A systems biology approach to suppress TNF-induced proinflammatory gene expressions

Hayashi, Kentaro; Piras, Vincent; Tabata, Sho; Tomita, Masaru; Selvarajoo, Kumar

doi:10.1186/1478-811X-11-84

Cell Communication and Signaling

Table 1 TNFR1 model A

From: A systems biology approach to suppress TNF-induced proinflammatory gene expressions

	Reaction			Formula and parameters (s^-1)						Remarks
1 ¹	TNFR1	→	TRADD	k ₁	*	TNFR1	k ₁	=	5e-3	Activation of TRADD by TNFR1
2 ²	TRADD	→	cIAP1/2	k ₂	*	TRADD	k ₂	=	2e-2	Formation of Complex 1 containing TRADD, cIAP1/2, TRAF2, TRAF5, RIP1 and the TAB/TAK complex
3 ³	cIAP1/2	→	TRAF2	k ₃	*	cIAP1/2	k ₃	=	1e-2
4 ⁴	cIAP1/2	→	TRAF5	k ₄	*	cIAP1/2	k ₄	=	8e-3
5 ⁵	TRAF2	→	RIP1	k ₅	*	TRAF2	k ₅	=	1e-3
6 ⁵	TRAF5	→	RIP1	k ₆	*	TRAF5	k ₆	=	1e-3
7 ⁶	TRADD	→	TRAF6	k ₇	*	TRADD	k ₇	=	2e-2	Activation of TRAF6 by TRADD
8 ⁵	TRAF6	→	RIP1	k ₈	*	TRAF6	k ₈	=	1e-4	Activation of RIP1 and TAK1 complex by TRAF6
9 ⁷	TRAF6	→	TAK1 complex	k ₉	*	TRAF6	k ₉	=	1.3e-4	Activation of RIP1 and TAK1 complex by TRAF6
10 ⁸	RIP1	→	LUBAC	k ₁₀	*	RIP1	k ₁₀	=	7e-3	Complex 1 ubiquitination by LUBAC and SHARPIN
11 ⁹	RIP1	→	SHARPIN	k ₁₁	*	RIP1	k ₁₁	=	7e-3
12 ⁷	LUBAC	→	TAK1 complex	k ₁₂	*	LUBAC	k ₁₂	=	1e-1
13	SHARPIN	→	IKK complex	k ₁₃	*	SHARPIN	k ₁₃	=	1e-2	Activation of IKK complex by Complex 1
14	TAK1 complex	→	IKK complex	k ₁₄	*	TAK1 complex	k ₁₄	=	1e-1	Activation of IKK complex by Complex 1
15 ¹⁰	IKK complex	→	IκBα	k ₁₅	*	IKK complex	k ₁₅	=	1e-2	Phosphorylation of IκBα by IKK
16	IκBα	→	NF-κBc	k ₁₆	*	IκBα	k ₁₆	=	8e-3	Degradation of IκBα forms NF-κB
17	NF-κBc	→	NF-κBn	k ₁₇	*	NF-κBc	k ₁₇	=	1.7e-2	Translocation of NF-κB to nucleus
18	TAK1 complex	→	MKK1/2	k ₁₈	*	TAK1 complex	k ₁₈	=	1.5e-3	Activation of MAP kinases kinases by TAK1 complex
19 ¹¹	TAK1 complex	→	MKK3/6	k ₁₉	*	TAK1 complex	k ₁₉	=	1e-2
20	TAK1 complex	→	MKK4/7	k ₂₀	*	TAK1 complex	k ₂₀	=	1e-2
21	MKK1/2	→	ERK	k ₂₁	*	MKK1/2	k ₂₁	=	5e-3	Activation of MAP kinases
22 ¹²	MKK3/6	→	p38	k ₂₂	*	MKK3/6	k ₂₂	=	5e-3
24	MKK4/7	→	JNK	k ₂₃	*	MKK4/7	k ₂₃	=	5e-3
24	p38	→	p38n	k ₂₄	*	p38	k ₂₄	=	5e-2	Translocation of MAP kinases into nucleus
25	JNK	→	JNKn	k ₂₅	*	JNK	k ₂₅	=	5e-2
26	ERK	→	ERKn	k ₂₆	*	ERK	k ₂₆	=	5e-3
27	p38n	→	AP1	k ₂₇	*	p38n	k ₂₇	=	1e-2	Activation of AP1 by MAP kinases
28	ERKn	→	AP1	k ₂₈	*	ERKn	k ₂₈	=	1e-2
29	JNKn	→	AP1	k ₂₉	*	JNKn	k ₂₉	=	1e-2
30	AP1	→	GI promoter	k ₃₀	*	AP1	k ₃₀	=	1e-1	Promoter binding of AP1 and NF-κB for group I genes
31	NF-κBn	→	GI promoter	k ₃₁	*	NF-κBn	k ₃₁	=	5e-3	Promoter binding of AP1 and NF-κB for group I genes
32	G1 promoter	→	GI pre-mRNA	k ₃₂	*	GI promoter	k ₃₂	=	1e-2	Group I genes transcription, splicing (1 step) and decay
33	GI pre-mRNA	→	GI mRNA	k ₃₃	*	GI pre-mRNA	k ₃₃	=	5e-2
34	GI mRNA	→	GI mRNA decay	k ₃₄	*	GI mRNA	k ₃₄	=	2e-3
35 ¹³	AP1	→	GII promoter	k ₃₅	*	AP1	k ₃₅	=	1.1e-2	Promoter binding of AP1 and NF-κB for group II genes
36	NF-κBn	→	GII promoter	k ₃₆	*	NF-κBn	k ₃₆	=	4e-3	Promoter binding of AP1 and NF-κB for group II genes
37	GII promoter	→	GII pre-mRNA/1	k ₃₇	*	GII promoter	k ₃₇	=	2e-3	Group II genes transcription, splicing (2 steps) and decay
38	GII pre-mRNA/1	→	GII pre-mRNA/2	k ₃₈	*	GII pre-mRNA/1	k ₃₈	=	5e-2
39	GII pre-mRNA/2	→	GII mRNA	k ₃₉	*	GII pre-mRNA/2	k ₃₉	=	5e-2
40 ¹³	GII mRNA	→	GII mRNA decay	k ₄₀	*	GII mRNA	k ₄₀	=	1.2e-4
41	AP1	→	GIII promoter	k ₄₁	*	AP1	k ₄₁	=	5e-3	Promoter binding of AP1 and NF-κB for group III genes
42	NF-κBn	→	GIII promoter	k ₄₂	*	NF-κBn	k ₄₂	=	1e-4	Promoter binding of AP1 and NF-κB for group III genes
43	GIII promoter	→	GIII pre-mRNA/1	k ₄₃	*	GIII promoter	k ₄₃	=	1e-1	Group III genes transcription, splicing (3 steps) and decay
44	GIII pre-mRNA/1	→	GIII pre-mRNA/2	k ₄₄	*	GIII pre-mRNA/1	k ₄₄	=	4e-4
45	GIII pre-mRNA/2	→	GIII pre-mRNA/3	k ₄₅	*	GIII pre-mRNA/2	k ₄₅	=	1e-3
46	GIII pre-mRNA/3	→	GIII mRNA	k ₄₆	*	GIII pre-mRNA/3	k ₄₆	=	2e-4
47	GIII mRNA	→	GIII mRNA decay	k ₄₇	*	GIII mRNA	k ₄₇	=	2e-5
48	*GI mRNA*	→	X1	k ₄₈	*	GI mRNA	k ₄₈	=	1e-5	Feedback processes via group I genes or NF-κB
49	*NF-κBn*	→	X1	k ₄₉	*	NF-κBn	k ₄₉	=	5e-1	Steps of the secondary feedback processes (cytosolic or autocrine signaling):
50	X1	→	X2	k ₅₀	*	X1	k ₅₀	=	2e-3
51	X2	→	X3	k ₅₁	*	X2	k ₅₁	=	2e-3
52	X3	→	X4	k ₅₂	*	X3	k ₅₂	=	2e-3
53	X4	→	X5	k ₅₃	*	X4	k ₅₃	=	2e-3
54	X5	→	X6	k ₅₄	*	X5	k ₅₄	=	2e-3
55	X6	→	X7	k ₅₅	*	X6	k ₅₅	=	2e-3	• expression (e.g. translation)
56	X7	→	X8	k ₅₆	*	X7	k ₅₆	=	2e-3	• transport (e.g. secretion)
57	X8	→	X9	k ₅₇	*	X8	k ₅₇	=	2e-3	• signaling (e.g. receptor binding, activation of transcription factors)
58	X9	→	*X10*	k ₅₈	*	X9	k ₅₈	=	2e-3
59	*X10*	→	*X11*	k ₅₉	*	X10	k ₅₉	=	2e-3
60	*X11*	→	*X12*	k ₆₀	*	X11	k ₆₀	=	2e-3
61	*X12*	→	*X13*	k ₆₁	*	X12	k ₆₁	=	2e-3
62	*X13*	→	*X14*	k ₆₂	*	X13	k ₆₂	=	2e-3
63	*X14*	→	*IκBα*	k ₆₃	*	X14	k ₆₃	=	2e-3	IκBα feedback activation
64	*X14*	→	Y	k ₆₄	*	X14	k ₆₄	=	1e-5	Group III feedback activation via transcription factor Y
65	Y	→	*GIII promoter*	k ₆₅	*	Y	k ₆₅	=	2e-3	Group III feedback activation via transcription factor Y

(1–12): in-silico knock-out conditions are performed by setting parameter values (k_i) to 0 for targeted reactions in TRADD KO (1), cIAP1/2 KO (2), TRAF2 KO (3), TRAF5 KO (4) TRAF2/5 DKO (3,4), RIP KO (5), TRAF6 KO (6), TAK1 complex KO (7), LUBAC KO (8), SHARPIN KO (9), IκBα KO (10), MKK3/6 KO (11) and p38 KO (12). (13) Kinetics of Group II mRNA transcription and decay processes were refitted after adding feedback (without feedback: k₃₅= 7e-3, k₄₀= 1.2e-5). Bold italic fonts (reactions 48–65) indicate additional feedback activation pathways required for group III continuous activation. * indicates the multiplication sign.

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ISSN: 1478-811X

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