Molecules

CD14(TLR4,MD2,LPS)

CD14 TLR4 MD2 LPS

MD2(CD14,TLR4,LPS)

MD2 CD14 TLR4 LPS

TLR4(MAL,TRAM,TLR4,CD14,MD2,LPS)

TLR4 MAL TRAM TLR4 CD14 MD2 LPS

TRAM(TLR4,TRIF)

TRAM TLR4 TRIF

TRIF(TRAM,TRAF6,RIP1,TRAF4,SARM)

TRIF TRAM TRAF6 RIP1 TRAF4 SARM

SARM(TRIF)

SARM TRIF

TRAF4(TRAF6,TAK1,TRIF)

TRAF4 TRAF6 TAK1 TRIF

IRAK1(IRAK4,MyD88,Tollip,TRAF6)

IRAK1 IRAK4 MyD88 Tollip TRAF6

Tollip(IRAK1)

Tollip IRAK1

IRAK4(Myd88,IRAKM,IRAK1)

IRAK4 Myd88 IRAKM IRAK1

IRAKM(IRAK4)

IRAKM IRAK4

RP1(TRIF,TRAF6,TAK1,p38)

RP1 TRIF TRAF6 TAK1 p38

TRAF6(IRAK1,TRIF,RP1,TAK1,TRAF4,A20,JNK,p38)

TRAF6 IRAK1 TRIF RP1 TAK1 TRAF4 A20 JNK p38

A20(TRAF6)

A20 TRAF6

MyD88(MAL,IRAK1,IRAK4,MyD88s)

MyD88 MAL IRAK1 IRAK4 MyD88s

MyD88s(MyD88,IRAK1)

MyD88s MyD88 IRAK1

MAL(TLR4,MyD88,SOCS1)

MAL TLR4 MyD88 SOCS1

LPS(MD2,TLR4,CD14,LPS)

LPS MD2 TLR4 CD14 LPS

TAK1(TRAF6,Activation~No~Yes)

TAK1 TRAF6 Activation No Yes

Ikk_Complex(Activation~No~Yes)

Ikk_Complex Activation No Yes

IkB(Phos~No~Yes,p65,p50,Degrade~No~Yes)

IkB Phos No Yes p65 p50 Degrade No Yes

Proteasome26s(IkB)

Proteasome26s IkB

TNF(TNFr)

TNF TNFr

TNFmRNA(Translation~On~Off)

TNFmRNA Translation On Off

A20mRNA(Translation~On~Off)

A20mRNA Translation On Off

iNOSmRNA(Translation~On~Off)

iNOSmRNA Translation On Off

IkBmRNA(Translation~On~Off)

IkBmRNA Translation On Off

DNA(A20,TNF,iNOS,IL10,IkB,c,c)

DNA A20 TNF iNOS IL10 IkB c c

Trash(c)

Trash c

Administer(c)

Administer c

NFkB(Transcription~No~Yes,Activation~No~Yes,Location~Cytoplasm~Nucleus)

NFkB Transcription No Yes Activation No Yes Location Cytoplasm Nucleus

Species

CD14(TLR4,MD2,LPS)

CD14 TLR4 MD2 LPS

MD2(CD14,TLR4,LPS)

MD2 CD14 TLR4 LPS

TLR4(MAL,TRAM,TLR4,CD14,MD2,LPS)

TLR4 MAL TRAM TLR4 CD14 MD2 LPS

TRAM(TLR4,TRIF)

TRAM TLR4 TRIF

MAL(TLR4,MyD88,SOCS1)

MAL TLR4 MyD88 SOCS1

TRIF(TRAM,TRAF6,RIP1,SARM,TRAF4)

TRIF TRAM TRAF6 RIP1 SARM TRAF4

MyD88(MAL,IRAK1,IRAK4,MyD88s)

MyD88 MAL IRAK1 IRAK4 MyD88s

RP1(TRIF,TRAF6,TAK1,p38)

RP1 TRIF TRAF6 TAK1 p38

IRAK1(IRAK4,MyD88,Tollip,TRAF6)

IRAK1 IRAK4 MyD88 Tollip TRAF6

IRAK4(Myd88,IRAKM,IRAK1)

IRAK4 Myd88 IRAKM IRAK1

TRAF6(IRAK1,TRIF,RP1,TAK1,TRAF4,A20,JNK,p38)

TRAF6 IRAK1 TRIF RP1 TAK1 TRAF4 A20 JNK p38

TAK1(TRAF6,Activation~No)

TAK1 TRAF6 Activation No

Ikk_Complex(Activation~No)

Ikk_Complex Activation No

Proteasome26s(IkB)

Proteasome26s IkB

IkB(Phos~No,p65,p50,Degrade~No)

IkB Phos No p65 p50 Degrade No

DNA(A20,TNF,iNOS,IL10,IkB,c,c)

DNA A20 TNF iNOS IL10 IkB c c

LPS(MD2,TLR4,CD14,LPS)

LPS MD2 TLR4 CD14 LPS

A20(TRAF6)

A20 TRAF6

NFkB(Transcription~No,Activation~No,Location~Cytoplasm)

NFkB Transcription No Activation No Location Cytoplasm

Observables

TNF(TNFr)

TNF TNFr

TAK1(TRAF6,Activation~Yes)

TAK1 TRAF6 Activation Yes

Ikk_Complex(Activation~Yes)

Ikk_Complex Activation Yes

A20(TRAF6)

A20 TRAF6

NFkB(Transcription~No,Activation~Yes,Location~Cytoplasm)

NFkB Transcription No Activation Yes Location Cytoplasm

NFkB(Transcription~No,Activation~Yes,Location~Nucleus)

NFkB Transcription No Activation Yes Location Nucleus

IkB(Degrade~Yes)

IkB Phos No Yes p65 p50 Degrade Yes

IkB(Degrade~No)

IkB Phos No Yes p65 p50 Degrade No
Molecules NFkB_Inactive NFkB(Activation~*!+)

NFkB(Activation!+)

NFkB Transcription No Yes Activation Location Cytoplasm Nucleus

IkB(Phos~No,p65,p50,Degrade~No)

IkB Phos No p65 p50 Degrade No

IkBmRNA(Translation~Off)

IkBmRNA Translation Off

DNA(IkB!0).NFkB(Transcription~Yes!0,Activation~Yes,Location~Nucleus)

DNA A20 TNF iNOS IL10 0IkB c c NFkB Transcription 0Yes Activation Yes Location Nucleus

NFkB(Transcription~No,Activation~No!0!1,Location~Cytoplasm).IkB(Phos~Yes,p65!0,p50!1,Degrade~No)

NFkB Transcription No Activation 0No Location Cytoplasm IkB Phos Yes 0p65 1p50 Degrade No

IkB(Phos~Yes,p65,p50,Degrade~Yes!0).Proteasome26s(IkB!0)

IkB Phos Yes p65 p50 Degrade 0Yes Proteasome26s 0IkB
Molecules Unbound_Cyto_NFkB NFkB(Location~Cytoplasm,Activation)

NFkB(Location~Cytoplasm,Activation)

NFkB Transcription No Yes Activation Location Cytoplasm
Molecules Inactive_Cyto_NFkB NFkB(Activation~*!0!1,Location~Cytoplasm).IkB(Phos~No,p65!0,p50!1,Degrade~No)

NFkB(Activation!0!1,Location~Cytoplasm).IkB(Phos~No,p65!0,p50!1,Degrade~No)

NFkB Transcription No Yes 0Activation Location Cytoplasm IkB Phos No 0p65 1p50 Degrade No

TNFmRNA(Translation~Off)

TNFmRNA Translation Off

DNA(TNF!0).NFkB(Transcription~Yes!0,Activation~Yes,Location~Nucleus)

DNA A20 0TNF iNOS IL10 IkB c c NFkB Transcription 0Yes Activation Yes Location Nucleus

DNA(A20!0).NFkB(Transcription~Yes!0,Activation~Yes,Location~Nucleus)

DNA 0A20 TNF iNOS IL10 IkB c c NFkB Transcription 0Yes Activation Yes Location Nucleus

Reaction Rules

LPS(MD2,TLR4,CD14,LPS) + MD2(CD14,TLR4,LPS) <-> LPS(MD2!0,TLR4,CD14,LPS).MD2(CD14,TLR4,LPS!0)

LPS 0 ⬆⬇MD2 TLR4 CD14 LPS MD2 CD14 TLR4 0 ⬆⬇LPS

LPS(MD2!0,TLR4,CD14,LPS).MD2(CD14,TLR4,LPS!0) + CD14(TLR4,MD2,LPS) <-> LPS(MD2!0,TLR4,CD14!1,LPS).MD2(CD14,TLR4,LPS!0).CD14(TLR4,MD2,LPS!1)

LPS 0MD2 TLR4 1 ⬆⬇CD14 LPS MD2 CD14 TLR4 0LPS CD14 TLR4 MD2 1 ⬆⬇LPS

LPS(MD2!0,TLR4,CD14!1,LPS).MD2(CD14,TLR4,LPS!0).CD14(TLR4,MD2,LPS!1) + TLR4(MAL,TRAM,TLR4,CD14,MD2,LPS) <-> LPS(MD2!0,TLR4!2,CD14!1,LPS).MD2(CD14!3,TLR4!4,LPS!0).CD14(TLR4!5,MD2!3,LPS!1).TLR4(MAL,TRAM,TLR4,CD14!5,MD2!4,LPS!2)

LPS 0MD2 2 ⬆⬇TLR4 1CD14 LPS MD2 3 ⬆⬇CD14 4 ⬆⬇TLR4 0LPS CD14 5 ⬆⬇TLR4 3 ⬆⬇MD2 1LPS TLR4 MAL TRAM TLR4 5 ⬆⬇CD14 4 ⬆⬇MD2 2 ⬆⬇LPS

TLR4(TLR4,CD14!+,LPS!+,MD2!+) + TLR4(TLR4,CD14!+,MD2!+,LPS!+) <-> TLR4(TLR4!0,CD14!+,LPS!+,MD2!+).TLR4(TLR4!0,CD14!+,LPS!+,MD2!+)

TLR4 MAL TRAM 0 ⬆⬇TLR4 CD14 MD2 LPS TLR4 MAL TRAM 0 ⬆⬇TLR4 CD14 MD2 LPS

TRAM(TLR4!0,TRIF).TLR4(TLR4!+,CD14!+,LPS!+,MD2!+,TRAM!0,MAL) + TRIF(TRAM,TRAF6!+,RIP1!+,TRAF4,SARM) <-> TRAM(TLR4!0,TRIF!1).TLR4(TLR4!+,CD14!+,LPS!+,MD2!+,TRAM!0,MAL).TRIF(TRAM!1,TRAF6!+,RIP1!+,TRAF4,SARM)

TRAM 0TLR4 1 ⬆⬇TRIF TLR4 MAL 0TRAM TLR4 CD14 MD2 LPS TRIF 1 ⬆⬇TRAM TRAF6 RIP1 TRAF4 SARM

TRAM(TLR4!0,TRIF!1).TLR4(TLR4!+,CD14!+,LPS!+,MD2!+,TRAM!0,MAL).TRIF(TRAM!1,TRAF6!+,RIP1!+,TRAF4,SARM) + TAK1(TRAF6,Activation~No) -> TRAM(TLR4!0,TRIF!1).TLR4(TLR4!+,CD14!+,LPS!+,MD2!+,TRAM!0,MAL).TRIF(TRAM!1,TRAF6!+,RIP1!+,TRAF4,SARM) + TAK1(TRAF6,Activation~Yes)

TRAM 0TLR4 1TRIF TLR4 MAL 0TRAM TLR4 CD14 MD2 LPS TRIF 1TRAM TRAF6 RIP1 TRAF4 SARM TAK1 TRAF6 Activation No Yes take all branches, once each, in any order⬇⬇

MyD88(MAL,IRAK1,IRAK4,MyD88s) + IRAK4(Myd88,IRAKM,IRAK1) <-> MyD88(MAL,IRAK1,IRAK4!0,MyD88s).IRAK4(Myd88!0,IRAKM,IRAK1)

MyD88 MAL IRAK1 0 ⬆⬇IRAK4 MyD88s IRAK4 0 ⬆⬇Myd88 IRAKM IRAK1

TLR4(TLR4!+,CD14!+,LPS!+,MD2!+,TRAM,MAL) + MAL(TLR4,MyD88,SOCS1) <-> TLR4(TLR4!+,CD14!+,LPS!+,MD2!+,TRAM,MAL!0).MAL(SOCS1,TLR4!0,MyD88)

TLR4 0 ⬆⬇MAL TRAM TLR4 CD14 MD2 LPS MAL 0 ⬆⬇TLR4 MyD88 SOCS1

TLR4(TLR4!+,CD14!+,LPS!+,MD2!+,TRAM,MAL!0).MAL(TLR4!0,MyD88,SOCS1) + IRAK1(IRAK4,MyD88!2,Tollip,TRAF6).MyD88(MAL,IRAK1!2,IRAK4!1,MyD88s).IRAK4(Myd88!1,IRAKM,IRAK1) <-> TLR4(TLR4!+,CD14!+,LPS!+,MD2!+,TRAM,MAL!0).MAL(TLR4!0,MyD88!4,SOCS1).IRAK1(IRAK4,MyD88!2,Tollip,TRAF6).MyD88(MAL!4,IRAK1!2,IRAK4!3,MyD88s).IRAK4(Myd88!3,IRAKM,IRAK1)

TLR4 0MAL TRAM TLR4 CD14 MD2 LPS MAL 0TLR4 4 ⬆⬇MyD88 SOCS1 IRAK1 IRAK4 2MyD88 Tollip TRAF6 MyD88 4 ⬆⬇MAL 2IRAK1 1 ⬆⬇IRAK4 MyD88s IRAK4 1 ⬆⬇Myd88 IRAKM IRAK1

TRAF6(IRAK1,TRIF,RP1,TRAF4,A20,JNK,p38,TAK1) + TLR4(TLR4!+,CD14!+,LPS!+,MD2!+,TRAM,MAL!0).MAL(TLR4!0,MyD88!1,SOCS1).IRAK1(IRAK4,MyD88!2,Tollip,TRAF6).MyD88(MAL!1,IRAK1!2,IRAK4!3,MyD88s).IRAK4(Myd88!3,IRAKM,IRAK1) <-> TRAF6(IRAK1!0,TRIF,RP1,TRAF4,A20,JNK,p38,TAK1).TLR4(TLR4!+,CD14!+,LPS!+,MD2!+,TRAM,MAL!1).MAL(TLR4!1,MyD88!2,SOCS1).IRAK1(IRAK4,MyD88!3,Tollip,TRAF6!0).MyD88(MAL!2,IRAK1!3,IRAK4!4,MyD88s).IRAK4(Myd88!4,IRAKM,IRAK1)

TRAF6 0 ⬆⬇IRAK1 TRIF RP1 TAK1 TRAF4 A20 JNK p38 TLR4 0 ⬆⬇MAL TRAM TLR4 CD14 MD2 LPS MAL 0 ⬆⬇TLR4 1 ⬆⬇MyD88 SOCS1 IRAK1 IRAK4 2 ⬆⬇MyD88 Tollip 0 ⬆⬇TRAF6 MyD88 1 ⬆⬇MAL 2 ⬆⬇IRAK1 3 ⬆⬇IRAK4 MyD88s IRAK4 3 ⬆⬇Myd88 IRAKM IRAK1

TRAF6(IRAK1!0,TRIF,RP1,TRAF4,A20,JNK,p38,TAK1).TLR4(TLR4!+,CD14!+,LPS!+,MD2!+,TRAM,MAL!1).MAL(TLR4!1,MyD88!2,SOCS1).IRAK1(IRAK4,MyD88!3,Tollip,TRAF6!0).MyD88(MAL!2,IRAK1!3,IRAK4!4,MyD88s).IRAK4(Myd88!4,IRAKM,IRAK1) + A20(TRAF6) -> TRAF6(IRAK1,TRIF,RP1,TAK1,TRAF4,A20,JNK,p38) + TLR4(TLR4!+,CD14!+,LPS!+,MD2!+,TRAM,MAL!0).MAL(TLR4!0,MyD88!1,SOCS1).IRAK1(IRAK4,MyD88!2,Tollip,TRAF6).MyD88(MAL!1,IRAK1!2,IRAK4!3,MyD88s).IRAK4(Myd88!3,IRAKM,IRAK1) + A20(TRAF6)

TRAF6 0 ⬆IRAK1 TRIF RP1 TAK1 TRAF4 A20 JNK p38 TLR4 1 ⬆MAL TRAM TLR4 CD14 MD2 LPS MAL 1 ⬆TLR4 2 ⬆MyD88 SOCS1 IRAK1 IRAK4 3 ⬆MyD88 Tollip 0 ⬆TRAF6 MyD88 2 ⬆MAL 3 ⬆IRAK1 4 ⬆IRAK4 MyD88s IRAK4 4 ⬆Myd88 IRAKM IRAK1 A20 TRAF6

TRAF6(IRAK1!0,TRIF,RP1,TRAF4,A20,JNK,p38,TAK1).TLR4(TLR4!+,CD14!+,LPS!+,MD2!+,TRAM,MAL!1).MAL(TLR4!1,MyD88!2,SOCS1).IRAK1(IRAK4,MyD88!3,Tollip,TRAF6!0).MyD88(MAL!2,IRAK1!3,IRAK4!4,MyD88s).IRAK4(Myd88!4,IRAKM,IRAK1) + TAK1(TRAF6,Activation~No) -> TRAF6(IRAK1!0,TRIF,RP1,TRAF4,A20,JNK,p38,TAK1).TLR4(TLR4!+,CD14!+,LPS!+,MD2!+,TRAM,MAL!1).MAL(TLR4!1,MyD88!2,SOCS1).IRAK1(IRAK4,MyD88!3,Tollip,TRAF6!0).MyD88(MAL!2,IRAK1!3,IRAK4!4,MyD88s).IRAK4(Myd88!4,IRAKM,IRAK1) + TAK1(TRAF6,Activation~Yes)

TRAF6 0IRAK1 TRIF RP1 TAK1 TRAF4 A20 JNK p38 TLR4 1MAL TRAM TLR4 CD14 MD2 LPS MAL 1TLR4 2MyD88 SOCS1 IRAK1 IRAK4 3MyD88 Tollip 0TRAF6 MyD88 2MAL 3IRAK1 4IRAK4 MyD88s IRAK4 4Myd88 IRAKM IRAK1 TAK1 TRAF6 Activation No Yes take all branches, once each, in any order⬇⬇

RP1(TRIF!0,TRAF6,TAK1,p38).TRIF(TRAM,TRAF6,RIP1!0,TRAF4,SARM) + TRAF6(IRAK1,TRIF,RP1,TAK1,TRAF4,A20,JNK,p38) <-> RP1(TRIF!0,TRAF6!1,TAK1,p38).TRIF(TRAM,TRAF6!2,RIP1!0,TRAF4,SARM).TRAF6(IRAK1,TRIF!2,RP1!1,TAK1,TRAF4,A20,JNK,p38)

RP1 0TRIF 1 ⬆⬇TRAF6 TAK1 p38 TRIF TRAM 2 ⬆⬇TRAF6 0RIP1 TRAF4 SARM TRAF6 IRAK1 2 ⬆⬇TRIF 1 ⬆⬇RP1 TAK1 TRAF4 A20 JNK p38

A20(TRAF6) + Ikk_Complex(Activation~Yes) -> A20(TRAF6) + Ikk_Complex(Activation~No)

A20 TRAF6 Ikk_Complex Activation No Yes take one or more branches, once each, in any order⬆⬆

Ikk_Complex(Activation~Yes) + NFkB(Transcription~No,Activation~No!0!1,Location~Cytoplasm).IkB(Phos~No,p65!0,p50!1,Degrade~No) -> Ikk_Complex(Activation~Yes) + NFkB(Transcription~No,Activation~No!0!1,Location~Cytoplasm).IkB(p65!0,p50!1,Degrade~No,Phos~Yes)

Ikk_Complex Activation Yes NFkB Transcription No Activation 0No Location Cytoplasm IkB Phos No Yes take all branches, once each, in any order⬇⬇ 0p65 1p50 Degrade No

NFkB(Transcription~No,Activation~Yes,Location~Cytoplasm) <-> NFkB(Transcription~No,Activation~Yes,Location~Nucleus)

NFkB Transcription No Activation Yes Location Cytoplasm Nucleus take all branches, once each, in any order⬇⬇

DNA(A20!0).NFkB(Transcription~Yes!0,Activation~Yes,Location~Nucleus) + IkB(Phos~No,p65,p50,Degrade~No) -> DNA(A20) + NFkB(Transcription~No,Activation~No!0!1,Location~Cytoplasm).IkB(Phos~No,p65!0,p50!1,Degrade~No)

DNA 0 ⬆A20 TNF iNOS IL10 IkB c c NFkB Transcription No 0 ⬆Yes take one or more branches, once each, in any order⬆⬆ Activation No 0 ⬇Yes take one or more branches, once each, in any order⬆⬆ Location Cytoplasm Nucleus take one or more branches, once each, in any order⬆⬆ IkB Phos No 0 ⬇p65 1 ⬇p50 Degrade No
NFkB_IkB_Bind: NFkB(Location~Cytoplasm,Activation~*)+IkB(Phos~No,p65,p50,Degrade~No)<->NFkB(Activation~*!0!1,Location~Cytoplasm).IkB(Phos~No,p65!0,p50!1,Degrade~No) NFkB_IkB_Bind,NFkB_IkB_Unbind

NFkB(Location~Cytoplasm,Activation) + IkB(Phos~No,p65,p50,Degrade~No) <-> NFkB(Activation!0!1,Location~Cytoplasm).IkB(Phos~No,p65!0,p50!1,Degrade~No)

NFkB Transcription No Yes 0 ⬆⬇Activation Location Cytoplasm IkB Phos No 0 ⬆⬇p65 1 ⬆⬇p50 Degrade No

IkB(Degrade~Yes!0).Proteasome26s(IkB!0) -> IkB(Degrade~Yes) + Proteasome26s(IkB)

IkB Phos No Yes p65 p50 Degrade 0 ⬆Yes Proteasome26s 0 ⬆IkB

TAK1(TRAF6,Activation~Yes) -> TAK1(TRAF6,Activation~No)

TAK1 TRAF6 Activation No Yes take one or more branches, once each, in any order⬆⬆

Ikk_Complex(Activation~Yes) -> Ikk_Complex(Activation~No)

Ikk_Complex Activation No Yes take one or more branches, once each, in any order⬆⬆

TAK1(TRAF6,Activation~Yes) + Ikk_Complex(Activation~No) -> TAK1(TRAF6,Activation~Yes) + Ikk_Complex(Activation~Yes)

TAK1 TRAF6 Activation Yes Ikk_Complex Activation No Yes take all branches, once each, in any order⬇⬇