Double

m21

0

false

infinite

0

unit false false false

--

Go back
809.5, 661.625
45.0, 12.75

IL-10: CREB{p}

--

e18

cso30:c:Complex

cso30:i:CC_Nucleoplasm

--

true true true true

csml-variable:Double

m22

0

false

infinite

0

unit false false false

--

Go back
809.5, 611.125
45.0, 9.75

IL-10

--

e19

cso30:c:Dna

cso30:i:CC_Nucleoplasm

--

--

p19

true true true true

csml-variable:Double

m23

0

false

infinite

0

unit false false false

--

Go back
303.74693271595356, 35.42839392056544
648.9020465781829, 995.9339563602422

--

e2

cso30:c:EntityBiologicalCompartment

cso30:i:CC_PlasmaMembrane_ExternalSideOfPlasmaMembrane_

--

--

--

true true true true

csml-variable:Double

m2

0

false

infinite

0

unit false true false

--

Go back
657.0, 289.0
29.0, 29.0

Egr-1{activated}

--

e20

cso30:c:Protein

cso30:i:CC_CellComponent

--

true true true true

csml-variable:Double

m24

10

false

infinite

0

unit false false false
InterProIPR007087
TRANSPATHMO000017190

--

Go back
316.72497364751723, 49.14649249302067
622.9459647150557, 968.4977592153326

--

e3

cso30:c:EntityBiologicalCompartment

cso30:i:CC_PlasmaMembrane_IntegralToPlasmaMembrane_

--

--

--

true true true true

csml-variable:Double

m3

0

false

infinite

0

unit false true false

--

Go back
340.7343493709101, 73.15316499481699
574.9272132682701, 920.4844142117391

--

e4

cso30:c:EntityBiologicalCompartment

cso30:i:CC_PlasmaMembrane_InternalSideOfPlasmaMembrane_

--

--

--

true true true true

csml-variable:Double

m4

0

false

infinite

0

unit false true false

--

Go back
564.5, 633.0
39.965397923875436, 21.314878892733564

ROS

--

e5

cso30:c:mRNA

cso30:i:CC_Nucleoplasm

--

--

p1

true true true true

csml-variable:Double

m5

0

false

infinite

0

unit false false false

--

Go back
535.1515399972127, 526.9517447862137
352.8852039967922, 338.2773381285361

--

e50

cso30:c:EntityBiologicalCompartment

cso30:i:CC_NuclearEnvelopeLumen

--

--

--

true true true true

csml-variable:Double

m50

0

false

infinite

0

unit false true false

--

Go back
573.2657705964937, 534.9684259219632
206.34255876162536, 327.8581182683142

--

e51

cso30:c:EntityBiologicalCompartment

cso30:i:CC_NuclearPore

--

--

--

true true true true

csml-variable:Double

m51

0

false

infinite

0

unit false true false

--

Go back
539.7515333454016, 531.4667400589764
343.6852173004143, 329.24734758301037

--

e52

cso30:c:EntityBiologicalCompartment

cso30:i:CC_NuclearInnerMembrane

--

--

--

true true true true

csml-variable:Double

m52

0

false

infinite

0

unit false true false

--

Go back
540.4086752522858, 532.1613547163244
342.3709334866457, 327.8581182683142

--

e53

cso30:c:EntityBiologicalCompartment

cso30:i:CC_NuclearLumen

--

--

--

true true true true

csml-variable:Double

m53

0

false

infinite

0

unit false true false

--

Go back
535.1515399972127, 526.9517447862137
352.8852039967922, 338.2773381285361

--

e54

cso30:c:EntityBiologicalCompartment

cso30:i:CC_NuclearOuterMembrane

--

--

--

true true true true

csml-variable:Double

m54

0

false

infinite

0

unit false true false

--

Go back
535.1515399972127, 526.9517447862137
352.8852039967922, 338.2773381285361

--

e55

cso30:c:EntityBiologicalCompartment

cso30:i:CC_Nucleus

--

--

--

true true true true

csml-variable:Double

m55

0

false

infinite

0

unit false true false

--

Go back
540.4086752522858, 532.1613547163244
342.3709334866457, 327.8581182683142

--

e56

cso30:c:EntityBiologicalCompartment

cso30:i:CC_Nucleoplasm

--

--

--

true true true true

csml-variable:Double

m56

0

false

infinite

0

unit false true false

--

Go back
792.7511674958021, 665.8746762558383
22.046328616528612, 21.09579527584873

--

e57

cso30:c:EntityBiologicalCompartment

cso30:i:CC_NuclearBody

--

--

--

true true true true

csml-variable:Double

m57

0

false

infinite

0

unit false true false

--

Go back
734.9226796899964, 763.1207282845752
62.42848115399488, 59.73686053193864

--

e58

cso30:c:EntityBiologicalCompartment

cso30:i:CC_Nucleolus

--

--

--

true true true true

csml-variable:Double

m58

0

false

infinite

0

unit false true false

--

Go back
535.1515399972127, 526.9517447862137
352.8852039967922, 338.2773381285361

--

e59

cso30:c:EntityBiologicalCompartment

cso30:i:CC_NuclearEnvelope

--

--

--

true true true true

csml-variable:Double

m59

0

false

infinite

0

unit false true false

--

Go back
559.5, 681.0
41.937716262975776, 22.366782006920413

cytokines

--

e6

cso30:c:mRNA

cso30:i:CC_Nucleoplasm

--

--

p2

true true true true

csml-variable:Double

m6

0

false

infinite

0

unit false false false

--

Go back
618.3245970308819, 677.2793986418785
11.175355900237466, 5.687556588833106

--

e60

cso30:c:EntityBiologicalCompartment

cso30:i:CC_Chromatin

--

--

--

true true true true

csml-variable:Double

m60

0

false

infinite

0

unit false true false

--

Go back
617.9514202646163, 660.3177589970531
38.25061854221929, 72.77726777837971

--

e61

cso30:c:EntityBiologicalCompartment

cso30:i:CC_NuclearChromosome

--

--

--

true true true true

csml-variable:Double

m61

0

false

infinite

0

unit false true false

--

Go back
633.9980212140356, 707.6525673081946
5.97082826024886, 6.311307774818833

--

e62

cso30:c:EntityBiologicalCompartment

cso30:i:CC_NuclearCentromere

--

--

--

true true true true

csml-variable:Double

m62

0

false

infinite

0

unit false true false

--

Go back
317.27862231332267, 58.48561203380595
636.3707431232407, 953.1404878551269

--

e7

cso30:c:EntityBiologicalCompartment

cso30:i:CC_Cell

--

--

--

true true true true

csml-variable:Double

m7

0

false

infinite

0

unit false true false

--

Go back
315.54727214410514, 90.12389928273521
610.4780367257704, 936.9608396112152

--

e8

cso30:c:EntityBiologicalCompartment

cso30:i:CC_Cell_WithoutCellWall_

--

--

--

true true true true

csml-variable:Double

m8

0

false

infinite

0

unit false true false

--

Go back
319.60751454336344, 76.25504491686502
607.6908696199176, 924.6728329808572

--

e9

cso30:c:EntityBiologicalCompartment

cso30:i:CC_Cytoplasm

--

--

--

true true true true

csml-variable:Double

m9

0

false

infinite

0

unit false true false

--

Go back
447.0, 627.0
25.0, 25.0

p1

p1

cso30:i:ME_Translation

cso30:i:CC_Cytosol

--

true true true true

--

and

mass

coefficient1:0.1
coefficient2:1.0
stoichiometry:c1 : 1
stoichiometry:c4 : 1
stoichiometry:c45 : 1
stoichiometry:c3 : 1

m155666*m5*m16*0.1

nodelay

--

true

0

false

PMID: 18336664 Endotoxin/lipopolysaccharide (LPS), a component of the cell wall of Gram-negative bacteria, is an important activator of Kupffer cells, stimulating the production of inflammatory and fibrogeniccytokines, as well as reactive oxygen species (ROS). PMID: 18336664, 9756487 One working model for the progression of alcoholic liver disease proposes that increased exposure of Kupffer cells to LPS during chronic ethanol consumption contributes to increased production of inflammatory mediators, in particular tumor necrosis factor TNF-alpha and ROS, leading to the progression of fatty liver, inflammation and fibrosis.

Go back
687.0, 679.0
25.0, 25.0

p10

p10

cso30:i:ME_GeneExpression

cso30:i:CC_Nucleoplasm

--

true true true true

--

and

mass

coefficient1:0.1
coefficient2:1.0
stoichiometry:c29 : 1
stoichiometry:c31 : 1

m230*0.1

nodelay

--

true

0

false

PMID: 18336664 IL-10 expression is induced by various inflammatory mediators, such as LPS and TNF-alpha. PMID: 18336664, 17537727 Interestingly, we found that initially adiponectin increases the production of TNF-alpha by RAW 264.7 macrophages; this TNF-alpha, in the continued presence of adiponectin, then increases production of IL-10.

Go back
714.0, 900.0
27.0, 27.0

p11

p11

cso30:i:ME_Translation

cso30:i:CC_Cytosol

--

true true true true

--

and

mass

coefficient1:0.1
coefficient2:1.0
stoichiometry:c32 : 1
stoichiometry:c40 : 1
stoichiometry:c33 : 1

m94230*m6806*0.1

nodelay

--

true

0

false

PMID: 18336664, 1940369, 1940799, 8386517 IL-10 then acts to limit excessive production of pro-inflammatory cytokines, including TNF-alpha and IL-1b by decreasing cytokine gene transcription, as well as regulating the stability and/or translation of target mRNAs. PMID: 18336664, 17537727 Treatment of RAW 264.7 macrophages with adiponectin increases the expression of IL-10 mRNA and peptide. PMID: 18336664, 17537727 Interestingly, we found that initially adiponectin increases the production of TNF-alpha by RAW 264.7 macrophages; this TNF-alpha, in the continued presence of adiponectin, then increases production of IL-10.

Go back
757.0, 934.0
27.0, 27.0

p12

p12

cso30:i:ME_Translation

cso30:i:CC_Cytosol

--

true true true true

--

and

mass

coefficient1:0.1
coefficient2:1.0
stoichiometry:c36 : 1
stoichiometry:c37 : 1
stoichiometry:c35 : 1

m93364*0.1

nodelay

--

true

0

false

PMID: 18336664, 1940369, 1940799, 8386517 IL-10 then acts to limit excessive production of pro-inflammatory cytokines, including TNF-alpha and IL-1b by decreasing cytokine gene transcription, as well as regulating the stability and/or translation of target mRNAs.

Go back
651.0, 655.0
25.0, 25.0

p13

p13

cso30:i:ME_GeneExpression

cso30:i:CC_Nucleoplasm

--

true true true true

--

and

mass

coefficient1:0.1
coefficient2:1.0
stoichiometry:c39 : 1
stoichiometry:c38 : 1

m6806*0.1

nodelay

--

true

0

false

PMID: 18336664, 15369797, 17537727 While the mechanisms for the long-term anti-inflammatory effects of adiponectin are not well understood, recent data suggest that adiponectin acts, at least in part, to increase the expression of anti-inflammatory mediators, such as interleukin (IL)-10. PMID: 18336664, 17537727 Treatment of RAW 264.7 macrophages with adiponectin increases the expression of IL-10 mRNA and peptide.

Go back
478.0, 762.0
27.0, 27.0

p14

p14

cso30:i:ME_Translation

cso30:i:CC_Cytosol

--

true true true true

--

and

mass

coefficient1:0.1
coefficient2:1.0
stoichiometry:c43 : 1
stoichiometry:c44 : 1
stoichiometry:c42 : 1

m93309*m6806*0.1

nodelay

--

true

0

false

PMID: 18336664, 17537727 Interestingly, we found that initially adiponectin increases the production of TNF-alpha by RAW 264.7 macrophages; this TNF-alpha, in the continued presence of adiponectin, then increases production of IL-10. PMID: 18336664 This initial gAcrp-mediated increase in TNF-alpha production by macrophages was mediated via activation of ERK1/2¢ªEgr-1 and nuclear factor (NF)-kappaB-dependent mechanisms.

Go back
526.0, 274.0
27.0, 27.0

p15

p15

cso30:i:ME_Phosphorylation

cso30:i:CC_Cytosol

--

true true true true

--

and

mass

coefficient1:0.1
coefficient2:1.0
stoichiometry:c50 : 1
stoichiometry:c51 : 1
stoichiometry:c52 : 1

m6806*m14*0.1

nodelay

--

true

0

false

PMID: 18336664 We next identified two parallel signaling pathways required for adiponectin-stimulated IL-10 transcription: (i) an ERK1/2- and protein kinase A (PKA)-dependent increase in cAMP response element-binding protein (CREB) phosphorylation which acted via the CRE in the IL-10 promoter.

Go back
527.0, 419.0
25.0, 25.0

p16

p16

cso30:i:ME_UnknownActivation

cso30:i:CC_Cytosol

--

true true true true

--

and

mass

coefficient1:0.1
coefficient2:1.0
stoichiometry:c53 : 1
stoichiometry:c54 : 1
stoichiometry:c55 : 1

m6806*m17*0.1

nodelay

--

true

0

false

PMID: 18336664 We next identified two parallel signaling pathways required for adiponectin-stimulated IL-10 transcription: (i) an ERK1/2- and protein kinase A (PKA)-dependent increase in cAMP response element-binding protein (CREB) phosphorylation which acted via the CRE in the IL-10 promoter.

Go back
670.0, 378.0
27.0, 27.0

p17

p17

cso30:i:ME_Phosphorylation

cso30:i:CC_Cytosol

--

true true true true

--

and

mass

coefficient1:0.1
coefficient2:1.0
stoichiometry:c56 : 1
stoichiometry:c58 : 1
stoichiometry:c59 : 1
stoichiometry:c57 : 1

m2057*m16522*m18*0.1

nodelay

--

true

0

false

PMID: 18336664 We next identified two parallel signaling pathways required for adiponectin-stimulated IL-10 transcription: (i) an ERK1/2- and protein kinase A (PKA)-dependent increase in cAMP response element-binding protein (CREB) phosphorylation which acted via the CRE in the IL-10 promoter.

Go back
732.0, 468.0
23.0, 23.0

p18

p18

cso30:i:ME_Translocation

cso30:i:CC_Cytosol

--

true true true true

--

and

mass

coefficient1:0.1
coefficient2:1.0
stoichiometry:c60 : 1
stoichiometry:c61 : 1

m19*0.1

nodelay

--

true

0

false

PMID: 18336664 We next identified two parallel signaling pathways required for adiponectin-stimulated IL-10 transcription: (i) an ERK1/2- and protein kinase A (PKA)-dependent increase in cAMP response element-binding protein (CREB) phosphorylation which acted via the CRE in the IL-10 promoter.

Go back
751.0, 603.0
25.0, 25.0

p19

p19

cso30:i:ME_Binding

cso30:i:CC_Nucleoplasm

--

true true true true

--

and

mass

coefficient1:0.1
coefficient2:1.0
stoichiometry:c63 : 1
stoichiometry:c65 : 1
stoichiometry:c64 : 1

m21*m23*0.1

nodelay

--

true

0

false

PMID: 18336664 We next identified two parallel signaling pathways required for adiponectin-stimulated IL-10 transcription: (i) an ERK1/2- and protein kinase A (PKA)-dependent increase in cAMP response element-binding protein (CREB) phosphorylation which acted via the CRE in the IL-10 promoter.

Go back
447.0, 675.0
25.0, 25.0

p2

p2

cso30:i:ME_Translation

cso30:i:CC_Cytosol

--

true true true true

--

and

mass

coefficient1:0.1
coefficient2:1.0
stoichiometry:c2 : 1
stoichiometry:c5 : 1
stoichiometry:c15 : 1
stoichiometry:c6 : 1

m155666*m6*0.1

nodelay

--

true

0

false

PMID: 18336664 Endotoxin/lipopolysaccharide (LPS), a component of the cell wall of Gram-negative bacteria, is an important activator of Kupffer cells, stimulating the production of inflammatory and fibrogeniccytokines, as well as reactive oxygen species (ROS). PMID: 18336664, 16410364, 10961870, 15033490 Adiponectin suppresses phagocytic activity, as well as lipopolysaccharide (LPS)- stimulated cytokine production in macrophages.

Go back
739.0, 683.0
25.0, 25.0

p20

p20

cso30:i:ME_GeneExpression

cso30:i:CC_Nucleoplasm

--

true true true true

--

and

mass

coefficient1:0.1
coefficient2:1.0
stoichiometry:c66 : 1
stoichiometry:c62 : 1

m22*0.1

nodelay

--

true

0

false

PMID: 18336664 We next identified two parallel signaling pathways required for adiponectin-stimulated IL-10 transcription: (i) an ERK1/2- and protein kinase A (PKA)-dependent increase in cAMP response element-binding protein (CREB) phosphorylation which acted via the CRE in the IL-10 promoter. PMID: 18336664 gAcrp-stimulated IL-10 expression was also dependent on the phosphorylation of cAMP response element-binding protein and the cAMP response element in the IL-10 promoter.

Go back
531.0, 191.0
26.0, 26.0

p21

p21

cso30:i:ME_UnknownActivation

cso30:i:CC_Cytosol

--

true true true true

--

and

mass

coefficient1:0.1
coefficient2:1.0
stoichiometry:c67 : 1
stoichiometry:c69 : 1
stoichiometry:c68 : 1

m12*m6806*0.1

nodelay

--

true

0

false

PMID: 18336664 We next identified two parallel signaling pathways required for adiponectin-stimulated IL-10 transcription: (i) an ERK1/2- and protein kinase A (PKA)-dependent increase in cAMP response element-binding protein (CREB) phosphorylation which acted via the CRE in the IL-10 promoter (Park, et al., unpubl. obs, 2007); and (ii) an NF-kappaB and Egr-1 pathway, leading to increased production of TNF-alpha.

Go back
594.0, 290.0
27.0, 27.0

p22

p22

cso30:i:ME_UnknownActivation

cso30:i:CC_Cytosol

--

true true true true

--

and

mass

coefficient1:0.1
coefficient2:1.0
stoichiometry:c70 : 1
stoichiometry:c72 : 1
stoichiometry:c71 : 1

m2058*m16522*0.1

nodelay

--

true

0

false

PMID: 18336664 We next identified two parallel signaling pathways required for adiponectin-stimulated IL-10 transcription: (i) an ERK1/2- and protein kinase A (PKA)-dependent increase in cAMP response element-binding protein (CREB) phosphorylation which acted via the CRE in the IL-10 promoter (Park, et al., unpubl. obs, 2007); and (ii) an NF-kappaB and Egr-1 pathway, leading to increased production of TNF-alpha.

Go back
658.0, 734.0
27.0, 27.0

p23

p23

cso30:i:ME_GeneExpression

cso30:i:CC_Nucleoplasm

--

true true true true

--

and

mass

coefficient1:0.1
coefficient2:1.0
stoichiometry:c76 : 1
stoichiometry:c73 : 1

m24*0.1

nodelay

--

true

0

false

PMID: 18336664 We next identified two parallel signaling pathways required for adiponectin-stimulated IL-10 transcription: (i) an ERK1/2- and protein kinase A (PKA)-dependent increase in cAMP response element-binding protein (CREB) phosphorylation which acted via the CRE in the IL-10 promoter (Park, et al., unpubl. obs, 2007); and (ii) an NF-kappaB and Egr-1 pathway, leading to increased production of TNF-alpha. PMID: 18336664 This initial gAcrp-mediated increase in TNF-alpha production by macrophages was mediated via activation of ERK1/2¢ªEgr-1 and nuclear factor (NF)-kappaB-dependent mechanisms.

Go back
659.0, 771.0
25.0, 25.0

p24

p24

cso30:i:ME_GeneExpression

cso30:i:CC_Nucleoplasm

--

true true true true

--

and

mass

coefficient1:0.1
coefficient2:1.0
stoichiometry:c75 : 1
stoichiometry:c74 : 1

m13*0.1

nodelay

--

true

0

false

PMID: 18336664 We next identified two parallel signaling pathways required for adiponectin-stimulated IL-10 transcription: (i) an ERK1/2- and protein kinase A (PKA)-dependent increase in cAMP response element-binding protein (CREB) phosphorylation which acted via the CRE in the IL-10 promoter (Park, et al., unpubl. obs, 2007); and (ii) an NF-kappaB and Egr-1 pathway, leading to increased production of TNF-alpha. PMID: 18336664 This initial gAcrp-mediated increase in TNF-alpha production by macrophages was mediated via activation of ERK1/2¢ªEgr-1 and nuclear factor (NF)-kappaB-dependent mechanisms.

Go back
443.0, 731.0
25.0, 25.0

p3

p3

cso30:i:ME_Translation

cso30:i:CC_Cytosol

--

true true true true

--

and

mass

coefficient1:0.1
coefficient2:1.0
stoichiometry:c7 : 1
stoichiometry:c9 : 1
stoichiometry:c34 : 1
stoichiometry:c46 : 1
stoichiometry:c8 : 1

m155666*m93309*m16*0.1

nodelay

--

true

0

false

PMID: 18336664, 9756487 One working model for the progression of alcoholic liver disease proposes that increased exposure of Kupffer cells to LPS during chronic ethanol consumption contributes to increased production of inflammatory mediators, in particular tumor necrosis factor TNF-alpha and ROS, leading to the progression of fatty liver, inflammation and fibrosis. PMID: 18336664, 1940369, 1940799, 8386517 IL-10 then acts to limit excessive production of pro-inflammatory cytokines, including TNF-alpha and IL-1b by decreasing cytokine gene transcription, as well as regulating the stability and/or translation of target mRNAs. PMID: 18336664 Increased IL-10 expression was ultimately required for the suppression of TLR4-mediated signaling by gAcrp.

Go back
371.0, 821.0
30.0, 30.0

p4

p4

cso30:i:ME_Oxidation

cso30:i:CC_Cytosol

--

true true true true

--

and

mass

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

m12273*m6806*0.1

nodelay

--

true

0

false

PMID: 18336664, 12840063 Importantly, treatment of mice with adiponectin during chronic ethanol exposure prevents the development of ethanol-induced liver injury,26 in part by increasing fatty acid oxidation in the liver, thus preventing ethanol-induced steatosis, as well as decreasing TNF-alpha expression.

Go back
596.0, 784.0
24.0, 24.0

p5

p5

cso30:i:ME_GeneExpression

cso30:i:CC_Nucleoplasm

--

true true true true

--

and

mass

coefficient1:0.1
coefficient2:1.0
stoichiometry:c14 : 1
stoichiometry:c41 : 1
stoichiometry:c13 : 1

m16*0.1

nodelay

--

true

0

false

PMID: 18336664, 12840063 Importantly, treatment of mice with adiponectin during chronic ethanol exposure prevents the development of ethanol-induced liver injury,26 in part by increasing fatty acid oxidation in the liver, thus preventing ethanol-induced steatosis, as well as decreasing TNF-alpha expression. PMID: 18336664, 16410364 Importantly, overnight treatment of Kupffer cells with adiponectin can normalize the chronic ethanol-induced sensitization of LPS-stimulated TNF-alpha expression, normalizing the increased production of ROS, as well as ERK1/2 and p38 phosphorylation.

Go back
386.0, 192.0
27.0, 27.0

p6

p6

cso30:i:ME_UnknownActivation

cso30:i:CC_Cytosol

--

true true true true

--

and

mass

coefficient1:0.1
coefficient2:1.0
stoichiometry:c16 : 1
stoichiometry:c18 : 1
stoichiometry:c23 : 1
stoichiometry:c49 : 1
stoichiometry:c17 : 1

m12*m155666*m16*0.1

nodelay

--

true

0

false

PMID: 18336664, 16410364, 15033490, 16325814 In particular, LPS-stimulated NK-kappaB and ERK1/2 activation are sensitive to the inhibitory effects of adiponectin.

Go back
382.0, 276.0
28.0, 28.0

p7

p7

cso30:i:ME_Phosphorylation

cso30:i:CC_Cytosol

--

true true true true

--

and

mass

coefficient1:0.1
coefficient2:1.0
stoichiometry:c19 : 1
stoichiometry:c22 : 1
stoichiometry:c47 : 1
stoichiometry:c21 : 1
stoichiometry:c20 : 1

m14*m16*m155666*0.1

nodelay

--

true

0

false

PMID: 18336664, 16410364, 15033490, 16325814 In particular, LPS-stimulated NK-kappaB and ERK1/2 activation are sensitive to the inhibitory effects of adiponectin. PMID: 18336664, 16410364 Importantly, overnight treatment of Kupffer cells with adiponectin can normalize the chronic ethanol-induced sensitization of LPS-stimulated TNF-alpha expression, normalizing the increased production of ROS, as well as ERK1/2 and p38 phosphorylation.

Go back
382.0, 353.0
25.0, 25.0

p8

p8

cso30:i:ME_Phosphorylation

cso30:i:CC_Cytosol

--

true true true true

--

and

mass

coefficient1:0.1
coefficient2:1.0
stoichiometry:c25 : 1
stoichiometry:c26 : 1
stoichiometry:c27 : 1
stoichiometry:c48 : 1
stoichiometry:c24 : 1

m155666*m20*m16*0.1

nodelay

--

true

0

false

PMID: 18336664, 16410364 Importantly, overnight treatment of Kupffer cells with adiponectin can normalize the chronic ethanol-induced sensitization of LPS-stimulated TNF-alpha expression, normalizing the increased production of ROS, as well as ERK1/2 and p38 phosphorylation.

Go back
648.0, 612.0
24.0, 24.0

p9

p9

cso30:i:ME_GeneExpression

cso30:i:CC_Nucleoplasm

--

true true true true

--

and

mass

coefficient1:0.1
coefficient2:1.0
stoichiometry:c28 : 1
stoichiometry:c30 : 1

m155666*0.1

nodelay

--

true

0

false

PMID: 18336664 IL-10 expression is induced by various inflammatory mediators, such as LPS and TNF-alpha.

Go back
232.0, 403.0

c1

c1

cso30:c:InputAssociation

--

true true true true

cso30:c:InputAssociation

threshold

--

0

1,

--

Go back
409.0, 836.0

c10

c10

cso30:c:InputProcess

--

true true true true

cso30:c:InputProcess

threshold

--

0

1,

--

Go back
401.0, 847.0

c11

c11

cso30:c:OutputProcess

--

true true true true

cso30:c:OutputProcess

threshold

--

0

1,

--

Go back
257.0, 667.0

c12

c12

cso30:c:InputAssociation

--

true true true true

cso30:c:InputAssociation

threshold

--

0

1,

--

Go back
608.0, 767.0

c13

c13

cso30:c:OutputProcess

--

true true true true

cso30:c:OutputProcess

threshold

--

0

1,

--

Go back
244.2654083894207, 667.0

c14

c14

cso30:c:InputInhibitor

--

true true true true

cso30:c:InputInhibitor

threshold

--

0

1,

--

Go back
271.0, 655.0

c15

c15

cso30:c:InputInhibitor

--

true true true true

cso30:c:InputInhibitor

threshold

--

0

1,

--

Go back
421.0, 206.0

c16

c16

cso30:c:InputProcess

--

true true true true

cso30:c:InputProcess

threshold

--

0

1,

--

Go back
413.0, 213.0

c17

c17

cso30:c:OutputProcess

--

true true true true

cso30:c:OutputProcess

threshold

--

0

1,

--

Go back
231.0, 207.6684375761455

c18

c18

cso30:c:InputAssociation

--

true true true true

cso30:c:InputAssociation

threshold

--

0

1,

--

Go back
418.0, 290.0

c19

c19

cso30:c:InputProcess

--

true true true true

cso30:c:InputProcess

threshold

--

0

1,

--

Go back
231.0, 403.0

c2

c2

cso30:c:InputAssociation

--

true true true true

cso30:c:InputAssociation

threshold

--

0

1,

--

Go back
410.0, 297.0

c20

c20

cso30:c:OutputProcess

--

true true true true

cso30:c:OutputProcess

threshold

--

0

1,

--

Go back
234.0, 291.5075761275869

c21

c21

cso30:c:InputAssociation

--

true true true true

cso30:c:InputAssociation

threshold

--

0

1,

--

Go back
262.0, 307.72844003899013

c22

c22

cso30:c:InputInhibitor

--

true true true true

cso30:c:InputInhibitor

threshold

--

0

1,

--

Go back
261.0, 222.8055421719791

c23

c23

cso30:c:InputInhibitor

--

true true true true

cso30:c:InputInhibitor

threshold

--

0

1,

--

Go back
407.0, 373.0

c24

c24

cso30:c:OutputProcess

--

true true true true

cso30:c:OutputProcess

threshold

--

0

1,

--

Go back
246.0, 369.04966975222464

c25

c25

cso30:c:InputAssociation

--

true true true true

cso30:c:InputAssociation

threshold

--

0

1,

--

Go back
415.0, 366.0

c26

c26

cso30:c:InputProcess

--

true true true true

cso30:c:InputProcess

threshold

--

0

1,

--

Go back
264.0, 381.59975421662773

c27

c27

cso30:c:InputInhibitor

--

true true true true

cso30:c:InputInhibitor

threshold

--

0

1,

--

Go back
233.0, 403.0

c28

c28

cso30:c:InputAssociation

--

true true true true

cso30:c:InputAssociation

threshold

--

0

1,

--

Go back
400.0, 695.292882744896

c29

c29

cso30:c:InputAssociation

--

true true true true

cso30:c:InputAssociation

threshold

--

0

1,

--

Go back
398.9949028347804, 640.0

c3

c3

cso30:c:OutputProcess

--

true true true true

cso30:c:OutputProcess

threshold

--

0

1,

--

Go back
672.0, 624.0

c30

c30

cso30:c:OutputProcess

--

true true true true

cso30:c:OutputProcess

threshold

--

0

1,

--

Go back
706.0, 647.4013489469979

c31

c31

cso30:c:OutputProcess

--

true true true true

cso30:c:OutputProcess

threshold

--

0

1,

--

Go back
728.0, 640.0

c32

c32

cso30:c:InputAssociation

--

true true true true

cso30:c:InputAssociation

threshold

--

0

1,

--

Go back
663.7766576685863, 917.0

c33

c33

cso30:c:OutputProcess

--

true true true true

cso30:c:OutputProcess

threshold

--

0

1,

--

Go back
458.57766458363994, 759.9580681687925

c34

c34

cso30:c:InputInhibitor

--

true true true true

cso30:c:InputInhibitor

threshold

--

0

1,

--

Go back
784.0, 948.0

c35

c35

cso30:c:OutputProcess

--

true true true true

cso30:c:OutputProcess

threshold

--

0

1,

--

Go back
771.0799960003, 834.0

c36

c36

cso30:c:InputAssociation

--

true true true true

cso30:c:InputAssociation

threshold

--

0

1,

--

Go back
656.0, 935.0

c37

c37

cso30:c:InputInhibitor

--

true true true true

cso30:c:InputInhibitor

threshold

--

0

1,

--

Go back
676.0, 639.5631664759627

c38

c38

cso30:c:OutputProcess

--

true true true true

cso30:c:OutputProcess

threshold

--

0

1,

--

Go back
271.0, 653.0

c39

c39

cso30:c:InputAssociation

--

true true true true

cso30:c:InputAssociation

threshold

--

0

1,

--

Go back
479.9958409147176, 640.2579303520877

c4

c4

cso30:c:InputAssociation

--

true true true true

cso30:c:InputAssociation

threshold

--

0

1,

--

Go back
255.98908380213646, 667.0

c40

c40

cso30:c:InputAssociation

--

true true true true

cso30:c:InputAssociation

threshold

--

0

1,

--

Go back
161.0, 532.0

c41

c41

cso30:c:InputAssociation

--

true true true true

cso30:c:InputAssociation

threshold

--

0

1,

--

Go back
407.67335566204815, 751.2626561567578

c42

c42

cso30:c:OutputProcess

--

true true true true

cso30:c:OutputProcess

threshold

--

0

1,

--

Go back
512.7181105699019, 748.0

c43

c43

cso30:c:InputAssociation

--

true true true true

cso30:c:InputAssociation

threshold

--

0

1,

--

Go back
259.0, 667.0

c44

c44

cso30:c:InputAssociation

--

true true true true

cso30:c:InputAssociation

threshold

--

0

1,

--

Go back
163.0, 532.0

c45

c45

cso30:c:InputAssociation

--

true true true true

cso30:c:InputAssociation

threshold

--

0

1,

--

Go back
160.0, 532.0

c46

c46

cso30:c:InputAssociation

--

true true true true

cso30:c:InputAssociation

threshold

--

0

1,

--

Go back
161.0, 288.28694092123123

c47

c47

cso30:c:InputAssociation

--

true true true true

cso30:c:InputAssociation

threshold

--

0

1,

--

Go back
163.0, 366.07130154784625

c48

c48

cso30:c:InputAssociation

--

true true true true

cso30:c:InputAssociation

threshold

--

0

1,

--

Go back
159.59300357433733, 204.19474071042504

c49

c49

cso30:c:InputAssociation

--

true true true true

cso30:c:InputAssociation

threshold

--

0

1,

--

Go back
479.9953552878064, 688.2725689302662

c5

c5

cso30:c:InputAssociation

--

true true true true

cso30:c:InputAssociation

threshold

--

0

1,

--

Go back
271.0, 308.9999913388959

c50

c50

cso30:c:InputAssociation

--

true true true true

cso30:c:InputAssociation

threshold

--

0

1,

--

Go back
483.0, 288.37169119481973

c51

c51

cso30:c:InputProcess

--

true true true true

cso30:c:InputProcess

threshold

--

0

1,

--

Go back
495.87628710416527, 296.0

c52

c52

cso30:c:OutputProcess

--

true true true true

cso30:c:OutputProcess

threshold

--

0

1,

--

Go back
271.0, 446.8943936081289

c53

c53

cso30:c:InputAssociation

--

true true true true

cso30:c:InputAssociation

threshold

--

0

1,

--

Go back
558.5923353935949, 391.0

c54

c54

cso30:c:InputProcess

--

true true true true

cso30:c:InputProcess

threshold

--

0

1,

--

Go back
552.0, 432.0

c55

c55

cso30:c:OutputProcess

--

true true true true

cso30:c:OutputProcess

threshold

--

0

1,

--

Go back
703.2905467105794, 360.0

c56

c56

cso30:c:InputProcess

--

true true true true

cso30:c:InputProcess

threshold

--

0

1,

--

Go back
697.0, 392.0

c57

c57

cso30:c:OutputProcess

--

true true true true

cso30:c:OutputProcess

threshold

--

0

1,

--

Go back
489.0, 330.0

c58

c58

cso30:c:InputProcess

--

true true true true

cso30:c:InputProcess

threshold

--

0

1,

--

Go back
632.0, 404.00829016433363

c59

c59

cso30:c:InputProcess

--

true true true true

cso30:c:InputProcess

threshold

--

0

1,

--

Go back
401.9943100988534, 688.0

c6

c6

cso30:c:OutputProcess

--

true true true true

cso30:c:OutputProcess

threshold

--

0

1,

--

Go back
744.0, 406.0

c60

c60

cso30:c:InputProcess

--

true true true true

cso30:c:InputProcess

threshold

--

0

1,

--

Go back
744.0, 491.0

c61

c61

cso30:c:OutputProcess

--

true true true true

cso30:c:OutputProcess

threshold

--

0

1,

--

Go back
735.6349772505464, 647.5536014515662

c62

c62

cso30:c:OutputProcess

--

true true true true

cso30:c:OutputProcess

threshold

--

0

1,

--

Go back
749.0, 578.0

c63

c63

cso30:c:InputProcess

--

true true true true

cso30:c:InputProcess

threshold

--

0

1,

--

Go back
776.0, 625.0

c64

c64

cso30:c:OutputProcess

--

true true true true

cso30:c:OutputProcess

threshold

--

0

1,

--

Go back
784.0, 616.0

c65

c65

cso30:c:InputProcess

--

true true true true

cso30:c:InputProcess

threshold

--

0

1,

--

Go back
771.5270992949498, 674.0

c66

c66

cso30:c:InputAssociation

--

true true true true

cso30:c:InputAssociation

threshold

--

0

1,

--

Go back
493.0, 205.21045345670586

c67

c67

cso30:c:InputProcess

--

true true true true

cso30:c:InputProcess

threshold

--

0

1,

--

Go back
502.50986776965385, 214.0

c68

c68

cso30:c:OutputProcess

--

true true true true

cso30:c:OutputProcess

threshold

--

0

1,

--

Go back
255.8186269055348, 207.31489304793092

c69

c69

cso30:c:InputAssociation

--

true true true true

cso30:c:InputAssociation

threshold

--

0

1,

--

Go back
211.88745607783972, 403.0

c7

c7

cso30:c:InputAssociation

--

true true true true

cso30:c:InputAssociation

threshold

--

0

1,

--

Go back
627.7415700784971, 273.0

c70

c70

cso30:c:InputProcess

--

true true true true

cso30:c:InputProcess

threshold

--

0

1,

--

Go back
621.0, 304.0

c71

c71

cso30:c:OutputProcess

--

true true true true

cso30:c:OutputProcess

threshold

--

0

1,

--

Go back
489.0, 307.4244853863217

c72

c72

cso30:c:InputAssociation

--

true true true true

cso30:c:InputAssociation

threshold

--

0

1,

--

Go back
630.9869706753918, 745.4563983243081

c73

c73

cso30:c:OutputProcess

--

true true true true

cso30:c:OutputProcess

threshold

--

0

1,

--

Go back
629.7415700784971, 757.3071142168176

c74

c74

cso30:c:OutputProcess

--

true true true true

cso30:c:OutputProcess

threshold

--

0

1,

--

Go back
496.0, 250.0

c75

c75

cso30:c:InputAssociation

--

true true true true

cso30:c:InputAssociation

threshold

--

0

1,

--

Go back
686.0, 304.0

c76

c76

cso30:c:InputAssociation

--

true true true true

cso30:c:InputAssociation

threshold

--

0

1,

--

Go back
408.0, 744.0

c8

c8

cso30:c:OutputProcess

--

true true true true

cso30:c:OutputProcess

threshold

--

0

1,

--

Go back
476.0, 744.0

c9

c9

cso30:c:InputAssociation

--

true true true true

cso30:c:InputAssociation

threshold

--

0

1,

--

Go back