_enti_e7
_enti_e8
_enti_e1
_enti_e9
_enti_e10
_enti_e2
_enti_e3
_enti_e4
_enti_e55
_enti_e16
_enti_e59
_enti_e53
_enti_e17
_enti_e18
_enti_e54
_enti_e52
_enti_e50
_enti_e51
_enti_e56
_enti_e61
_enti_e57
_enti_e58
_enti_e60
_enti_e62
g2_fact_g2
g1_fact_g1
g2_fact_g12
g2_fact_g13
g1_fact_g14
g1_fact_g3
p1_propro_p1
PMID: 17621314, 17048703, 11432202, 16807108
Although nearly all TLRs recruit MyD88, only some recruit Mal, TRAM and TRIF, giving rise to specificity in signalling.
PMID: 17621314, 7848516
sTLRs compete with TLR agonists and are highly effective in the first line of negative regulation, as they directly attenuate TLR signalling and therefore prevent acute inflammatory responses.
c1 cso30:c:InputProcess connector
c2 cso30:c:InputProcess connector
c37 cso30:c:InputInhibitor connector
c3 cso30:c:OutputProcess connector
p2_propro_p2
PMID: 17621314, 17048703, 11432202, 16807108
Although nearly all TLRs recruit MyD88, only some recruit Mal, TRAM and TRIF, giving rise to specificity in signalling.
c4 cso30:c:InputProcess connector
c6 cso30:c:InputProcess connector
c5 cso30:c:OutputProcess connector
p3_propro_p3
PMID: 17621314, 15557191
The mechanism involved in sTLR-4 inhibition to date is not fully understood, however, it has been hypothesized that sTLR-4 may block the interaction between TLR-4 and its co-receptors MD2 and CD14, leading to the termination of signalling.
c7 cso30:c:InputProcess connector
c8 cso30:c:InputProcess connector
c9 cso30:c:OutputProcess connector
p4_propro_p4
PMID: 17621314, 15557191
The mechanism involved in sTLR-4 inhibition to date is not fully understood, however, it has been hypothesized that sTLR-4 may block the interaction between TLR-4 and its co-receptors MD2 and CD14, leading to the termination of signalling.
PMID: 17621314, 15557191
The mechanism involved in sTLR-4 inhibition to date is not fully understood, however, it has been hypothesized that sTLR-4 may block the interaction between TLR-4 and its co-receptors MD2 and CD14, leading to the termination of signalling.
c10 cso30:c:InputProcess connector
c11 cso30:c:InputProcess connector
c38 cso30:c:InputInhibitor connector
c12 cso30:c:OutputProcess connector
p5_propro_p5
PMID: 17621314, 12447442, 12447441
Mal plays a critical role in host response as demonstrated by the total absence of pro-inflammatory cytokine production during either TLR-2 or TLR-4 signalling.
c13 cso30:c:InputProcess connector
c14 cso30:c:InputProcess connector
c15 cso30:c:OutputProcess connector
p6_propro_p6
PMID: 17621314
TRIF has been shown to be critical for signalling by lipopolysaccharide (LPS) via TLR-4 and for signalling by polyI:C via TLR-3, while TRAM was shown to be required for TLR-4 signalling only.
c16 cso30:c:InputProcess connector
c17 cso30:c:InputProcess connector
c18 cso30:c:OutputProcess connector
p7_propro_p7
PMID: 17621314, 17048703, 16807108, 16698941
TRIF has been found to induce the expression of IFN-beta in response to TLR-4 and TLR-3 ligands.
PMID: 17621314
To date, it is still unclear in regards to the exact mechanism of how SARM inhibits TRIF function, however, it can be hypothesized from finding by Bowie and colleagues, who demonstrated that SARM and TRIF weakly interact in resting cells and upon LPS stimulation, increase in stability possibly preventing the recruitment of downstream effector molecules to TRIF.
c19 cso30:c:InputProcess connector
c20 cso30:c:InputProcess connector
c160 cso30:c:InputInhibitor connector
c21 cso30:c:OutputProcess connector
p8_propro_p8
PMID: 17621314
TRIF has been shown to be critical for signalling by lipopolysaccharide (LPS) via TLR-4 and for signalling by polyI:C via TLR-3, while TRAM was shown to be required for TLR-4 signalling only.
c22 cso30:c:InputProcess connector
c23 cso30:c:InputProcess connector
c24 cso30:c:OutputProcess connector
p9_propro_p9
PMID: 17621314, 17048703, 16807108, 16698941
TRIF has been found to induce the expression of IFN-beta in response to TLR-4 and TLR-3 ligands.
PMID: 17621314
To date, it is still unclear in regards to the exact mechanism of how SARM inhibits TRIF function, however, it can be hypothesized from finding by Bowie and colleagues, who demonstrated that SARM and TRIF weakly interact in resting cells and upon LPS stimulation, increase in stability possibly preventing the recruitment of downstream effector molecules to TRIF.
c25 cso30:c:InputProcess connector
c26 cso30:c:InputProcess connector
c161 cso30:c:InputInhibitor connector
c27 cso30:c:OutputProcess connector
p10_propro_p10
PMID: 17621314, 16230348
Upon stimulation with PGN, MALP-2 and Pam3CSK-4 (ligands of TLR-2), cells displayed an enhanced activation and expression of NF-kappaB, TNF-alpha, IL-1beta and IL-8.
c28 cso30:c:InputProcess connector
c29 cso30:c:InputProcess connector
c30 cso30:c:OutputProcess connector
p11_propro_p11
PMID: 17621314, 12447442, 12447441
Mal plays a critical role in host response as demonstrated by the total absence of pro-inflammatory cytokine production during either TLR-2 or TLR-4 signalling.
c31 cso30:c:InputProcess connector
c32 cso30:c:InputProcess connector
c33 cso30:c:OutputProcess connector
p12_propro_p12
PMID: 17621314, 7848516
sTLRs compete with TLR agonists and are highly effective in the first line of negative regulation, as they directly attenuate TLR signalling and therefore prevent acute inflammatory responses.
c34 cso30:c:InputProcess connector
c35 cso30:c:InputProcess connector
c36 cso30:c:OutputProcess connector
p13_propro_p13
PMID: 17621314, 11986301
sTLR-2 was found to inhibit IL-8 and tumour necrosis factor (TNF) through the direct interaction with co-receptor sCD14 following stimulation with bacterial lipopeptide.
c40 cso30:c:InputProcess connector
c41 cso30:c:InputProcess connector
c39 cso30:c:OutputProcess connector
p14_propro_p14
PMID: 17621314, 11986301
sTLR-2 was found to inhibit IL-8 and tumour necrosis factor (TNF) through the direct interaction with co-receptor sCD14 following stimulation with bacterial lipopeptide.
c42 cso30:c:InputProcess connector
c43 cso30:c:InputProcess connector
c44 cso30:c:OutputProcess connector
p15_propro_p15
PMID: 17621314, 12538665
Subsequent studies showed the preferential recruitment of MyD88s-MyD88 heterodimers in favour of MyD88 homodimers, which allowed the recruitment of IRAK-1 resulting in the ablation of IRAK-1 phosphorylation.
c45 cso30:c:InputProcess connector
c46 cso30:c:OutputProcess connector
p16_propro_p16
PMID: 17621314, 12538665
Subsequent studies showed the preferential recruitment of MyD88s-MyD88 heterodimers in favour of MyD88 homodimers, which allowed the recruitment of IRAK-1 resulting in the ablation of IRAK-1 phosphorylation.
PMID: 17621314, 12885415
This phosphorylation is normally mediated by IRAK-4, but in the presence of MyD88s, IRAK-4 is not recruited to the signalling complex.
c47 cso30:c:InputProcess connector
c48 cso30:c:InputProcess connector
c50 cso30:c:InputProcess connector
c56 cso30:c:InputInhibitor connector
c49 cso30:c:OutputProcess connector
p17_propro_p17
PMID: 17621314, 12538665
Subsequent studies showed the preferential recruitment of MyD88s-MyD88 heterodimers in favour of MyD88 homodimers, which allowed the recruitment of IRAK-1 resulting in the ablation of IRAK-1 phosphorylation.
c51 cso30:c:InputProcess connector
c52 cso30:c:InputProcess connector
c53 cso30:c:OutputProcess connector
p18_propro_p18
PMID: 17621314, 12885415
This phosphorylation is normally mediated by IRAK-4, but in the presence of MyD88s, IRAK-4 is not recruited to the signalling complex.
PMID: 17621314, 11751856
Tollip also interacts with IRAK-1 leading to a decrease in IRAK-1 autophosphorylation and NF-kappaB activation.
c54 cso30:c:InputProcess connector
c186 cso30:c:InputInhibitor connector
c55 cso30:c:OutputProcess connector
p19_propro_p19
PMID: 17621314, 12150927
It was also discovered in vitro that IRAK-M prevents dissociation of IRAK-1/IRAK-4 from the MyD88 receptor complex, therefore inhibiting the association of IRAK-1 with TRAF-6.
c57 cso30:c:InputProcess connector
c63 cso30:c:InputInhibitor connector
c58 cso30:c:OutputProcess connector
c59 cso30:c:OutputProcess connector
p20_propro_p20
PMID: 17621314, 12150927
It was also discovered in vitro that IRAK-M prevents dissociation of IRAK-1/IRAK-4 from the MyD88 receptor complex, therefore inhibiting the association of IRAK-1 with TRAF-6.
PMID: 17621314
The exact mechanism of how TRAF-6 is targeted for the negative regulation of TLR-mediated signalling by FLN29 is undefined, however, it is suggested that FLN29 may inhibit downstream of TRAF-6 based on current findings.
c62 cso30:c:InputProcess connector
c60 cso30:c:InputProcess connector
c346 cso30:c:InputInhibitor connector
c61 cso30:c:OutputProcess connector
p21_propro_p21
PMID: 17621314, 15004556
This study showed a direct interaction between ST2L and MyD88 and Mal, but not TRIF or IRAK.
c64 cso30:c:InputProcess connector
c65 cso30:c:InputProcess connector
c68 cso30:c:OutputProcess connector
p22_propro_p22
PMID: 17621314, 15004556
This study showed a direct interaction between ST2L and MyD88 and Mal, but not TRIF or IRAK.
c66 cso30:c:InputProcess connector
c67 cso30:c:InputProcess connector
c69 cso30:c:OutputProcess connector
p23_propro_p23
PMID: 17621314, 11359817
sST2 binds to macrophages through a putative ST2 receptor.
c70 cso30:c:InputProcess connector
c71 cso30:c:InputProcess connector
c72 cso30:c:OutputProcess connector
p24_propro_p24
PMID: 17621314, 15557191, 11359817
Following the addition of sST2 to LPS-stimulated macrophages, there was significant suppression of mRNA expression of TLR-1 and TLR-4, leading to reduced pro-inflammatory cytokine production.
c75 cso30:c:InputAssociation connector
c77 cso30:c:InputAssociation connector
c73 cso30:c:OutputProcess connector
p25_propro_p25
PMID: 17621314, 15557191, 11359817
Following the addition of sST2 to LPS-stimulated macrophages, there was significant suppression of mRNA expression of TLR-1 and TLR-4, leading to reduced pro-inflammatory cytokine production.
PMID: 17621314, 15623538
TGF-beta1 inhibits TLR-4 expression by suppressing LPS-mediated responses and is also able to induce MyD88 degradation through interactions via its DD.
c76 cso30:c:InputAssociation connector
c78 cso30:c:InputAssociation connector
c313 cso30:c:InputInhibitor connector
c74 cso30:c:OutputProcess connector
p26_propro_p26
PMID: 17621314, 14993616
LPS stimulation in mouse models caused an increase in SIGIRR expression in various tissues, implicating its importance in the regulation of inflammatory responses.
c80 cso30:c:InputAssociation connector
c79 cso30:c:OutputProcess connector
p27_propro_p27
PMID: 17621314, 12925853
Similarly to ST2, this suggests that SIGIRR acts on the MyD88-dependent pathway as SIGIRR has been shown to form complexes with IL-1 receptor complex molecules, IRAK and TRAF-6 upon IL-1 stimulation in vitro.
c81 cso30:c:InputProcess connector
c82 cso30:c:InputProcess connector
c83 cso30:c:OutputProcess connector
p28_propro_p28
PMID: 17621314, 12925853
Similarly to ST2, this suggests that SIGIRR acts on the MyD88-dependent pathway as SIGIRR has been shown to form complexes with IL-1 receptor complex molecules, IRAK and TRAF-6 upon IL-1 stimulation in vitro.
c86 cso30:c:InputProcess connector
c176 cso30:c:InputProcess connector
c85 cso30:c:OutputProcess connector
p29_propro_p29
PMID: 17621314, 12925853
Similarly to ST2, this suggests that SIGIRR acts on the MyD88-dependent pathway as SIGIRR has been shown to form complexes with IL-1 receptor complex molecules, IRAK and TRAF-6 upon IL-1 stimulation in vitro.
PMID: 17621314, 10854325
Toll-interacting protein (Tollip) is a protein which interacts with the IL-1R accessory protein and is responsible for bringing IRAK to the receptor complex.
c87 cso30:c:InputProcess connector
c90 cso30:c:InputProcess connector
c89 cso30:c:InputProcess connector
c88 cso30:c:OutputProcess connector
p30_propro_p30
PMID: 17621314, 12925853
Similarly to ST2, this suggests that SIGIRR acts on the MyD88-dependent pathway as SIGIRR has been shown to form complexes with IL-1 receptor complex molecules, IRAK and TRAF-6 upon IL-1 stimulation in vitro.
PMID: 17621314
The exact mechanism of how TRAF-6 is targeted for the negative regulation of TLR-mediated signalling by FLN29 is undefined, however, it is suggested that FLN29 may inhibit downstream of TRAF-6 based on current findings.
c91 cso30:c:InputProcess connector
c92 cso30:c:InputProcess connector
c347 cso30:c:InputInhibitor connector
c93 cso30:c:OutputProcess connector
p31_propro_p31
PMID: 17621314, 12925853
Similarly to ST2, this suggests that SIGIRR acts on the MyD88-dependent pathway as SIGIRR has been shown to form complexes with IL-1 receptor complex molecules, IRAK and TRAF-6 upon IL-1 stimulation in vitro.
c94 cso30:c:InputProcess connector
c95 cso30:c:InputProcess connector
c96 cso30:c:OutputProcess connector
p32_propro_p32
PMID: 17621314, 14715412
It was also shown that the overexpression of SIGIRR in bone marrow-derived DCs leads to the inhibition of IL-1 and -18-mediated activation of NF-kappaB.
PMID: 17621314, 15852007
This was also observed in vivo as NF-kappaB activation was downregulated.
PMID: 17621314, 15125834, 15173580
For example, beta-arrestin-1 and beta-arrestin-2 have been shown to directly interact with IkappaB-alpha, preventing its phosphorylation and subsequent degradation, as well as blocking TNF-induced phosphorylation and degradation of IkappaB-alpha.
PMID: 17621314, 15125834, 15173580
beta-arrestin-1 and beta-arrestin-2 have recently been identified as negative regulators of TLR-IL-1R-mediated signalling pathways augmenting NF-kappaB activation.
c97 cso30:c:InputProcess connector
c104 cso30:c:InputAssociation connector
c105 cso30:c:InputInhibitor connector
c113 cso30:c:InputInhibitor connector
c273 cso30:c:InputInhibitor connector
c278 cso30:c:InputInhibitor connector
c333 cso30:c:InputInhibitor connector
c98 cso30:c:OutputProcess connector
p33_propro_p33
PMID: 17621314, 15589175
After initial activation of the TLR signalling pathways, TRAILR appears to stabilize IkappaB-alpha resulting in the decrease of nuclear translocation of NF-kappaB.
PMID: 17621314, 15334086
A20, was originally associated with TNF mediated NF-kappaB activation, but has also been identified as a cysteine protease de-ubiquitylating protein able to prevent TLR signalling via TRAF-6. Ablation of TLR-mediated signalling is the result of the cleavage of a polyubiquitin chain in TRAF-6 that in turn inhibits NFkappaB translocation to the nucleus.
c99 cso30:c:InputProcess connector
c117 cso30:c:InputInhibitor connector
c100 cso30:c:OutputProcess connector
c101 cso30:c:OutputProcess connector
p34_propro_p34
PMID: 17621314, 15334086
A20, was originally associated with TNF mediated NF-kappaB activation, but has also been identified as a cysteine protease de-ubiquitylating protein able to prevent TLR signalling via TRAF-6. Ablation of TLR-mediated signalling is the result of the cleavage of a polyubiquitin chain in TRAF-6 that in turn inhibits NFkappaB translocation to the nucleus.
c102 cso30:c:InputProcess connector
c103 cso30:c:OutputProcess connector
p35_propro_p35
PMID: 17621314, 16426569
This study showed that sST2 suppressed the production of IL-6, IL-1beta and TNF-alpha by binding to THP-1 cells, in turn reducing the binding affinity of NF-kappaB to the IL-6 promoter, leading to the degradation of IkappaB following LPS stimulation.
c121 cso30:c:InputAssociation connector
c122 cso30:c:OutputProcess connector
p36_propro_p36
PMID: 17621314, 16426569
This study showed that sST2 suppressed the production of IL-6, IL-1beta and TNF-alpha by binding to THP-1 cells, in turn reducing the binding affinity of NF-kappaB to the IL-6 promoter, leading to the degradation of IkappaB following LPS stimulation.
PMID: 17621314, 11986301
sTLR-2 was found to inhibit IL-8 and tumour necrosis factor (TNF) through the direct interaction with co-receptor sCD14 following stimulation with bacterial lipopeptide.
PMID: 17621314, 16230348
Upon stimulation with PGN, MALP-2 and Pam3CSK-4 (ligands of TLR-2), cells displayed an enhanced activation and expression of NF-kappaB, TNF-alpha, IL-1beta and IL-8.
c125 cso30:c:InputAssociation connector
c146 cso30:c:InputInhibitor connector
c123 cso30:c:OutputProcess connector
p37_propro_p37
PMID: 17621314, 16426569
This study showed that sST2 suppressed the production of IL-6, IL-1beta and TNF-alpha by binding to THP-1 cells, in turn reducing the binding affinity of NF-kappaB to the IL-6 promoter, leading to the degradation of IkappaB following LPS stimulation.
PMID: 17621314, 16230348
Upon stimulation with PGN, MALP-2 and Pam3CSK-4 (ligands of TLR-2), cells displayed an enhanced activation and expression of NF-kappaB, TNF-alpha, IL-1beta and IL-8.
c126 cso30:c:InputAssociation connector
c426 cso30:c:OutputProcess connector
p39_propro_p39
PMID: 17621314, 16303092
In order for inhibitory effects to be exerted by RP105, it requires its own coreceptor MD1 before an interaction with the TLR-4/MD2 complex is possible.
c106 cso30:c:InputProcess connector
c107 cso30:c:InputProcess connector
c108 cso30:c:OutputProcess connector
p40_propro_p40
PMID: 17621314, 16303092
In order for inhibitory effects to be exerted by RP105, it requires its own coreceptor MD1 before an interaction with the TLR-4/MD2 complex is possible.
PMID: 17621314, 16303092
Divanovic et al., found that upon stimulation with LPS, RP105 directly interacts with the TLR-4/MD2 complex sequestering sites available for LPS binding.
c109 cso30:c:InputProcess connector
c110 cso30:c:InputProcess connector
c112 cso30:c:InputAssociation connector
c111 cso30:c:OutputProcess connector
p41_propro_p41
PMID: 17621314, 15589175
After initial activation of the TLR signalling pathways, TRAILR appears to stabilize IkappaB-alpha resulting in the decrease of nuclear translocation of NF-kappaB.
c114 cso30:c:InputProcess connector
c115 cso30:c:InputProcess connector
c116 cso30:c:OutputProcess connector
p42_propro_p42
PMID: 17621314, 16426569
This study showed that sST2 suppressed the production of IL-6, IL-1beta and TNF-alpha by binding to THP-1 cells, in turn reducing the binding affinity of NF-kappaB to the IL-6 promoter, leading to the degradation of IkappaB following LPS stimulation.
c118 cso30:c:InputProcess connector
c119 cso30:c:InputProcess connector
c136 cso30:c:InputInhibitor connector
c120 cso30:c:OutputProcess connector
p43_propro_p43
PMID: 17621314, 16426569
This study showed that sST2 suppressed the production of IL-6, IL-1beta and TNF-alpha by binding to THP-1 cells, in turn reducing the binding affinity of NF-kappaB to the IL-6 promoter, leading to the degradation of IkappaB following LPS stimulation.
PMID: 17621314, 16670302
PI3K class I enzymes were shown to affect NF-kappaB activation and IL-12 production, where as the class III PI3Ks were shown to be involved in both NF-kappaB activation as well as the production of IL-6, IL-12 and TNF-alpha.
PMID: 17621314, 16670302
In recent studies by Kuo et al., they demonstrated that the class I and class III PI3K enzymes have distinct negative regulatory roles in TLR signalling in response to CpG DNA/ODN.
c130 cso30:c:InputAssociation connector
c133 cso30:c:InputInhibitor connector
c305 cso30:c:InputInhibitor connector
c127 cso30:c:OutputProcess connector
p44_propro_p44
PMID: 17621314, 16426569
This study showed that sST2 suppressed the production of IL-6, IL-1beta and TNF-alpha by binding to THP-1 cells, in turn reducing the binding affinity of NF-kappaB to the IL-6 promoter, leading to the degradation of IkappaB following LPS stimulation.
PMID: 17621314, 16670302
PI3K class I enzymes were shown to affect NF-kappaB activation and IL-12 production, where as the class III PI3Ks were shown to be involved in both NF-kappaB activation as well as the production of IL-6, IL-12 and TNF-alpha.
PMID: 17621314, 16670302
In recent studies by Kuo et al., they demonstrated that the class I and class III PI3K enzymes have distinct negative regulatory roles in TLR signalling in response to CpG DNA/ODN.
PMID: 17621314, 16221674
Mashima et al., found FLN29 overexpression in macrophage RAW cells stimulated with LPS caused a significant decrease in TNF-alpha and nitric oxide activation and production.
c131 cso30:c:InputAssociation connector
c134 cso30:c:InputInhibitor connector
c304 cso30:c:InputInhibitor connector
c348 cso30:c:InputInhibitor connector
c129 cso30:c:OutputProcess connector
p45_propro_p45
PMID: 17621314, 16426569
This study showed that sST2 suppressed the production of IL-6, IL-1beta and TNF-alpha by binding to THP-1 cells, in turn reducing the binding affinity of NF-kappaB to the IL-6 promoter, leading to the degradation of IkappaB following LPS stimulation.
c135 cso30:c:InputInhibitor connector
c425 cso30:c:InputAssociation connector
c128 cso30:c:OutputProcess connector
p46_propro_p46
c137 cso30:c:InputProcess connector
c138 cso30:c:InputProcess connector
c139 cso30:c:OutputProcess connector
p47_propro_p47
PMID: 17621314, 16286016
It must be noted that there are conflicting reports on the actions of ST2, as Schmitz et al. recently described that ST2 was a receptor for the recently identified member of the IL-1 family namely IL-33, which exerts its biological effects via ST2 enhancing activation of NF-kappaB and MAPK.
PMID: 17621314, 15125834, 15173580
For example, beta-arrestin-1 and beta-arrestin-2 have been shown to directly interact with IkappaB-alpha, preventing its phosphorylation and subsequent degradation, as well as blocking TNF-induced phosphorylation and degradation of IkappaB-alpha.
c140 cso30:c:InputProcess connector
c142 cso30:c:InputAssociation connector
c274 cso30:c:InputInhibitor connector
c280 cso30:c:InputInhibitor connector
c141 cso30:c:OutputProcess connector
p38_propro_p38
PMID: 17621314, 11120784
It was demonstrated in mouse models that the presence of sTLR-4 following LPS stimulation inhibited NF-kappaB activation in vitro.
c147 cso30:c:InputProcess connector
c149 cso30:c:InputProcess connector
c148 cso30:c:OutputProcess connector
p50_propro_p50
PMID: 17621314
The treatment of cells with LPS resulted in significantly increased levels of SARM proteins, suggesting a mechanism for how SARM is involved in specifically regulating TRIF-dependent TLR-3 and TLR-4 inflammatory esponses through a negative-feedback mechanism.
c154 cso30:c:InputAssociation connector
c155 cso30:c:InputAssociation connector
c153 cso30:c:OutputProcess connector
p51_propro_p51
PMID: 17621314
To date, it is still unclear in regards to the exact mechanism of how SARM inhibits TRIF function, however, it can be hypothesized from finding by Bowie and colleagues, who demonstrated that SARM and TRIF weakly interact in resting cells and upon LPS stimulation, increase in stability possibly preventing the recruitment of downstream effector molecules to TRIF.
c156 cso30:c:InputProcess connector
c158 cso30:c:InputProcess connector
c159 cso30:c:InputAssociation connector
c157 cso30:c:OutputProcess connector
p52_propro_p52
PMID: 17621314, 15082713
IRAK-2a and IRAK-2b were found in overexpression studies to enhance NFkappaB activation.
PMID: 17621314, 15082713
The overexpression of IRAK-2c and IRAK-2d, which lack the N-terminal DD, were shown in fibroblasts to have inhibitory effects on NF-kappaB activation following LPS stimulation.
PMID: 17621314, 15125834, 15173580
For example, beta-arrestin-1 and beta-arrestin-2 have been shown to directly interact with IkappaB-alpha, preventing its phosphorylation and subsequent degradation, as well as blocking TNF-induced phosphorylation and degradation of IkappaB-alpha.
c162 cso30:c:InputAssociation connector
c164 cso30:c:InputProcess connector
c168 cso30:c:InputInhibitor connector
c170 cso30:c:InputInhibitor connector
c172 cso30:c:InputAssociation connector
c275 cso30:c:InputInhibitor connector
c279 cso30:c:InputInhibitor connector
c165 cso30:c:OutputProcess connector
p53_propro_p53
PMID: 17621314, 15082713
IRAK-2a and IRAK-2b were found in overexpression studies to enhance NFkappaB activation.
PMID: 17621314, 15082713
The overexpression of IRAK-2c and IRAK-2d, which lack the N-terminal DD, were shown in fibroblasts to have inhibitory effects on NF-kappaB activation following LPS stimulation.
PMID: 17621314, 15125834, 15173580
For example, beta-arrestin-1 and beta-arrestin-2 have been shown to directly interact with IkappaB-alpha, preventing its phosphorylation and subsequent degradation, as well as blocking TNF-induced phosphorylation and degradation of IkappaB-alpha.
c163 cso30:c:InputAssociation connector
c166 cso30:c:InputProcess connector
c169 cso30:c:InputInhibitor connector
c171 cso30:c:InputInhibitor connector
c173 cso30:c:InputAssociation connector
c281 cso30:c:InputInhibitor connector
c167 cso30:c:OutputProcess connector
p54_propro_p54
PMID: 17621314, 10854325
Toll-interacting protein (Tollip) is a protein which interacts with the IL-1R accessory protein and is responsible for bringing IRAK to the receptor complex.
c84 cso30:c:InputProcess connector
c175 cso30:c:InputProcess connector
c174 cso30:c:OutputProcess connector
p55_propro_p55
PMID: 17621314, 11751856
There are three known isoforms of Tollip, however, Tollip-1 has been shown to bind TLR-2 and TLR-4, and in overexpression studies leads to the subsequent inhibition of NF-kappaB activation.
c177 cso30:c:InputProcess connector
c178 cso30:c:InputProcess connector
c179 cso30:c:OutputProcess connector
p56_propro_p56
PMID: 17621314, 11751856
There are three known isoforms of Tollip, however, Tollip-1 has been shown to bind TLR-2 and TLR-4, and in overexpression studies leads to the subsequent inhibition of NF-kappaB activation.
c180 cso30:c:InputProcess connector
c181 cso30:c:InputProcess connector
c182 cso30:c:OutputProcess connector
p57_propro_p57
PMID: 17621314, 11751856
Tollip also interacts with IRAK-1 leading to a decrease in IRAK-1 autophosphorylation and NF-kappaB activation.
c184 cso30:c:InputProcess connector
c183 cso30:c:InputProcess connector
c185 cso30:c:OutputProcess connector
p58_propro_p58
PMID: 17621314, 11751856
Tollip also interacts with IRAK-1 leading to a decrease in IRAK-1 autophosphorylation and NF-kappaB activation.
PMID: 17621314, 11751856
There are three known isoforms of Tollip, however, Tollip-1 has been shown to bind TLR-2 and TLR-4, and in overexpression studies leads to the subsequent inhibition of NF-kappaB activation.
PMID: 17621314, 15334086
A20, was originally associated with TNF mediated NF-kappaB activation, but has also been identified as a cysteine protease de-ubiquitylating protein able to prevent TLR signalling via TRAF-6. Ablation of TLR-mediated signalling is the result of the cleavage of a polyubiquitin chain in TRAF-6 that in turn inhibits NFkappaB translocation to the nucleus.
PMID: 17621314
Investigators identified that SOCS-1 directly inhibits Mal-dependent p65 phosphorylation and subsequent NF-kappaB transactivation.
PMID: 17621314, 15125834, 15173580
For example, beta-arrestin-1 and beta-arrestin-2 have been shown to directly interact with IkappaB-alpha, preventing its phosphorylation and subsequent degradation, as well as blocking TNF-induced phosphorylation and degradation of IkappaB-alpha.
PMID: 17621314, 15125834, 15173580
beta-arrestin-1 and beta-arrestin-2 have recently been identified as negative regulators of TLR-IL-1R-mediated signalling pathways augmenting NF-kappaB activation.
PMID: 17621314, 16378096
The binding of beta-arrestins to the TRAF-N domain in TRAF-6 prevents autoubiquitination, thus preventing downstream activation of NF-kappaB and AP- 1 Wang et al.
PMID: 17621314, 16670302
PI3K class I enzymes were shown to affect NF-kappaB activation and IL-12 production, where as the class III PI3Ks were shown to be involved in both NF-kappaB activation as well as the production of IL-6, IL-12 and TNF-alpha.
PMID: 17621314, 16670302
In recent studies by Kuo et al., they demonstrated that the class I and class III PI3K enzymes have distinct negative regulatory roles in TLR signalling in response to CpG DNA/ODN.
PMID: 17621314, 10385526, 11390377
LIND has been identified as an LPS-inducible A20-binding inhibitor of NFkappa-B and shares sequence homology to A20-binding inhibitor of NF-kappaB activation (ABIN)1 and ABIN-2.
PMID: 17621314, 17088249
Subsequent coexpression studies using MyD88, IRAK-1, TRAF-6 and downstream IKKbeta with ABIN-3 revealed that ABIN-3 inhibits MyD88, IRAK-1 and TRAF-6-mediated NF-kappaB activation, however has no effect on IKKbeta induced activation.
PMID: 17621314
Further investigations by Wang et al. revealed that Fliih was able to inhibit TLR-4MyD88-dependent activation of NF-kappaB.
PMID: 17621314
Furthermore, overexpression studies in HEK-293 cells cotransfected with TLR-2, TLR-3, TLR-4 and TLR-9, stimulated with their appropriate ligands and increasing doses of TRAF-4, resulted in luciferase analysis showing a decrease in activation of both NF-kappaB and the IFN-beta promoter, but not in TNF-alpha receptor-mediated signalling.
c187 cso30:c:InputProcess connector
c190 cso30:c:InputInhibitor connector
c191 cso30:c:InputInhibitor connector
c192 cso30:c:InputInhibitor connector
c230 cso30:c:InputInhibitor connector
c271 cso30:c:InputInhibitor connector
c276 cso30:c:InputInhibitor connector
c282 cso30:c:InputInhibitor connector
c299 cso30:c:InputInhibitor connector
c302 cso30:c:InputInhibitor connector
c329 cso30:c:InputInhibitor connector
c332 cso30:c:InputInhibitor connector
c338 cso30:c:InputInhibitor connector
c413 cso30:c:InputAssociation connector
c503 cso30:c:InputInhibitor connector
c188 cso30:c:OutputProcess connector
p59_propro_p59
PMID: 17621314
With decreasing levels of IRAK-1 phosphorylation, it has been observed there is an increase in Tollip phosphorylation.
c193 cso30:c:InputProcess connector
c194 cso30:c:OutputProcess connector
p60_propro_p60
PMID: 17621314, 11751856
This is though to be a mechanism that allows the release of Tollip from the Tollip/IRAK-1 complex resulting in the termination of its negative regulatory actions.
c195 cso30:c:InputProcess connector
c196 cso30:c:OutputProcess connector
c197 cso30:c:OutputProcess connector
p61_propro_p61
PMID: 17621314, 1381359, 2118515
A20 is a zinc ring finger protein which is expressed in numerous cell types and rapidly increases in expression in response to LPS and TNF, implicating it as a possible regulator of inflammatory responses.
c202 cso30:c:InputAssociation connector
c200 cso30:c:OutputProcess connector
p62_propro_p62
PMID: 17621314, 1381359, 2118515
A20 is a zinc ring finger protein which is expressed in numerous cell types and rapidly increases in expression in response to LPS and TNF, implicating it as a possible regulator of inflammatory responses.
c199 cso30:c:InputAssociation connector
c201 cso30:c:OutputProcess connector
p63_propro_p63
PMID: 17621314, 15334086
A20, was originally associated with TNF mediated NF-kappaB activation, but has also been identified as a cysteine protease de-ubiquitylating protein able to prevent TLR signalling via TRAF-6. Ablation of TLR-mediated signalling is the result of the cleavage of a polyubiquitin chain in TRAF-6 that in turn inhibits NFkappaB translocation to the nucleus.
PMID: 17621314, 16378096
The binding of beta-arrestins to the TRAF-N domain in TRAF-6 prevents autoubiquitination, thus preventing downstream activation of NF-kappaB and AP- 1 Wang et al.
PMID: 17621314, 11057907
Ubc13 E2 ubiquitin-conjugating enzyme is known to olyubiquitinate TRAF-2 and TRAF-6 through their attached K63 polyubiquitin chains.
c198 cso30:c:InputProcess connector
c204 cso30:c:InputInhibitor connector
c289 cso30:c:InputInhibitor connector
c290 cso30:c:InputInhibitor connector
c457 cso30:c:InputAssociation connector
c203 cso30:c:OutputProcess connector
p64_propro_p64
PMID: 17621314, 15107846
Triad3A when overexpressed results in substantial degradation of TLR-4 and TLR-9, which lead to a decrease in signal transduction, but did not effect TLR-2 or TLR-3 mediated signalling.
c206 cso30:c:InputProcess connector
c207 cso30:c:InputAssociation connector
c209 cso30:c:OutputProcess connector
p65_propro_p65
PMID: 17621314, 15107846
Triad3A when overexpressed results in substantial degradation of TLR-4 and TLR-9, which lead to a decrease in signal transduction, but did not effect TLR-2 or TLR-3 mediated signalling.
c205 cso30:c:InputProcess connector
c208 cso30:c:InputAssociation connector
c210 cso30:c:OutputProcess connector
p66_propro_p66
PMID: 17621314, 16968706
Recent studies have also suggested that Triad3A is able to target other TIR domain-containing adaptors including RIP-1, TRIF and Mal.
c211 cso30:c:InputProcess connector
c213 cso30:c:InputAssociation connector
c212 cso30:c:OutputProcess connector
p67_propro_p67
PMID: 17621314, 16968706
Recent studies have also suggested that Triad3A is able to target other TIR domain-containing adaptors including RIP-1, TRIF and Mal.
c214 cso30:c:InputProcess connector
c215 cso30:c:InputAssociation connector
c218 cso30:c:OutputProcess connector
p68_propro_p68
PMID: 17621314, 16968706
Recent studies have also suggested that Triad3A is able to target other TIR domain-containing adaptors including RIP-1, TRIF and Mal.
c216 cso30:c:InputProcess connector
c217 cso30:c:OutputProcess connector
p69_propro_p69
PMID: 17621314, 12433365, 12433373
LPS induces SOC-1 expression in macrophages and SOCS-1-/- mice are hypersensitive to LPS-induced endotoxic shock.
c220 cso30:c:InputAssociation connector
c219 cso30:c:OutputProcess connector
p70_propro_p70
PMID: 17621314, 16415872
Recent investigations by Mansell et al. have shown the mechanism for SOCS-1 directly regulating TLR-2 and TLR-4-mediated signalling by argeting Mal for polyubiquitination and subsequent proteosomal degradation.
c226 cso30:c:InputProcess connector
c222 cso30:c:OutputProcess connector
p71_propro_p71
PMID: 17621314, 16415872
Recent investigations by Mansell et al. have shown the mechanism for SOCS-1 directly regulating TLR-2 and TLR-4-mediated signalling by argeting Mal for polyubiquitination and subsequent proteosomal degradation.
c224 cso30:c:InputProcess connector
c225 cso30:c:OutputProcess connector
c229 cso30:c:OutputProcess connector
p72_propro_p72
PMID: 17621314, 16415872
Activation of Brunton’s tyrosine kinase is critical for mediating the Mal and SOCS-1 interaction (acting as an E3 ubiquitin ligase) resulting in Mal polyubiquitination and subsequent proteosomal degradation.
c221 cso30:c:InputProcess connector
c223 cso30:c:InputProcess connector
c228 cso30:c:InputAssociation connector
c227 cso30:c:OutputProcess connector
p73_propro_p73
PMID: 17621314
The coupling of beta-arrestins to the GPCRs occurs following binding of a ligand to the appropriate receptor.
c231 cso30:c:InputProcess connector
c233 cso30:c:InputProcess connector
c232 cso30:c:OutputProcess connector
p74_propro_p74
PMID: 17621314, 10995467, 10725339, 11861753
Beta-arrestins are adaptor molecules that are able to form complexes with G proteincoupled receptors (GPCRs), are involved in the desensitization and endocytosis of various cell surface receptors as well as being shown to bind molecules involved in the MAP signalling pathway including Erk-1/-2, JNK, p38 and members of the Src kinase family.
c234 cso30:c:InputProcess connector
c235 cso30:c:InputProcess connector
c236 cso30:c:OutputProcess connector
p75_propro_p75
PMID: 17621314, 10995467, 10725339, 11861753
Beta-arrestins are adaptor molecules that are able to form complexes with G proteincoupled receptors (GPCRs), are involved in the desensitization and endocytosis of various cell surface receptors as well as being shown to bind molecules involved in the MAP signalling pathway including Erk-1/-2, JNK, p38 and members of the Src kinase family.
PMID: 17621314
This results in the interaction of b-arrestins with the signalling complexes and the subsequent mediation of phosphorylation and ubiquitination of MAP kinase target molecules.
c241 cso30:c:InputProcess connector
c237 cso30:c:InputProcess connector
c242 cso30:c:OutputProcess connector
p76_propro_p76
PMID: 17621314, 10995467, 10725339, 11861753
Beta-arrestins are adaptor molecules that are able to form complexes with G proteincoupled receptors (GPCRs), are involved in the desensitization and endocytosis of various cell surface receptors as well as being shown to bind molecules involved in the MAP signalling pathway including Erk-1/-2, JNK, p38 and members of the Src kinase family.
PMID: 17621314
This results in the interaction of b-arrestins with the signalling complexes and the subsequent mediation of phosphorylation and ubiquitination of MAP kinase target molecules.
c243 cso30:c:InputProcess connector
c238 cso30:c:InputProcess connector
c244 cso30:c:OutputProcess connector
p77_propro_p77
PMID: 17621314, 10995467, 10725339, 11861753
Beta-arrestins are adaptor molecules that are able to form complexes with G proteincoupled receptors (GPCRs), are involved in the desensitization and endocytosis of various cell surface receptors as well as being shown to bind molecules involved in the MAP signalling pathway including Erk-1/-2, JNK, p38 and members of the Src kinase family.
PMID: 17621314
This results in the interaction of b-arrestins with the signalling complexes and the subsequent mediation of phosphorylation and ubiquitination of MAP kinase target molecules.
c245 cso30:c:InputProcess connector
c239 cso30:c:InputProcess connector
c246 cso30:c:OutputProcess connector
p78_propro_p78
PMID: 17621314, 10995467, 10725339, 11861753
Beta-arrestins are adaptor molecules that are able to form complexes with G proteincoupled receptors (GPCRs), are involved in the desensitization and endocytosis of various cell surface receptors as well as being shown to bind molecules involved in the MAP signalling pathway including Erk-1/-2, JNK, p38 and members of the Src kinase family.
PMID: 17621314
This results in the interaction of b-arrestins with the signalling complexes and the subsequent mediation of phosphorylation and ubiquitination of MAP kinase target molecules.
c247 cso30:c:InputProcess connector
c240 cso30:c:InputProcess connector
c248 cso30:c:OutputProcess connector
p79_propro_p79
PMID: 17621314
This results in the interaction of b-arrestins with the signalling complexes and the subsequent mediation of phosphorylation and ubiquitination of MAP kinase target molecules.
c249 cso30:c:InputProcess connector
c250 cso30:c:OutputProcess connector
p80_propro_p80
PMID: 17621314
This results in the interaction of b-arrestins with the signalling complexes and the subsequent mediation of phosphorylation and ubiquitination of MAP kinase target molecules.
c251 cso30:c:InputProcess connector
c252 cso30:c:OutputProcess connector
p81_propro_p81
PMID: 17621314
This results in the interaction of b-arrestins with the signalling complexes and the subsequent mediation of phosphorylation and ubiquitination of MAP kinase target molecules.
c253 cso30:c:InputProcess connector
c254 cso30:c:OutputProcess connector
p82_propro_p82
PMID: 17621314
This results in the interaction of b-arrestins with the signalling complexes and the subsequent mediation of phosphorylation and ubiquitination of MAP kinase target molecules.
c255 cso30:c:InputProcess connector
c256 cso30:c:OutputProcess connector
p83_propro_p83
PMID: 17621314
This results in the interaction of b-arrestins with the signalling complexes and the subsequent mediation of phosphorylation and ubiquitination of MAP kinase target molecules.
c257 cso30:c:InputProcess connector
c258 cso30:c:OutputProcess connector
p84_propro_p84
PMID: 17621314
This results in the interaction of b-arrestins with the signalling complexes and the subsequent mediation of phosphorylation and ubiquitination of MAP kinase target molecules.
c259 cso30:c:InputProcess connector
c260 cso30:c:OutputProcess connector
p85_propro_p85
PMID: 17621314
This results in the interaction of b-arrestins with the signalling complexes and the subsequent mediation of phosphorylation and ubiquitination of MAP kinase target molecules.
c261 cso30:c:InputProcess connector
c262 cso30:c:OutputProcess connector
p86_propro_p86
PMID: 17621314
This results in the interaction of b-arrestins with the signalling complexes and the subsequent mediation of phosphorylation and ubiquitination of MAP kinase target molecules.
c263 cso30:c:InputProcess connector
c264 cso30:c:OutputProcess connector
p87_propro_p87
PMID: 17621314, 15125834, 15173580
For example, beta-arrestin-1 and beta-arrestin-2 have been shown to directly interact with IkappaB-alpha, preventing its phosphorylation and subsequent degradation, as well as blocking TNF-induced phosphorylation and degradation of IkappaB-alpha.
c265 cso30:c:InputProcess connector
c266 cso30:c:InputProcess connector
c267 cso30:c:OutputProcess connector
p88_propro_p88
PMID: 17621314, 15125834, 15173580
For example, beta-arrestin-1 and beta-arrestin-2 have been shown to directly interact with IkappaB-alpha, preventing its phosphorylation and subsequent degradation, as well as blocking TNF-induced phosphorylation and degradation of IkappaB-alpha.
c268 cso30:c:InputProcess connector
c270 cso30:c:InputProcess connector
c269 cso30:c:OutputProcess connector
p49_propro_p49
PMID: 17621314, 15125834, 15173580
For example, beta-arrestin-1 and beta-arrestin-2 have been shown to directly interact with IkappaB-alpha, preventing its phosphorylation and subsequent degradation, as well as blocking TNF-induced phosphorylation and degradation of IkappaB-alpha.
c150 cso30:c:InputProcess connector
c152 cso30:c:InputAssociation connector
c272 cso30:c:InputInhibitor connector
c277 cso30:c:InputInhibitor connector
c151 cso30:c:OutputProcess connector
p89_propro_p89
PMID: 17621314, 16378096
Wang et al., demonstrated using overexpression studies in HEK-293 cells, that beta-arrestin-1 and beta-arrestin-2 co-immunoprecipitated with TRAF-6, showing direct interactions.
c283 cso30:c:InputProcess connector
c285 cso30:c:InputProcess connector
c287 cso30:c:OutputProcess connector
p90_propro_p90
PMID: 17621314, 16378096
Wang et al., demonstrated using overexpression studies in HEK-293 cells, that beta-arrestin-1 and beta-arrestin-2 co-immunoprecipitated with TRAF-6, showing direct interactions.
c284 cso30:c:InputProcess connector
c286 cso30:c:InputProcess connector
c288 cso30:c:OutputProcess connector
p91_propro_p91
PMID: 17621314, 16378096
The binding of beta-arrestins to the TRAF-N domain in TRAF-6 prevents autoubiquitination, thus preventing downstream activation of NF-kappaB and AP- 1 Wang et al.
c291 cso30:c:InputProcess connector
c401 cso30:c:InputAssociation connector
c292 cso30:c:OutputProcess connector
p92_propro_p92
PMID: 17621314, 17418896
Further studies also revealed that both bera-arrestin-1 and beta-arrestin-2 depletion using siRNA transfection resulted in the marked decrease of IL-8 production following LPS treatment.
c294 cso30:c:InputAssociation connector
c296 cso30:c:InputAssociation connector
c297 cso30:c:InputInhibitor connector
c298 cso30:c:InputInhibitor connector
c295 cso30:c:OutputProcess connector
p93_propro_p93
PMID: 17621314, 16670302
PI3K class I enzymes were shown to affect NF-kappaB activation and IL-12 production, where as the class III PI3Ks were shown to be involved in both NF-kappaB activation as well as the production of IL-6, IL-12 and TNF-alpha.
PMID: 17621314, 16670302
PI3K class I enzymes were shown to affect NF-kappaB activation and IL-12 production, where as the class III PI3Ks were shown to be involved in both NF-kappaB activation as well as the production of IL-6, IL-12 and TNF-alpha.
PMID: 17621314, 16670302
In recent studies by Kuo et al., they demonstrated that the class I and class III PI3K enzymes have distinct negative regulatory roles in TLR signalling in response to CpG DNA/ODN.
c301 cso30:c:InputAssociation connector
c303 cso30:c:InputInhibitor connector
c306 cso30:c:InputInhibitor connector
c300 cso30:c:OutputProcess connector
p94_propro_p94
PMID: 17621314, 15623538
TGF-beta1 inhibits TLR-4 expression by suppressing LPS-mediated responses and is also able to induce MyD88 degradation through interactions via its DD.
c307 cso30:c:InputProcess connector
c308 cso30:c:InputProcess connector
c309 cso30:c:OutputProcess connector
p95_propro_p95
PMID: 17621314, 15623538
TGF-beta1 inhibits TLR-4 expression by suppressing LPS-mediated responses and is also able to induce MyD88 degradation through interactions via its DD.
c310 cso30:c:InputProcess connector
c311 cso30:c:OutputProcess connector
c312 cso30:c:OutputProcess connector
p96_propro_p96
PMID: 17621314, 15330257
IL-10 is also shown to inhibit the production of pro-inflammatory cytokines through LPS, and in human DCs is known to downregulate IL-12 production through TLR-3- and TLR-4-mediated signalling.
c317 cso30:c:InputAssociation connector
c319 cso30:c:InputInhibitor connector
c321 cso30:c:InputAssociation connector
c314 cso30:c:OutputProcess connector
p97_propro_p97
PMID: 17621314, 15330257
IL-10 is also shown to inhibit the production of pro-inflammatory cytokines through LPS, and in human DCs is known to downregulate IL-12 production through TLR-3- and TLR-4-mediated signalling.
c316 cso30:c:InputAssociation connector
c318 cso30:c:InputAssociation connector
c320 cso30:c:InputInhibitor connector
c315 cso30:c:OutputProcess connector
p98_propro_p98
PMID: 17621314, 12161427
Previous studies have shown that ATF-3 is able to protect endothelial cells against TNF-induced apoptosis by decreasing p53 transcription.
c324 cso30:c:InputInhibitor connector
c322 cso30:c:OutputProcess connector
p99_propro_p99
PMID: 17621314, 12161427
Previous studies have shown that ATF-3 is able to protect endothelial cells against TNF-induced apoptosis by decreasing p53 transcription.
c323 cso30:c:InputAssociation connector
c325 cso30:c:InputInhibitor connector
p100_propro_p100
PMID: 17621314, 10385526, 11390377
LIND has been identified as an LPS-inducible A20-binding inhibitor of NFkappa-B and shares sequence homology to A20-binding inhibitor of NF-kappaB activation (ABIN)1 and ABIN-2.
c326 cso30:c:InputProcess connector
c327 cso30:c:InputProcess connector
c328 cso30:c:OutputProcess connector
p101_propro_p101
PMID: 17621314, 10385526, 11390377
LIND has been identified as an LPS-inducible A20-binding inhibitor of NFkappa-B and shares sequence homology to A20-binding inhibitor of NF-kappaB activation (ABIN)1 and ABIN-2.
c331 cso30:c:InputAssociation connector
c330 cso30:c:OutputProcess connector
p102_propro_p102
PMID: 17621314, 16424162
Flightless I homolog (Fliih), primarily expressed in the cytoplasm, was identified as a MyD88 interacting partner in murine macrophages stimulated with lipid A.
c334 cso30:c:InputProcess connector
c335 cso30:c:InputProcess connector
c337 cso30:c:InputAssociation connector
c336 cso30:c:OutputProcess connector
p103_propro_p103
PMID: 17621314, 16424162
Co-immunoprecipitation studies using HEK-293T cells expressing TLR-4 showed that Fliih directly interferes with the interaction of MyD88 and TLR-4 upon LPS stimulation.
c339 cso30:c:InputProcess connector
c341 cso30:c:InputProcess connector
c342 cso30:c:InputInhibitor connector
c340 cso30:c:OutputProcess connector
p104_propro_p104
PMID: 17621314
Further investigations using RAW cells overexpressing FLN29 showed an interaction with endogenous TRAF-6.
c343 cso30:c:InputProcess connector
c344 cso30:c:InputProcess connector
c345 cso30:c:OutputProcess connector
p105_propro_p105
PMID: 17621314, 16221674
Mashima et al., found FLN29 overexpression in macrophage RAW cells stimulated with LPS caused a significant decrease in TNF-alpha and nitric oxide activation and production.
c349 cso30:c:InputInhibitor connector
c351 cso30:c:InputAssociation connector
c350 cso30:c:OutputProcess connector
p106_propro_p106
PMID: 17621314, 16230348
Upon stimulation with PGN, MALP-2 and Pam3CSK-4 (ligands of TLR-2), cells displayed an enhanced activation and expression of NF-kappaB, TNF-alpha, IL-1beta and IL-8.
c352 cso30:c:InputProcess connector
c353 cso30:c:InputProcess connector
c354 cso30:c:OutputProcess connector
p107_propro_p107
PMID: 17621314, 16230348
Upon stimulation with PGN, MALP-2 and Pam3CSK-4 (ligands of TLR-2), cells displayed an enhanced activation and expression of NF-kappaB, TNF-alpha, IL-1beta and IL-8.
c355 cso30:c:InputProcess connector
c357 cso30:c:InputProcess connector
c356 cso30:c:OutputProcess connector
p108_propro_p108
PMID: 17621314, 16230348
Upon stimulation with PGN, MALP-2 and Pam3CSK-4 (ligands of TLR-2), cells displayed an enhanced activation and expression of NF-kappaB, TNF-alpha, IL-1beta and IL-8.
PMID: 17621314, 16230348
Yoshida et al. identified that CYLD is induced through recognition of TLR-2 ligands during bacterial infection, and is able to inhibit activation of both NF-kB and MAPK p38, leading to the subsequent inhibition of pro-inflammatory cytokines through a negative-feedback mechanism. .
c358 cso30:c:InputProcess connector
c360 cso30:c:InputAssociation connector
c367 cso30:c:InputInhibitor connector
c359 cso30:c:OutputProcess connector
p109_propro_p109
PMID: 17621314, 16230348
Upon stimulation with PGN, MALP-2 and Pam3CSK-4 (ligands of TLR-2), cells displayed an enhanced activation and expression of NF-kappaB, TNF-alpha, IL-1beta and IL-8.
PMID: 17621314, 11986301
sTLR-2 was found to inhibit IL-8 and tumour necrosis factor (TNF) through the direct interaction with co-receptor sCD14 following stimulation with bacterial lipopeptide.
c362 cso30:c:InputAssociation connector
c493 cso30:c:InputInhibitor connector
c361 cso30:c:OutputProcess connector
p110_propro_p110
PMID: 17621314, 16230348
Yoshida et al. identified that CYLD is induced through recognition of TLR-2 ligands during bacterial infection, and is able to inhibit activation of both NF-kB and MAPK p38, leading to the subsequent inhibition of pro-inflammatory cytokines through a negative-feedback mechanism. .
c364 cso30:c:InputAssociation connector
c363 cso30:c:OutputProcess connector
p111_propro_p111
PMID: 17621314, 16230348
Yoshida et al. identified that CYLD is induced through recognition of TLR-2 ligands during bacterial infection, and is able to inhibit activation of both NF-kB and MAPK p38, leading to the subsequent inhibition of pro-inflammatory cytokines through a negative-feedback mechanism. .
c366 cso30:c:InputAssociation connector
c365 cso30:c:OutputProcess connector
p113_propro_p113
PMID: 17621314
Further co-immunoprecipitation studies demonstrated interactions of CYLD with TRAF-6 and TRAF-7, and colocalization studies confirmed this finding.
c372 cso30:c:InputProcess connector
c373 cso30:c:InputProcess connector
c374 cso30:c:OutputProcess connector
p114_propro_p114
PMID: 17621314
Further co-immunoprecipitation studies demonstrated interactions of CYLD with TRAF-6 and TRAF-7, and colocalization studies confirmed this finding.
c375 cso30:c:InputProcess connector
c376 cso30:c:InputProcess connector
c377 cso30:c:OutputProcess connector
p115_propro_p115
PMID: 17621314, 10627275, 12184814
Eleven mammalian DUSPs have been identified to contain an MAPK binding domain and of those DUSP-1 and DUSP-2 (also known as phosphatase of activated cells-1 (PAC-1)) are most closely affiliated with immune cells.
c378 cso30:c:InputProcess connector
c379 cso30:c:InputProcess connector
c380 cso30:c:OutputProcess connector
p48_propro_p48
PMID: 17621314, 16286016
It must be noted that there are conflicting reports on the actions of ST2, as Schmitz et al. recently described that ST2 was a receptor for the recently identified member of the IL-1 family namely IL-33, which exerts its biological effects via ST2 enhancing activation of NF-kappaB and MAPK.
c143 cso30:c:InputProcess connector
c145 cso30:c:InputAssociation connector
c144 cso30:c:OutputProcess connector
p112_propro_p112
c368 cso30:c:InputProcess connector
c370 cso30:c:InputInhibitor connector
c371 cso30:c:InputAssociation connector
c369 cso30:c:OutputProcess connector
p116_propro_p116
PMID: 17621314, 12444149, 15590669, 15485842
DUSP-1 overexpression in vitro using macrophages was shown to inhibit phosphorylation of MAPK resulting in the decreased expression of pro-inflammatory cytokines TNF-alpha and IL-6 in response to various TLR ligands.
c381 cso30:c:InputProcess connector
c388 cso30:c:InputInhibitor connector
c189 cso30:c:InputAssociation connector
c382 cso30:c:OutputProcess connector
p117_propro_p117
PMID: 17621314, 12444149, 15590669, 15485842
DUSP-1 overexpression in vitro using macrophages was shown to inhibit phosphorylation of MAPK resulting in the decreased expression of pro-inflammatory cytokines TNF-alpha and IL-6 in response to various TLR ligands.
c385 cso30:c:InputAssociation connector
c384 cso30:c:OutputProcess connector
p118_propro_p118
PMID: 17621314, 12444149, 15590669, 15485842
DUSP-1 overexpression in vitro using macrophages was shown to inhibit phosphorylation of MAPK resulting in the decreased expression of pro-inflammatory cytokines TNF-alpha and IL-6 in response to various TLR ligands.
c386 cso30:c:InputAssociation connector
c387 cso30:c:OutputProcess connector
p119_propro_p119
PMID: 17621314
Furthermore, co-immunoprecipitation studies showed a physical interaction between DUSP-2 and p38, Jnk and Erk.
c389 cso30:c:InputProcess connector
c390 cso30:c:InputProcess connector
c391 cso30:c:OutputProcess connector
p120_propro_p120
PMID: 17621314
Furthermore, co-immunoprecipitation studies showed a physical interaction between DUSP-2 and p38, Jnk and Erk.
c392 cso30:c:InputProcess connector
c393 cso30:c:InputProcess connector
c394 cso30:c:OutputProcess connector
p121_propro_p121
PMID: 17621314
Furthermore, co-immunoprecipitation studies showed a physical interaction between DUSP-2 and p38, Jnk and Erk.
c396 cso30:c:InputProcess connector
c397 cso30:c:InputProcess connector
c395 cso30:c:OutputProcess connector
p123_propro_p123
PMID: 17621314
DUSP-2/PAC-1 is primarily known for its role in inactivating p38 and ERK in vitro.
c402 cso30:c:InputProcess connector
c405 cso30:c:InputInhibitor connector
c398 cso30:c:InputAssociation connector
c403 cso30:c:OutputProcess connector
p124_propro_p124
PMID: 17621314
Co-immunoprecipitation studies using the HEK-293-TLR-2 cells showed that CYLD acted as a negative regulator of the MAPK p38 pathway, as CYLD inhibited PGN-induced phosphorylation of IkappaB-alpha, MKK3/6 and p38.
c406 cso30:c:InputProcess connector
c408 cso30:c:InputAssociation connector
c409 cso30:c:InputInhibitor connector
c407 cso30:c:OutputProcess connector
p125_propro_p125
PMID: 17621314, 17157040
It was shown through a series of mutational analyses that SHP-2 could bind specifically to the N terminus of TBK-1 to exert inhibitory effects on downstream signalling, as the binding of SHP-2 to TBK-1 suppresses TBK-1-mediated phosphorylation and subsequent cytokine production.
c410 cso30:c:InputProcess connector
c411 cso30:c:InputProcess connector
c416 cso30:c:InputInhibitor connector
c412 cso30:c:OutputProcess connector
p126_propro_p126
PMID: 17621314, 17157040
It was shown through a series of mutational analyses that SHP-2 could bind specifically to the N terminus of TBK-1 to exert inhibitory effects on downstream signalling, as the binding of SHP-2 to TBK-1 suppresses TBK-1-mediated phosphorylation and subsequent cytokine production.
c293 cso30:c:InputProcess connector
c414 cso30:c:InputProcess connector
c415 cso30:c:OutputProcess connector
p127_propro_p127
PMID: 17621314
IRF-3 activation was also shown to be inhibited in the presence of SHP-2 as RAW cells transfected with increasing doses of SHP-2 dose dependently decreased IRF-3 activation.
c417 cso30:c:InputProcess connector
c421 cso30:c:InputAssociation connector
c423 cso30:c:InputInhibitor connector
c418 cso30:c:OutputProcess connector
p128_propro_p128
PMID: 17621314
IRF-3 activation was also shown to be inhibited in the presence of SHP-2 as RAW cells transfected with increasing doses of SHP-2 dose dependently decreased IRF-3 activation.
c419 cso30:c:InputProcess connector
c422 cso30:c:InputAssociation connector
c424 cso30:c:InputInhibitor connector
c420 cso30:c:OutputProcess connector
p129_propro_p129
PMID: 17621314, 17157040
SH-2 containing protein tyrosine phosphatase-2 (SHP-2) has been implicated as a negative regulator of IFN-beta production through TLR-3 and TLR-4-mediated signalling.
PMID: 17621314
This results in the inhibition of IRF-3 in response to TLR-3 and TLR-4.
c132 cso30:c:InputAssociation connector
c427 cso30:c:InputAssociation connector
c436 cso30:c:InputInhibitor connector
c124 cso30:c:OutputProcess connector
p130_propro_p130
PMID: 17621314, 16699525
Peptidyl-prolyl isomerase (Pin)-1, consisting of a short N-terminal domain and a catalytic C-terminal domain is only able to directly interact with IRF-3 after IRF-3 has been phosphorylated on Ser 339.
c428 cso30:c:InputProcess connector
c429 cso30:c:InputProcess connector
c430 cso30:c:OutputProcess connector
p131_propro_p131
PMID: 17621314
The mechanism involved in negatively regulating IRF-3 is achieved by Pin-1 binding directly to IRF-3 leading to its polyubiquitination and subsequent proteosomal degradation.
c431 cso30:c:InputProcess connector
c432 cso30:c:OutputProcess connector
p132_propro_p132
PMID: 17621314
The mechanism involved in negatively regulating IRF-3 is achieved by Pin-1 binding directly to IRF-3 leading to its polyubiquitination and subsequent proteosomal degradation.
c433 cso30:c:InputProcess connector
c434 cso30:c:OutputProcess connector
c435 cso30:c:OutputProcess connector
p133_propro_p133
PMID: 17621314, 14690596
Through mutational analyses of critical binding sites on the p65 subunit, the Thr254-Pro binding site was identified as critical for Pin-1 interactions.
c437 cso30:c:InputProcess connector
c439 cso30:c:InputProcess connector
c438 cso30:c:OutputProcess connector
p134_propro_p134
PMID: 17621314
Without interactions at Thr-254, p65 cannot be phosphorylated, resulting in the p65 protein being unstable for the subsequent translocation into the nucleus and its targeting for proteosomal degradation.
c442 cso30:c:InputProcess connector
c443 cso30:c:OutputProcess connector
c444 cso30:c:OutputProcess connector
p135_propro_p135
PMID: 17621314
Without interactions at Thr-254, p65 cannot be phosphorylated, resulting in the p65 protein being unstable for the subsequent translocation into the nucleus and its targeting for proteosomal degradation.
c440 cso30:c:InputProcess connector
c441 cso30:c:OutputProcess connector
p136_propro_p136
PMID: 17621314
Without interactions at Thr-254, p65 cannot be phosphorylated, resulting in the p65 protein being unstable for the subsequent translocation into the nucleus and its targeting for proteosomal degradation.
c445 cso30:c:InputProcess connector
c446 cso30:c:OutputProcess connector
p137_propro_p137
PMID: 17621314
Further studies looking at the negative regulatory effects of SOCS-1 on p65 showed that SOCS-1 binds in an area of close proximity to that of Pin-1.
c447 cso30:c:InputProcess connector
c449 cso30:c:InputProcess connector
c448 cso30:c:OutputProcess connector
p138_propro_p138
PMID: 17621314
As SOCS-1 is known to polyubiquitination p65 and suppress NF-kappaB activation, Ryo et al. wanted to investigate if SOCS-1 had any effect on the stability and ubiquitination of p65 in the presence of Pin-1.
PMID: 17621314
Overexpression studies both in vitro and in vivo of SOCS-1, SOCS-1 mutant and Pin-1 showed that Pin-1 protects p65 from SOCS-1 destabilization through blocking its degradation, and was also able to inhibit SOCS-1-mediated ubiquitination.
c450 cso30:c:InputProcess connector
c455 cso30:c:InputInhibitor connector
c451 cso30:c:OutputProcess connector
c452 cso30:c:OutputProcess connector
p139_propro_p139
PMID: 17621314
Overexpression studies both in vitro and in vivo of SOCS-1, SOCS-1 mutant and Pin-1 showed that Pin-1 protects p65 from SOCS-1 destabilization through blocking its degradation, and was also able to inhibit SOCS-1-mediated ubiquitination.
c453 cso30:c:InputProcess connector
c456 cso30:c:InputInhibitor connector
c454 cso30:c:OutputProcess connector
p141_propro_p141
PMID: 17621314, 11057907
Ubc13 E2 ubiquitin-conjugating enzyme is known to olyubiquitinate TRAF-2 and TRAF-6 through their attached K63 polyubiquitin chains.
c460 cso30:c:InputProcess connector
c462 cso30:c:InputAssociation connector
c461 cso30:c:OutputProcess connector
p142_propro_p142
PMID: 17621314
TRAF-6 and TRAF-2 are involved in the ubiquitination of downstream adaptor molecule NF-kappaB essential modulator (NEMO) in response to antigen receptor induced NF-kappaB activation.
c463 cso30:c:InputProcess connector
c465 cso30:c:InputAssociation connector
c464 cso30:c:OutputProcess connector
p143_propro_p143
PMID: 17621314
TRAF-6 and TRAF-2 are involved in the ubiquitination of downstream adaptor molecule NF-kappaB essential modulator (NEMO) in response to antigen receptor induced NF-kappaB activation.
c466 cso30:c:InputProcess connector
c468 cso30:c:InputAssociation connector
c467 cso30:c:OutputProcess connector
p122_propro_p122
PMID: 17621314
DUSP-2/PAC-1 is primarily known for its role in inactivating p38 and ERK in vitro.
c383 cso30:c:InputProcess connector
c400 cso30:c:InputAssociation connector
c404 cso30:c:InputInhibitor connector
c469 cso30:c:InputAssociation connector
c399 cso30:c:OutputProcess connector
p140_propro_p140
PMID: 17621314
Results indicated that phosphorylation of Jnk and p38 was significantly reduced in Ubc13f l/f l Cd19 Cre B cells upon stimulation with anti-IgM compared to wild type.
c458 cso30:c:InputProcess connector
c470 cso30:c:InputAssociation connector
c459 cso30:c:OutputProcess connector
p144_propro_p144
PMID: 17621314
Phosphorylation of signalling adaptor NEMO in vitro has been suggested to be dependent on Ubc13 under IL-1beta induction.
c471 cso30:c:InputProcess connector
c473 cso30:c:InputAssociation connector
c474 cso30:c:InputAssociation connector
c472 cso30:c:OutputProcess connector
p145_propro_p145
PMID: 17621314, 12974773
Studies have revealed that mycobacteria directly interact with DC-SIGN in order to regulate TLR-4 mediated signalling responses in DCs.
PMID: 17621314, 12974773
Specifically the ligand responsible for modulating TLR-4 responses is ManLAM, a cell-wall component of Mycobacterium tuberculosis. The mechanism by which ManLAM negatively regulates TLR-4 is by binding to DC-SIGN, impairing LPS-induced DC maturation and the marked increase of IL-10 that has known immunosuppressive properties.
c475 cso30:c:InputProcess connector
c476 cso30:c:InputProcess connector
c477 cso30:c:OutputProcess connector
p146_propro_p146
PMID: 17621314, 12974773
Specifically the ligand responsible for modulating TLR-4 responses is ManLAM, a cell-wall component of Mycobacterium tuberculosis. The mechanism by which ManLAM negatively regulates TLR-4 is by binding to DC-SIGN, impairing LPS-induced DC maturation and the marked increase of IL-10 that has known immunosuppressive properties.
c478 cso30:c:InputAssociation connector
c479 cso30:c:InputInhibitor connector
p147_propro_p147
PMID: 17621314, 12974773
Specifically the ligand responsible for modulating TLR-4 responses is ManLAM, a cell-wall component of Mycobacterium tuberculosis. The mechanism by which ManLAM negatively regulates TLR-4 is by binding to DC-SIGN, impairing LPS-induced DC maturation and the marked increase of IL-10 that has known immunosuppressive properties.
c481 cso30:c:InputAssociation connector
c482 cso30:c:InputAssociation connector
c480 cso30:c:OutputProcess connector
p148_propro_p148
c483 cso30:c:InputProcess connector
c485 cso30:c:InputAssociation connector
c484 cso30:c:OutputProcess connector
p149_propro_p149
PMID: 17621314, 17462920
ManLAM binds DC-SIGN in human DCs modulating TLR signalling by activating the serine and threonine kinase Raf-1, allowing the subsequent phosphorylation and acetylation of the p65 unit of NF-kappaB.
PMID: 17621314, 17462920
Further investigations revealed that the specific phosphorylation event of Ser 276 on p65 is critical for Raf-1-dependent acetylation and the prolonged transcription of the IL-10 gene.
c486 cso30:c:InputProcess connector
c488 cso30:c:InputAssociation connector
c487 cso30:c:OutputProcess connector
p150_propro_p150
PMID: 17621314, 17462920
ManLAM binds DC-SIGN in human DCs modulating TLR signalling by activating the serine and threonine kinase Raf-1, allowing the subsequent phosphorylation and acetylation of the p65 unit of NF-kappaB.
PMID: 17621314, 17462920
Further investigations revealed that the specific phosphorylation event of Ser 276 on p65 is critical for Raf-1-dependent acetylation and the prolonged transcription of the IL-10 gene.
c489 cso30:c:InputProcess connector
c490 cso30:c:OutputProcess connector
p151_propro_p151
PMID: 17621314
Two consequences of p65 acetylation are, first, the increased expression of IL-10 and, second, there is a prolonged activation of p65 and therefore prolonged NF-kappaB activity allowing increased transcription of the IL-10 gene.
c492 cso30:c:InputAssociation connector
c491 cso30:c:OutputProcess connector
p152_propro_p152
PMID: 17621314, 16052631
Takeshita et al., using cytosolic components of nicotinamide adenine dinucleotide phosphate oxidase, namely p47phox, p67phox, p40phox and rac2, described the interaction between p47phox and TRAF-4 resulting in the suppression of TLR-mediated signalling through TRAF-6 and TRIF.
c494 cso30:c:InputProcess connector
c495 cso30:c:InputProcess connector
c496 cso30:c:OutputProcess connector
p153_propro_p153
PMID: 17621314, 16052631
Following this observation, co-immunoprecipitation studies confirmed a physical interaction with not only p47phox, but also with TRAF-6, TRIF and IRAK-1, suggesting that TRAF-4 is able to form complexes with these molecules.
PMID: 17621314, 16052631
Possible mechanisms suggested by Takeshita et al., for the negative regulation of TLR-mediated signalling by NADH oxidase is via a novel TRAFTRAF dimerization, through the interaction of p47phox with TRAF-4, TRAF-6 and TRIF.
c498 cso30:c:InputProcess connector
c499 cso30:c:InputProcess connector
c500 cso30:c:InputProcess connector
c501 cso30:c:InputProcess connector
c502 cso30:c:InputProcess connector
c497 cso30:c:OutputProcess connector
p154_propro_p154
PMID: 17621314
Furthermore, overexpression studies in HEK-293 cells cotransfected with TLR-2, TLR-3, TLR-4 and TLR-9, stimulated with their appropriate ligands and increasing doses of TRAF-4, resulted in luciferase analysis showing a decrease in activation of both NF-kappaB and the IFN-beta promoter, but not in TNF-alpha receptor-mediated signalling.
c505 cso30:c:InputInhibitor connector
c504 cso30:c:OutputProcess connector
TLRs_enti_MO000019395
TLRs
TLR3_enti_MO000019398
TLR3
TLR2_enti_MO000019397
TLR2
MyD88_enti_MO000016573
MyD88
IRAK-1_enti_MO000000213
IRAK-1
IRAK-M_enti_MO000016569
IRAK-M
IRAK-4_enti_MO000039077
IRAK-4
TRAF6_enti_MO000000212
TRAF6
MAL_enti_MO000068831
MAL
TRAM_enti_MO000041132
TRAM
TRIF_enti_MO000041125
TRIF
p50:RelA-p65:IkappaB-alpha{p}_enti_MO000000254
p50:RelA-p65:IkappaB-alpha{p}
p50:RelA-p65:IkappaB-alpha_enti_MO000038724
p50:RelA-p65:IkappaB-alpha
LPS_enti_MO000016882
LPS
CD14_enti_MO000018132
CD14
TNF-alpha_enti_MO000000289
TNF-alpha
TNF-alpha_enti_G010329
TNF-alpha
IL-8_enti_MO000017264
IL-8
ST2_enti_MO000044786
ST2
ST2L_enti_MO000044794
ST2L
sst2_enti_MO000018424
sst2
TLR1_enti_G010961
TLR1
Tlr4_enti_G010693
Tlr4
TLR9_enti_MO000042012
TLR9
IFN-beta_enti_G010228
IFN-beta
IFNbeta_enti_MO000016660
IFNbeta
IL-6_enti_G010262
IL-6
IL-6_enti_MO000007384
IL-6
IL-1beta_enti_G010389
IL-1beta
IL-1beta_enti_MO000016597
IL-1beta
MAPKs_enti_MO000000077
MAPKs
IKK-alpha:IKK-beta:IKK-gamma_enti_MO000016661
IKK-alpha:IKK-beta:IKK-gamma
SIGIRR_enti_MO000066718
SIGIRR
RP105_enti_MO000016653
RP105
MD-1_enti_MO000022200
MD-1
DcTRAIL-R1_enti_MO000043372
DcTRAIL-R1
TRAF4_enti_MO000016964
TRAF4
Tollip_enti_MO000019406
Tollip
Tollip:IRAK_enti_MO000039097
Tollip:IRAK
TRIAD3_enti_MO000061958
TRIAD3
A20_enti_MO000016591
A20
SOCS-1_enti_MO000017004
SOCS-1
JNK_enti_MO000000023
JNK
p38_enti_MO000000022
p38
beta-arrestin_enti_MO000017072
beta-arrestin
beta-arrestin1_enti_MO000017073
beta-arrestin1
beta-arrestin2_enti_MO000017074
beta-arrestin2
ERK1_enti_MO000004670
ERK1
ERK2_enti_MO000004676
ERK2
GPCR_enti_MO000000314
GPCR
IL-12_enti_MO000017265
IL-12
IL-12 p40_enti_G010657
IL-12 p40
TGFbeta1_enti_MO000017443
TGFbeta1
IL-10_enti_MO000017247
IL-10
ATF-3_enti_MO000036861
ATF-3
CYLD_enti_MO000041169
CYLD
PGN_enti_MO000042032
PGN
ERK_enti_MO000000011
ERK
TRAF7_enti_MO000064816
TRAF7
SHP-2_enti_MO000016886
SHP-2
IRF-3_enti_MO000007694
IRF-3
IRF-3{p}_enti_MO000041456
IRF-3{p}
ligand_enti_e5
ligand
ligand: TLR_enti_e6
ligand: TLR
ligand: TLR: MyD88_enti_e11
ligand: TLR: MyD88
TLR4: MD-2_enti_e12
TLR4: MD-2
LPS: CD14_enti_e13
LPS: CD14
LPS: CD14: TLR4: MD-2_enti_e14
LPS: CD14: TLR4: MD-2
LPS: CD14: TLR4: MD-2: MAL_enti_e15
LPS: CD14: TLR4: MD-2: MAL
poly I: C_enti_e19
poly I: C
poly I: C: TLR3_enti_e20
poly I: C: TLR3
polyI: C: TLR3: TRIF_enti_e21
polyI: C: TLR3: TRIF
LPS: CD14: TLR4: MD-2: TRAM_enti_e22
LPS: CD14: TLR4: MD-2: TRAM
LPS: CD14: TLR4: MD-2: TRAM: TRIF_enti_e23
LPS: CD14: TLR4: MD-2: TRAM: TRIF
PGN: TLR2_enti_e24
PGN: TLR2
PGN: TLR2: MAL_enti_e25
PGN: TLR2: MAL
sTLR_enti_e26
sTLR
ligand: sTLR_enti_e27
ligand: sTLR
sTLR2_enti_e29
sTLR2
sCD14_enti_e30
sCD14
Lipoprotein_enti_e31
Lipoprotein
Lipoprotein: sCD14_enti_e32
Lipoprotein: sCD14
Lipoprotein: sCD14: sTLR2_enti_e33
Lipoprotein: sCD14: sTLR2
ligand: TLR: MyD88: MyD88_enti_e34
ligand: TLR: MyD88: MyD88
ligand: TLR: MyD88: MyD88: IRAK-1: IRAK-4_enti_e35
ligand: TLR: MyD88: MyD88: IRAK-1: IRAK-4
MyD88s_enti_e36
MyD88s
ligand: TLR: MyD88: MyD88s_enti_e37
ligand: TLR: MyD88: MyD88s
ligand: TLR: MyD88: MyD88: IRAK-1{p}: IRAK-4_enti_e38
ligand: TLR: MyD88: MyD88: IRAK-1{p}: IRAK-4
IRAK-1{p}: IRAK-4_enti_e40
IRAK-1{p}: IRAK-4
IRAK-1{p}: IRAK-4: TRAF6_enti_e41
IRAK-1{p}: IRAK-4: TRAF6
ST2L: MAL_enti_e42
ST2L: MAL
MyD88: ST2L_enti_e43
MyD88: ST2L
ssT2: ST2_enti_e44
ssT2: ST2
SIGIRR_enti_e45
SIGIRR
IL-1_enti_e46
IL-1
IL-1RI: IL-1RII_enti_e47
IL-1RI: IL-1RII
IL-1: IL-1RI: IL-1RII_enti_e48
IL-1: IL-1RI: IL-1RII
IL-1: IL-1RI: IL-1RII: MyD88_enti_e49
IL-1: IL-1RI: IL-1RII: MyD88
IL-1: IL-1RI: IL-1RII: MyD88: IRAK-1: Tollip: IRAK-4_enti_e63
IL-1: IL-1RI: IL-1RII: MyD88: IRAK-1: Tollip: IRAK-4
IL-1: IL-1RI: IL-1RII: MyD88: IRAK-1: IRAK-4: TRAF6_enti_e64
IL-1: IL-1RI: IL-1RII: MyD88: IRAK-1: IRAK-4: TRAF6
IL-1: IL-1RI: IL-1RII: MyD88: IRAK-1: IRAK-4: TRAF6: SIGIRR_enti_e65
IL-1: IL-1RI: IL-1RII: MyD88: IRAK-1: IRAK-4: TRAF6: SIGIRR
p50:RelA-p65_enti_e66
p50:RelA-p65
protein remnants_enti_e67
p50:RelA-p65{nucleus}_enti_e68
p50:RelA-p65{nucleus}
RP105: MD-1_enti_e69
RP105: MD-1
RP105: MD-1: TLR4: MD-2_enti_e70
RP105: MD-1: TLR4: MD-2
TRAIL_enti_e71
TRAIL
TRAIL: DcTRAIL-R1_enti_e72
TRAIL: DcTRAIL-R1
IL-6_enti_e73
IL-6
IL-6: p50: RelA-p65_enti_e74
IL-6: p50: RelA-p65
iL-33_enti_e76
iL-33
IL-23: ST2_enti_e77
IL-23: ST2
MAPKs{activated}_enti_e78
MAPKs{activated}
TLR4_enti_e79
TLR4
LPS: sTLR4_enti_e80
LPS: sTLR4
SARM_enti_e28
SARM
SARM_enti_e75
SARM
SARM: TRIF_enti_e81
SARM: TRIF
IRAK-2a_enti_e82
IRAK-2a
IRAK-2b_enti_e83
IRAK-2b
IRAK-2c_enti_e84
IRAK-2c
IRAK-2d_enti_e85
IRAK-2d
IL-1: IL-1RI: IL-1RII: IL-1RAcP_enti_e87
IL-1: IL-1RI: IL-1RII: IL-1RAcP
IL-1RAcP_enti_e86
IL-1RAcP
Tollip-1_enti_e88
Tollip-1
Tollip-1: TLR4_enti_e90
Tollip-1: TLR4
Tollip-1: TLR2_enti_e91
Tollip-1: TLR2
TLR4_enti_e89
TLR4
ligand: TLR: MyD88: MyD88: IRAK-1: Tollip-1: IRAK-4_enti_e39
ligand: TLR: MyD88: MyD88: IRAK-1: Tollip-1: IRAK-4
ligand: TLR: MyD88: MyD88: IRAK-1: Tollip-1{p}: IRAK-4_enti_e92
ligand: TLR: MyD88: MyD88: IRAK-1: Tollip-1{p}: IRAK-4
A20_enti_e93
A20
TNF-alpha{extracellular}_enti_e94
TNF-alpha{extracellular}
IRAK-1{p}: IRAK-4: TRAF6{ub}_enti_e95
IRAK-1{p}: IRAK-4: TRAF6{ub}
RIP-1_enti_e96
RIP-1
SOCS-1_enti_e97
SOCS-1
MAL{ub}: SOCS-1_enti_e98
MAL{ub}: SOCS-1
MAL: SOCS-1_enti_e99
MAL: SOCS-1
BTK_enti_e100
BTK
GPCR ligand: GPCR_enti_e101
GPCR ligand: GPCR
GPCR ligand_enti_e102
GPCR ligand
GPCR ligand: GPCR: beta-arrestin_enti_e103
GPCR ligand: GPCR: beta-arrestin
GPCR ligand: GPCR: beta-arrestin: ERK1_enti_e104
GPCR ligand: GPCR: beta-arrestin: ERK1
GPCR ligand: GPCR: beta-arrestin: ERK2_enti_e105
GPCR ligand: GPCR: beta-arrestin: ERK2
GPCR ligand: GPCR: beta-arrestin: JNK_enti_e106
GPCR ligand: GPCR: beta-arrestin: JNK
GPCR ligand: GPCR: beta-arrestin: p38_enti_e107
GPCR ligand: GPCR: beta-arrestin: p38
GPCR ligand: GPCR: beta-arrestin: ERK1{p}_enti_e108
GPCR ligand: GPCR: beta-arrestin: ERK1{p}
GPCR ligand: GPCR: beta-arrestin: ERK2{p}_enti_e109
GPCR ligand: GPCR: beta-arrestin: ERK2{p}
GPCR ligand: GPCR: beta-arrestin: JNK{p}_enti_e110
GPCR ligand: GPCR: beta-arrestin: JNK{p}
GPCR ligand: GPCR: beta-arrestin: p38{p}_enti_e111
GPCR ligand: GPCR: beta-arrestin: p38{p}
GPCR ligand: GPCR: beta-arrestin: ERK1{p}{ub}_enti_e112
GPCR ligand: GPCR: beta-arrestin: ERK1{p}{ub}
GPCR ligand: GPCR: beta-arrestin: ERK2{p}{ub}_enti_e113
GPCR ligand: GPCR: beta-arrestin: ERK2{p}{ub}
GPCR ligand: GPCR: beta-arrestin: JNK{p}{ub}_enti_e114
GPCR ligand: GPCR: beta-arrestin: JNK{p}{ub}
GPCR ligand: GPCR: beta-arrestin: p38{p}{ub}_enti_e115
GPCR ligand: GPCR: beta-arrestin: p38{p}{ub}
p50:RelA-p65:IkappaB-alpha: beta-arrestin-1_enti_e116
p50:RelA-p65:IkappaB-alpha: beta-arrestin-1
p50:RelA-p65:IkappaB-alpha: beta-arrestin-2_enti_e117
p50:RelA-p65:IkappaB-alpha: beta-arrestin-2
TRAF6: beta-arrestin-1_enti_e118
TRAF6: beta-arrestin-1
TRAF6: beta-arrestin2_enti_e119
TRAF6: beta-arrestin2
AP-1{activated}_enti_e120
AP-1{activated}
AP-1_enti_e121
AP-1
IL-8_enti_e122
IL-8
PI3K class I_enti_e123
PI3K class I
PI3K class III_enti_e124
PI3K class III
TGFbeta1: MyD88_enti_e125
TGFbeta1: MyD88
cytokine_enti_e126
cytokine
cytokine_enti_e127
cytokine
p53_enti_e128
p53
LIND_enti_e129
LIND
LIND: A20_enti_e130
LIND: A20
LIND_enti_e131
LIND
ABIN-3_enti_e132
ABIN-3
Fliih_enti_e133
Fliih
Fliih: MyD88_enti_e134
Fliih: MyD88
lipid A_enti_e135
lipid A
LPS: CD14: TLR4: MD-2: MAL: MyD88_enti_e136
LPS: CD14: TLR4: MD-2: MAL: MyD88
FLN29_enti_e137
FLN29
FLN29: TRAF6_enti_e138
FLN29: TRAF6
nitric oxide_enti_e139
nitric oxide
MALP-2_enti_e140
MALP-2
MALP-2: TLR2_enti_e141
MALP-2: TLR2
Pam3CSK-4_enti_e142
Pam3CSK-4
Pam3CSK-4: TLR2_enti_e143
Pam3CSK-4: TLR2
CYLD_enti_e144
CYLD
CYLD: TRAF6_enti_e145
CYLD: TRAF6
TRAF6: CYLD_enti_e146
TRAF6: CYLD
DUSP_enti_e147
DUSP
DUSP: MAPKs_enti_e148
DUSP: MAPKs
DUSP-1_enti_e149
DUSP-1
DUSP-2_enti_e150
DUSP-2
p38_enti_e151
p38
DUSP-2: P38_enti_e152
DUSP-2: P38
DUSP-2: ERK_enti_e153
DUSP-2: ERK
DUSP-2: JNK_enti_e154
DUSP-2: JNK
JNK_enti_e155
JNK
p38{p}_enti_e156
p38{p}
ERK{activated}_enti_e157
ERK{activated}
DUSP-2: PAC-1_enti_e158
DUSP-2: PAC-1
TAK1_enti_e159
TAK1
IRAK-1{p}: IRAK-4: TRAF6{ub}: TAK1_enti_e160
IRAK-1{p}: IRAK-4: TRAF6{ub}: TAK1
SHP-2: TAK1_enti_e161
SHP-2: TAK1
PIN-1_enti_e162
PIN-1
PIN-1: IRF-3{p}_enti_e163
PIN-1: IRF-3{p}
PIN-1: IRF-3{p}{ub}_enti_e164
PIN-1: IRF-3{p}{ub}
p65_enti_e165
p65
PIN-1: p65_enti_e166
PIN-1: p65
PIN-1: p65{p}_enti_e167
PIN-1: p65{p}
p65{p}_enti_e168
p65{p}
SOCS-1: p65_enti_e169
SOCS-1: p65
p65{ub}_enti_e170
p65{ub}
Ubc13_enti_e171
Ubc13
TRAF2_enti_e173
TRAF2
TRAF2{ub}_enti_e174
TRAF2{ub}
IKK-alpha:IKK-beta:IKK-gamma{ub}_enti_e175
IKK-alpha:IKK-beta:IKK-gamma{ub}
JNK{p}_enti_e172
JNK{p}
IKK-alpha:IKK-beta:IKK-gamma{p}_enti_e176
IKK-alpha:IKK-beta:IKK-gamma{p}
DC-SIGN_enti_e177
DC-SIGN
ManLAM_enti_e178
ManLAM
ManLAM: DC-SIGN_enti_e179
ManLAM: DC-SIGN
IL-10_enti_e180
IL-10
Raf1_enti_e181
Raf1
Raf1{activated}_enti_e182
Raf1{activated}
p50: RelA-p65{p}_enti_e183
p50: RelA-p65{p}
p50: RelA-p65{Ac}_enti_e184
p50: RelA-p65{Ac}
p47phox_enti_e185
p47phox
p47phox: TRAF4_enti_e186
p47phox: TRAF4
p47phox: TRIF: TRAF4: TRAF6: IRAK1: _enti_e187
p47phox: TRIF: TRAF4: TRAF6: IRAK1: