_enti_e7
_enti_e1
_enti_e10
_enti_e4
_enti_e2
_enti_e3
_enti_e55
_enti_e53
_enti_e59
_enti_e54
_enti_e50
_enti_e52
_enti_e51
_enti_e56
_enti_e57
_enti_e61
_enti_e58
_enti_e62
_enti_e60
g1_fact_g1
g2_fact_g12
g2_fact_g13
g1_fact_g14
p2_propro_p2
PMID: 12472665, 7508914
Three enzymes, kallikrein, factor XIa and XIIa, in the blood clotting system have the ability to cleave pro-MSP
c7 cso30:c:InputProcess connector
c4 cso30:c:InputAssociation connector
c10 cso30:c:OutputProcess connector
p2_propro_p3
PMID: 12472665, 7508914
Three enzymes, kallikrein, factor XIa and XIIa, in the blood clotting system have the ability to cleave pro-MSP
c8 cso30:c:InputProcess connector
c5 cso30:c:InputAssociation connector
c11 cso30:c:OutputProcess connector
p2_propro_p4
PMID: 12472665, 7508914
Three enzymes, kallikrein, factor XIa and XIIa, in the blood clotting system have the ability to cleave pro-MSP
c9 cso30:c:InputProcess connector
c6 cso30:c:InputAssociation connector
c12 cso30:c:OutputProcess connector
p5_propro_p5
PMID: 12472665, 8188657, 8609228
Pro-MSP activation was also observed in wound fluids collected from surgical patients [32], presumably mediated by tissue proteases such as epidermal growth factor-binding protein and nerve growth factor-γ[32], or by cell-surface proteases located on tissue macrophages [28].
c13 cso30:c:InputAssociation connector
c15 cso30:c:InputProcess connector
c17 cso30:c:OutputProcess connector
p6_propro_p6
PMID: 12472665, 8188657, 8609228
Pro-MSP activation was also observed in wound fluids collected from surgical patients [32], presumably mediated by tissue proteases such as epidermal growth factor-binding protein and nerve growth factor-γ[32], or by cell-surface proteases located on tissue macrophages [28].
c14 cso30:c:InputAssociation connector
c16 cso30:c:InputProcess connector
c159 cso30:c:OutputProcess connector
p7_propro_p7
PMID: 12472665, 8188657, 8609228
Pro-MSP activation was also observed in wound fluids collected from surgical patients [32], presumably mediated by tissue proteases such as epidermal growth factor-binding protein and nerve growth factor-γ[32], or by cell-surface proteases located on tissue macrophages [28].
c18 cso30:c:InputAssociation connector
c19 cso30:c:InputProcess connector
c20 cso30:c:OutputProcess connector
p8_propro_p8
PMID: 12472665, 7939629, 7732008, 8062829
MSP binds the RON receptor.
c22 cso30:c:InputProcess connector
c1 cso30:c:InputProcess connector
c23 cso30:c:OutputProcess connector
p9_propro_p9
PMID: 12472665, 7514598, 9794431
The inhibitory effect of MSP on macrophages was first demonstrated in vitro, in which treatment of mouse peritoneal macrophages with physiological concentrations of MSP inhibits lipopolysaccharides (LPS)- or cytokine-induced inducible NO synthase (iNOS) and NO production
c24 cso30:c:InputAssociation connector
c89 cso30:c:InputAssociation connector
c26 cso30:c:InputInhibitor connector
c25 cso30:c:OutputProcess connector
p10_propro_p10
The inhibitory effect of MSP on macrophages was first demonstrated in vitro, in which treatment of mouse peritoneal macrophages with physiological concentrations of MSP inhibits lipopolysaccharides (LPS)- or cytokine-induced inducible NO synthase (iNOS) and NO production
c28 cso30:c:InputAssociation connector
c31 cso30:c:InputInhibitor connector
c30 cso30:c:InputAssociation connector
c29 cso30:c:OutputProcess connector
p12_propro_p12
PMID: 12472665,
LPS-induced cyclooxygenase-2 (Cox-2) expression and prostaglandin E2 (PGE2) production by macrophages was also inhibited by MSP
c37 cso30:c:InputInhibitor connector
c40 cso30:c:InputAssociation connector
c36 cso30:c:OutputProcess connector
p14_propro_p14
PMID: 12472665, 10557102, 10878375
Recently, it was shown that double-stranded RNA-regulated protein kinase (PKR) also plays a critical role in LPS-induced iNOS expression.
Inactivation of PKR gene results in the failure of iNOS induction by LPS
c41 cso30:c:InputProcess connector
c81 cso30:c:InputAssociation connector
c42 cso30:c:OutputProcess connector
p15_propro_p15
PMID: 12472665, 10878375
Inactivation of PKR gene results in the failure of iNOS induction by LPS
c43 cso30:c:InputAssociation connector
c82 cso30:c:InputInhibitor connector
c44 cso30:c:OutputProcess connector
p16_propro_p16
PMID: 12472665, 10586055
RON activation affect IFN-γ-induced STAT1 phosphorylation and IRF-1 or IRF-2 expression
c45 cso30:c:InputAssociation connector
c46 cso30:c:OutputProcess connector
c47 cso30:c:OutputProcess connector
p17_propro_p17
PMID: 12472665, 10586055
RON activation affect IFN-γ-induced STAT1 phosphorylation and IRF-1 or IRF-2 expression
c48 cso30:c:InputAssociation connector
c50 cso30:c:OutputProcess connector
p18_propro_p18
PMID: 12472665, 10586055
RON activation affect IFN-γ-induced STAT1 phosphorylation and IRF-1 or IRF-2 expression
c49 cso30:c:InputAssociation connector
c51 cso30:c:OutputProcess connector
p19_propro_p19
PMID: 12472665, 10586055
After LPS and IFN-γ stimulation, nuclear translocation of NFκB was significantly reduced upon RON activation
c62 cso30:c:InputInhibitor connector
c66 cso30:c:InputProcess connector
c53 cso30:c:InputAssociation connector
c56 cso30:c:OutputProcess connector
p20_propro_p20
PMID: 12472665, 10586055
After LPS and IFN-γ stimulation, nuclear translocation of NFκB was significantly reduced upon RON activation
c61 cso30:c:InputInhibitor connector
c67 cso30:c:InputProcess connector
c77 cso30:c:InputAssociation connector
c57 cso30:c:OutputProcess connector
p21_propro_p21
PMID: 12472665, 10586055
RON activation also caused decreased binding of NFκB to its consensus sequence [
c58 cso30:c:InputProcess connector
c59 cso30:c:InputProcess connector
c63 cso30:c:InputInhibitor connector
c60 cso30:c:OutputProcess connector
p22_propro_p22
PMID: 12472665,10837071,10847627, 11521070
In mouse macrophages, two separate but cooperative signalling pathways are involved in the induction of iNOS expression: LPS-induced TRL4 > MyD88 > IRAK > IKK > nuclear factor kappa-B (NFκB) pathway [54, 55] and interferon-γ (IFN-γ)-induced JAK/STAT/IFN-response factor-1 (IRF-1) pathway [5456]
NFκB is normally sequestered in the cytoplasm by NFκB inhibitor protein IκBs such as IκBα[64]. LPS stimulation causes the degradation of IκBα, which releases NFκB, leading to its nuclear translocation [64]
Using Raw264.7 cells expressing RON, we demonstrated that MSP treatment significantly prevents the decrease of LPS-induced IκBα degradationFirst, we found that MSP inhibits LPS-induced IκBα degradation in macrophages
c68 cso30:c:InputInhibitor connector
c108 cso30:c:InputAssociation connector
c54 cso30:c:InputProcess connector
c64 cso30:c:OutputProcess connector
c65 cso30:c:OutputProcess connector
p24_propro_p24
PMID: 12472665, 10837071
LPS stimulation causes the degradation of IκBα, which releases NFκB, leading to its nuclear translocation
c73 cso30:c:InputProcess connector
c34 cso30:c:InputInhibitor connector
c74 cso30:c:OutputProcess connector
p25_propro_p25
PMID: 12472665, 9804806
IKKβ, also known as IKK1, is the intermediate upstream kinase responsible for the phosphorylation of IκBs including IκBα[65]. Reduced phosphorylation and decreased degradation of IκBα suggest that MSP may affect LPS-induced IKKβ activity
c78 cso30:c:InputInhibitor connector
c55 cso30:c:InputAssociation connector
c129 cso30:c:InputProcess connector
c33 cso30:c:InputAssociation connector
c79 cso30:c:OutputProcess connector
p1_propro_p1
PMID: 12472665, 9794431
Wortmannin, a specific inhibitor of PI-3 kinase, prevented the inhibitory effect of RON on iNOS gene transcription activity and NO production induced by LPS and IFN-γ
c2 cso30:c:InputProcess connector
c3 cso30:c:InputProcess connector
c32 cso30:c:InputInhibitor connector
c21 cso30:c:OutputProcess connector
p31_propro_p31
PMID: 12472665, 7514598, 9794431
The inhibitory effect of MSP on macrophages was first demonstrated in vitro, in which treatment of mouse peritoneal macrophages with physiological concentrations of MSP inhibits lipopolysaccharides (LPS)- or cytokine-induced inducible NO synthase (iNOS) and NO production
PMID: 12472665, 10725742
Blocking NO production by transforming growth factor-β and MSP prevented LPS-induced inhibition of RON expression
c94 cso30:c:InputInhibitor connector
c105 cso30:c:InputAssociation connector
c160 cso30:c:InputInhibitor connector
c93 cso30:c:OutputProcess connector
p32_propro_p32
Studies of deletion of successive regions, which encompass potential SP-1 sites, suggested that SP-1 or a protein with a binding specificity similar to SP-1 may be involved in the positive regulation of the RON gene transcription
PMID: 12472665, 10725742
We have shown that a chemical NO donor, S-nitroglutathione (GSNO) or S-nitroso-N-acetylpenicillamine (SNAP), directly inhibits the RON expression when added to cell culture
PMID: 12472665, 10725742
We have shown that in mice injected intraperitoneally with LPS, RON expression is significantly reduced or lost in the peritoneal macrophages [72]. The levels of RON mRNA and protein were also diminished in cultured macrophages following LPS stimulation
PMID: 12472665, 10725742
Interestingly, tumour necrosis factor-α together with IFN-γ abrogated the macrophage RON expression, although each individual cytokine alone had no effect
c97 cso30:c:InputAssociation connector
c39 cso30:c:InputInhibitor connector
c52 cso30:c:InputInhibitor connector
c84 cso30:c:InputInhibitor connector
c86 cso30:c:InputInhibitor connector
c98 cso30:c:OutputProcess connector
p33_propro_p33
PMID: 12472665, 9467940, 7632741
Studies of deletion of successive regions, which encompass potential SP-1 sites, suggested that SP-1 or a protein with a binding specificity similar to SP-1 may be involved in the positive regulation of the RON gene transcription
PMID: 12472665, 10725742
We have shown that a chemical NO donor, S-nitroglutathione (GSNO) or S-nitroso-N-acetylpenicillamine (SNAP), directly inhibits the RON expression when added to cell culture
PMID: 12472665, 10725742
We have shown that in mice injected intraperitoneally with LPS, RON expression is significantly reduced or lost in the peritoneal macrophages [72]. The levels of RON mRNA and protein were also diminished in cultured macrophages following LPS stimulation
PMID: 12472665, 10725742
Interestingly, tumour necrosis factor-α together with IFN-γ abrogated the macrophage RON expression, although each individual cytokine alone had no effect
c95 cso30:c:InputAssociation connector
c35 cso30:c:InputInhibitor connector
c38 cso30:c:InputInhibitor connector
c70 cso30:c:InputInhibitor connector
c80 cso30:c:InputInhibitor connector
c85 cso30:c:InputInhibitor connector
c96 cso30:c:OutputProcess connector
p34_propro_p34
PMID: 12472665
IFN-gamma binds its receptor.
c99 cso30:c:InputProcess connector
c100 cso30:c:InputProcess connector
c101 cso30:c:OutputProcess connector
p35_propro_p35
PMID: 12472665
cytokine binds its receptor
c102 cso30:c:InputProcess connector
c103 cso30:c:InputProcess connector
c104 cso30:c:OutputProcess connector
p36_propro_p36
PMID: 12472665
LPS binds its receptor.
c92 cso30:c:InputProcess connector
c106 cso30:c:InputProcess connector
c107 cso30:c:OutputProcess connector
p39_propro_p39
PMID: 12472665, 9794431
Wortmannin, a specific inhibitor of PI-3 kinase, prevented the inhibitory effect of RON on iNOS gene transcription activity and NO production induced by LPS and IFN-γ[
c117 cso30:c:InputAssociation connector
c121 cso30:c:InputInhibitor connector
c119 cso30:c:OutputProcess connector
p40_propro_p40
PMID: 12472665, 9794431
Wortmannin, a specific inhibitor of PI-3 kinase, prevented the inhibitory effect of RON on iNOS gene transcription activity and NO production induced by LPS and IFN-γ[
c116 cso30:c:InputAssociation connector
c120 cso30:c:InputInhibitor connector
c118 cso30:c:OutputProcess connector
p41_propro_p41
PMID: 12472665, 9794431
Wortmannin, a specific inhibitor of PI-3 kinase, prevented the inhibitory effect of RON on iNOS gene transcription activity and NO production induced by LPS and IFN-γ
PMID: 12472665, 10725742
Blocking NO production by transforming growth factor-β and MSP prevented LPS-induced inhibition of RON expression
PMID: 12472665, 7514598, 9794431
The inhibitory effect of MSP on macrophages was first demonstrated in vitro, in which treatment of mouse peritoneal macrophages with physiological concentrations of MSP inhibits lipopolysaccharides (LPS)- or cytokine-induced inducible NO synthase (iNOS) and NO production
c131 cso30:c:InputAssociation connector
c133 cso30:c:InputInhibitor connector
c163 cso30:c:InputInhibitor connector
c27 cso30:c:InputInhibitor connector
c130 cso30:c:OutputProcess connector
p42_propro_p42
PMID: 12472665, 9794431
Wortmannin, a specific inhibitor of PI-3 kinase, prevented the inhibitory effect of RON on iNOS gene transcription activity and NO production induced by LPS and IFN-γ
PMID: 12472665, 10725742
Blocking NO production by transforming growth factor-β and MSP prevented LPS-induced inhibition of RON expression
c126 cso30:c:InputAssociation connector
c128 cso30:c:InputInhibitor connector
c164 cso30:c:InputInhibitor connector
c125 cso30:c:OutputProcess connector
p43_propro_p43
PMID: 12472665
TNF-alpha binds its receptor.
c134 cso30:c:InputProcess connector
c135 cso30:c:InputProcess connector
c136 cso30:c:OutputProcess connector
p44_propro_p44
c69 cso30:c:InputProcess connector
c76 cso30:c:InputProcess connector
c139 cso30:c:OutputProcess connector
p45_propro_p45
PMID: 12472665, 10847627, 11521070
In mouse macrophages, two separate but cooperative signalling pathways are involved in the induction of iNOS expression: LPS-induced TRL4 > MyD88 > IRAK > IKK > nuclear factor kappa-B (NFκB) pathway [54, 55] and interferon-γ (IFN-γ)-induced JAK/STAT/IFN-response factor-1 (IRF-1) pathway [5456]
c141 cso30:c:InputProcess connector
c140 cso30:c:InputProcess connector
c142 cso30:c:OutputProcess connector
p46_propro_p46
PMID: 12472665, 10847627, 11521070
In mouse macrophages, two separate but cooperative signalling pathways are involved in the induction of iNOS expression: LPS-induced TRL4 > MyD88 > IRAK > IKK > nuclear factor kappa-B (NFκB) pathway [54, 55] and interferon-γ (IFN-γ)-induced JAK/STAT/IFN-response factor-1 (IRF-1) pathway [5456]
c144 cso30:c:InputProcess connector
c143 cso30:c:InputAssociation connector
c145 cso30:c:OutputProcess connector
p47_propro_p47
PMID: 12472665, 10847627, 11521070
In mouse macrophages, two separate but cooperative signalling pathways are involved in the induction of iNOS expression: LPS-induced TRL4 > MyD88 > IRAK > IKK > nuclear factor kappa-B (NFκB) pathway [54, 55] and interferon-γ (IFN-γ)-induced JAK/STAT/IFN-response factor-1 (IRF-1) pathway [5456]
c146 cso30:c:InputAssociation connector
c75 cso30:c:InputProcess connector
c148 cso30:c:OutputProcess connector
p50_propro_p50
PMID: 12472665, 10847627, 11521070
In mouse macrophages, two separate but cooperative signalling pathways are involved in the induction of iNOS expression: LPS-induced TRL4 > MyD88 > IRAK > IKK > nuclear factor kappa-B (NFκB) pathway [54, 55] and interferon-γ (IFN-γ)-induced JAK/STAT/IFN-response factor-1 (IRF-1) pathway [5456]
c154 cso30:c:InputAssociation connector
c91 cso30:c:InputInhibitor connector
c155 cso30:c:OutputProcess connector
p49_propro_p49
In mouse macrophages, two separate but cooperative signalling pathways are involved in the induction of iNOS expression: LPS-induced TRL4 > MyD88 > IRAK > IKK > nuclear factor kappa-B (NFκB) pathway [54, 55] and interferon-γ (IFN-γ)-induced JAK/STAT/IFN-response factor-1 (IRF-1) pathway [5456]
c152 cso30:c:InputAssociation connector
c153 cso30:c:InputProcess connector
c156 cso30:c:OutputProcess connector
p51_propro_p51
PMID: 12472665, 10847627, 11521070, 11536325
In mouse macrophages, two separate but cooperative signalling pathways are involved in the induction of iNOS expression: LPS-induced TRL4 > MyD88 > IRAK > IKK > nuclear factor kappa-B (NFκB) pathway [54, 55] and interferon-γ (IFN-γ)-induced JAK/STAT/IFN-response factor-1 (IRF-1) pathway [5456]
c157 cso30:c:InputAssociation connector
c90 cso30:c:InputInhibitor connector
c158 cso30:c:OutputProcess connector
Pro-MSP_enti_e5
Pro-MSP
RON receptor_enti_e6
RON receptor
Kallikrein_enti_e12
Kallikrein
FactorXIa_enti_e13
FactorXIa
FctorXIIa_enti_e14
FctorXIIa
MSP_enti_e15
MSP
EGFBP_enti_e16
EGFBP
NGF-gamma_enti_e17
NGF-gamma
Cell surface proteases_enti_e18
Cell surface proteases
RON receptor{active}:MSP_enti_e19
RON receptor{active}:MSP
inos_enti_e20
inos
iNOS_enti_e21
iNOS
LPS_enti_e8
LPS
cytokine_enti_e9
cytokine
cox-2_enti_e22
cox-2
IFN-gamma_enti_e23
IFN-gamma
PKR_enti_e24
PKR
PKR{active}_enti_e25
PKR{active}
STAT1_enti_e26
STAT1
STAT1{p}_enti_e27
STAT1{p}
IRF-1_enti_e28
IRF-1
IRF-2_enti_e29
IRF-2
NFKappB{active}_enti_e31
NFKappB{active}
DNA_enti_e32
DNA
NFKappaB:DNA_enti_e33
NFKappaB:DNA
NFKB:IKB_enti_e30
NFKB:IKB
NFKB{active}_enti_e34
NFKB{active}
NFKB:IKB{p}_enti_e36
NFKB:IKB{p}
PI-3kinase_enti_e11
PI-3kinase
RON receptor:MSP:PI-3kinase_enti_e38
RON receptor:MSP:PI-3kinase
RON_enti_e39
RON
TNF-alpha_enti_e40
TNF-alpha
GSNO_enti_e41
GSNO
SNAP_enti_e42
SNAP
NO_enti_e43
NO
SP-1_enti_e44
SP-1
unknown protein_enti_e45
unknown protein
IFN-gamma receptor_enti_e46
IFN-gamma receptor
IFN-gamma:receptor_enti_e47
IFN-gamma:receptor
receptor_enti_e48
receptor
cytokine:receptor_enti_e49
cytokine:receptor
TLR4_enti_e64
TLR4
LPS:TLR4_enti_e65
LPS:TLR4
TGFbeta_enti_e66
TGFbeta
wortmannin_enti_e67
wortmannin
TNF-alpha receptor_enti_e68
TNF-alpha receptor
TNF_alpha:receptor_enti_e69
TNF_alpha:receptor
protein remnants_enti_e35
receptor_enti_e70
receptor
TGFbeta:receptor_enti_e71
TGFbeta:receptor
MyD88_enti_e72
MyD88
LPS:TLR4:MyD88_enti_e73
LPS:TLR4:MyD88
IRAK_enti_e74
IRAK
IRAK{active}_enti_e75
IRAK{active}
IKKalpha:beta:gamma_enti_e37
IKKalpha:beta:gamma
IKK{active}_enti_e76
IKK{active}
IRF-1_enti_e77
IRF-1
IRF-1{active}_enti_e78
IRF-1{active}