re112
reaction_n1
species_82 + species_11 = s118
re113
reaction_n2
s118 > species_12 + species_82
re114
reaction_n3
species_12 + species_82 = s119
re115
reaction_n8
species_12 + species_85 = s120
re116
reaction_n7
∅ > species_30
re117
reaction_n10
s120 > s122
re121
reaction_n9
species_26 + species_95 = s122
re126
reaction_n12
s122 + species_24 = s126
re135
reaction-v1
species_5 + species_107 = species_78
re136
reaction-51
species_48 > species_108
re137
reaction-18
species_16 > species_8 + species_108
re138
reaction-17
species_9 + species_108 = species_16
re140
reaction-v11
species_85 + species_20 = species_90
re141
reaction-v12
species_90 > species_84 + species_20
re142
reaction-v24
species_87 + species_20 = species_101
re143
reaction-v25
species_101 > species_91 + species_20
re144
reaction-v15
species_95 + species_24 = species_94
re145
reaction-v16
species_94 > species_96 + species_24
re147
reaction-v27
species_92 + species_24 = species_102
re148
reaction-v28
species_102 > species_103 + species_24
re153
reaction_n11
species_20 + s120 = s135
re157
reaction_n4
species_9 + species_84 = s138
re158
reaction_n5
s138 > species_9 + species_85
re159
reaction_n6
species_85 + species_9 = s139
re160
reaciton-2
s140 + species_4 = species_6
re161
reaction_n13
s135 > species_20 + species_12 + species_84
re162
reaction_n14
s135 > species_85 + species_11 + species_20
re163
reaction_n15
s126 > species_26 + species_24 + species_96
re164
reaction_n16
s126 > species_95 + species_28 + species_24
reaction_1
reaction-1
species_2 + species_1 = species_3
reaction_100
reaction-v23
species_99 > ∅
reaction_103
reaction-v26
{2.0}species_95 = species_92
reaction_106
reaction-v29
species_96 + species_95 = species_103
reaction_107
reaction-v30
species_84 + species_100 = species_104
reaction_108
reaction-v32
species_105 > species_99 + species_81 + species_84 + species_108
reaction_109
reaction-v33
species_105 > species_99 + species_106
reaction_110
reaction-v31
species_108 + species_104 = species_105
reaction_12
reaction-19
species_12 + species_20 = species_21
reaction_13
reaction-21
species_14 + species_20 = species_22
reaction_14
reaction-20
species_21 > species_11 + species_20
reaction_15
reaction-22
species_22 > species_18 + species_20
reaction_16
reaction-23
species_11 + species_12 = species_18
reaction_17
reaction-24
species_14 > species_23
reaction_18
reaction-28
species_24 + species_23 = species_25
reaction_19
reaction-26
species_24 + species_26 = species_27
reaction_20
reaction-27
species_27 > species_28 + species_24
reaction_21
reaction-29
species_25 > species_24 + species_29
reaction_22
reaction-31
species_28 > species_11
reaction_23
reaction-32
∅ > species_30
reaction_24
reaction-33
species_30 > species_31
reaction_25
reaction-34
∅ > species_19
reaction_26
reaction-35
species_9 + species_19 = species_15
reaction_27
reaction-36
species_31 > ∅
reaction_28
reaction-37
species_19 > ∅
reaction_29
reaction-40
species_33 + species_32 = species_34
reaction_3
reaction-3
species_3 + species_6 = species_7
reaction_30
reaction-41
species_35 + species_34 = species_37
reaction_31
reaction-42
species_38 + species_37 = species_39
reaction_32
reaction-43
species_39 = species_40 + species_37
reaction_33
reaction-44
species_40 + species_41 = species_42
reaction_34
reaction-45
species_42 = species_43 + species_44
reaction_35
reaction-46
species_37 + species_43 = species_45
reaction_36
reaction-47
species_45 = species_37 + species_38
reaction_37
reaction-48
species_37 = species_46 + species_9
reaction_38
reaction-49
species_46 = species_47 + species_48
reaction_39
reaction-39
species_16 = species_33
reaction_4
reaction-8
species_9 + species_11 = species_10
reaction_40
reaction-50
species_47 = species_32 + species_35
reaction_42
reaction-52
species_33 = species_9 + species_48
reaction_43
reaction-53
species_32 + species_48 = species_36
reaction_44
reaction-54
species_34 = species_9 + species_36
reaction_45
reaction-55
species_35 + species_36 = species_46
reaction_46
reaction-56
species_33 + species_47 = species_37
reaction_47
reaction-57
species_49 + species_44 = species_50
reaction_48
reaction-58
species_50 > species_41 + species_49
reaction_49
reaction-59
species_44 + species_51 = species_52
reaction_5
reaction-6
{2.0}species_7 = species_8
reaction_50
reaction-60
species_52 > species_53 + species_44
reaction_51
reaction-61
species_44 + species_53 = species_54
reaction_52
reaction-62
species_54 > species_55 + species_44
reaction_53
reaction-63
species_55 + species_57 = species_56
reaction_54
reaction-64
species_56 > species_57 + species_53
reaction_55
reaction-65
species_53 + species_57 = species_58
reaction_56
reaction-66
species_58 > species_57 + species_51
reaction_57
reaction-67
species_55 + species_59 = species_60
reaction_58
reaction-68
species_60 > species_61 + species_55
reaction_59
reaction-69
species_55 + species_61 = species_62
reaction_6
reaction-7
species_8 > species_9
reaction_60
reaction-70
species_62 > species_63 + species_55
reaction_61
reaction-72
species_65 > species_64 + species_61
reaction_62
reaction-73
species_61 + species_64 = species_66
reaction_63
reaction-74
species_66 > species_64 + species_59
reaction_64
reaction-71
species_63 + species_64 = species_65
reaction_65
reaction-25
species_23 = {2.0}species_26
reaction_66
reaction-30
species_29 = species_26 + species_28
reaction_7
reaction-9
species_10 > species_9 + species_12
reaction_73
reaction-38
species_15 > species_8 + species_19
reaction_74
reaction-75
species_74 > species_75
reaction_75
reaction-76
species_75 > species_74
reaction_76
reaction-77
{2.0}species_75 = species_76
reaction_79
reaction-v3
{2.0}species_80 = species_81
reaction_8
reaction-10
species_9 + species_12 = species_13
reaction_80
reaction-v2
species_79 + species_78 = species_80
reaction_81
reaction-v4
species_81 > species_82
reaction_82
reaction-v5
species_82 + species_84 = species_83
reaction_83
reaction-v6
species_83 > species_82 + species_85
reaction_84
reaction-v7
species_82 + species_85 = species_86
reaction_85
reaction-v8
{2.0}species_85 = species_87
reaction_86
reaction-v9
species_82 + species_108 = species_88
reaction_87
reaction-v10
species_88 > species_81 + species_108
reaction_9
reaction-16
{2.0}species_12 = species_14
reaction_90
reaction-v13
species_84 + species_85 = species_91
reaction_91
reaction-v14
species_87 > species_92
reaction_94
reaction-v17
species_96 > species_84
reaction_95
reaction-v18
∅ > species_97
reaction_96
reaction-v19
species_97 > species_98
reaction_97
reaction-v20
∅ > species_99
reaction_98
reaction-v21
species_99 + species_82 = species_100
reaction_99
reaction-v22
species_98 > ∅
Assignment rules
s136 = species_86 + 2.0 * species_101 + s135 + species_90 + 2.0 * species_102 + s126 + species_94 + 2.0 * species_87 + s120 + species_85 + species_91 + 2.0 * species_92 + s122 + species_95 + species_103 + s139
s137 = s119 + species_13 + s135 + 2.0 * species_22 + species_21 + s126 + 2.0 * species_25 + species_27 + s120 + s122 + 2.0 * species_14 + species_12 + species_18 + 2.0 * species_23 + species_26 + species_29
Function definitions
function_3(substrate, Km, V) = V * substrate / (Km + substrate)
function_1(parameter_52, parameter_53, species_23) = parameter_52 * species_23 / (parameter_53 + species_23)
function_2(parameter_55, species_31) = parameter_55 * species_31
function_activation(v, a, b, k) = v * a * b / (b + k)
function_4_reaction_n7_1(parameter_231, parameter_232, species_92) = parameter_231 * species_92 / (parameter_232 + species_92)
function_9(c2, parameter_171, species_102) = c2 * parameter_171 * species_102
function_8(c2, parameter_169, parameter_170, species_102, species_24, species_92) = c2 * (parameter_169 * species_24 * species_92 - parameter_170 * species_102)
function_7(parameter_159, species_98) = parameter_159 * species_98
function_6(parameter_156, parameter_157, species_92) = parameter_156 * species_92 / (parameter_157 + species_92)
function_5(c2, parameter_155, species_94) = c2 * parameter_155 * species_94
function_4(c2, parameter_152, parameter_153, species_24, species_94, species_95) = c2 * (parameter_152 * species_24 * species_95 - parameter_153 * species_94)
Note that constraints are not enforced in simulations. It remains the responsibility of the user to verify that simulation results satisfy these constraints.
Elucidating the crosstalk mechanism between IFN-gamma and IL-6 via mathematical modelling.
- PubMed: 23384097
- PubMed Central: PMC3599299
- DOI: 10.1186/1471-2105-14-41
- ISSN: 1471-2105
- URL: https://ncbi.nlm.nih.gov/pubmed/23384097
Abstract
RESULTS: Using established mathematical models and new experimental observations of the crosstalk between the IFN-gamma and IL-6 pathways, we constructed a new crosstalk model that considers three possible crosstalk levels: (1) the competition between STAT1 and STAT3 for common receptor docking sites; (2) the mutual negative regulation between SOCS1 and SOCS3; and (3) the negative regulatory effects of the formation of STAT1/3 heterodimers. A number of simulations were tested to explore the consequences of cross-regulation between the two pathways. The simulation results agreed well with the experimental data, thereby demonstrating the effectiveness and correctness of the model.
CONCLUSION: In this study, we developed a crosstalk model of the IFN-gamma and IL-6 pathways to theoretically investigate their cross-regulation mechanism. The simulation experiments showed the importance of the three crosstalk levels between the two pathways. In particular, the unbalanced competition between STAT1 and STAT3 for IFNR and gp130 led to preferential activation of IFN-gamma and IL-6, while at the same time the formation of STAT1/3 heterodimers enhanced preferential signal transduction by sequestering a fraction of the activated STATs. The model provided a good explanation of the experimental observations and provided insights that may inform further research to facilitate a better understanding of the cross-regulation mechanism between the two pathways.