_enti_e7
_enti_e8
_enti_e9
_enti_e1
_enti_e10
_enti_e3
_enti_e2
_enti_e4
_enti_e55
_enti_e6
_enti_e92
_enti_e59
_enti_e53
_enti_e89
_enti_e90
_enti_e11
_enti_e5
_enti_e56
_enti_e52
_enti_e51
_enti_e50
_enti_e54
_enti_e91
_enti_e88
_enti_e87
_enti_e93
_enti_e58
_enti_e61
_enti_e57
_enti_e86
_enti_e60
_enti_e62
_enti_e85
g2_fact_g2
g1_fact_g14
g2_fact_g12
g2_fact_g13
g1_fact_g1
g3_fact_g4
g1_fact_g6
g2_fact_g5
g1_fact_g3
p1_propro_p1
PMID: 18641647, 9237759, 11323673, 10364168
The leucine-rich repeats of the TLR ectodomains bind to pathogen-associated molecular patterns (PAMPs), such as the bacterial cell-wall component lipopolysaccharide (a ligand of TLR4), bacterial flagellin (a ligand of TLR5), and lipoprotein and peptidoglycan (which are recognized by TLR2 complexed with TLR1 or TLR6).
c1 cso30:c:InputProcess connector
c2 cso30:c:InputProcess connector
c3 cso30:c:OutputProcess connector
p2_propro_p2
PMID: 18641647, 9237759, 11323673, 10364168
The leucine-rich repeats of the TLR ectodomains bind to pathogen-associated molecular patterns (PAMPs), such as the bacterial cell-wall component lipopolysaccharide (a ligand of TLR4), bacterial flagellin (a ligand of TLR5), and lipoprotein and peptidoglycan (which are recognized by TLR2 complexed with TLR1 or TLR6).
c4 cso30:c:InputProcess connector
c5 cso30:c:InputProcess connector
c6 cso30:c:OutputProcess connector
p3_propro_p3
PMID: 18641647, 9237759, 11323673, 10364168
The leucine-rich repeats of the TLR ectodomains bind to pathogen-associated molecular patterns (PAMPs), such as the bacterial cell-wall component lipopolysaccharide (a ligand of TLR4), bacterial flagellin (a ligand of TLR5), and lipoprotein and peptidoglycan (which are recognized by TLR2 complexed with TLR1 or TLR6).
c7 cso30:c:InputProcess connector
c8 cso30:c:InputProcess connector
c9 cso30:c:OutputProcess connector
p4_propro_p4
PMID: 18641647, 9237759, 11323673, 10364168
The leucine-rich repeats of the TLR ectodomains bind to pathogen-associated molecular patterns (PAMPs), such as the bacterial cell-wall component lipopolysaccharide (a ligand of TLR4), bacterial flagellin (a ligand of TLR5), and lipoprotein and peptidoglycan (which are recognized by TLR2 complexed with TLR1 or TLR6).
c10 cso30:c:InputProcess connector
c11 cso30:c:InputProcess connector
c12 cso30:c:OutputProcess connector
p5_propro_p5
PMID: 18641647
TLR7 and TLR8 respond to guanosine- or uridine-rich singlestranded RNA (ssRNA) from viruses and the synthetic imidazoquinoline compounds imiquimod and R848.PMID: 18641647
c13 cso30:c:InputProcess connector
c14 cso30:c:InputProcess connector
c15 cso30:c:OutputProcess connector
p6_propro_p6
PMID: 18641647
TLR7 and TLR8 respond to guanosine- or uridine-rich singlestranded RNA (ssRNA) from viruses and the synthetic imidazoquinoline compounds imiquimod and R848.
c16 cso30:c:InputProcess connector
c17 cso30:c:InputProcess connector
c18 cso30:c:OutputProcess connector
p7_propro_p7
PMID: 18641647, 11130078, 11470918
TLR9 seems to detect ssDNA molecules that contain unmethylated CpG-containing motifs, which are commonly found in the genomes of viruses and bacteria.
c19 cso30:c:InputProcess connector
c40 cso30:c:InputProcess connector
c21 cso30:c:OutputProcess connector
p8_propro_p8
PMID: 18641647
TLR7 and TLR8 respond to guanosine- or uridine-rich singlestranded RNA (ssRNA) from viruses and the synthetic imidazoquinoline compounds imiquimod and R848.
c22 cso30:c:InputProcess connector
c23 cso30:c:InputProcess connector
c24 cso30:c:OutputProcess connector
p9_propro_p9
PMID: 18641647
TLR7 and TLR8 respond to guanosine- or uridine-rich singlestranded RNA (ssRNA) from viruses and the synthetic imidazoquinoline compounds imiquimod and R848.
c25 cso30:c:InputProcess connector
c26 cso30:c:InputProcess connector
c27 cso30:c:OutputProcess connector
p10_propro_p10
PMID: 18641647
TLR7 and TLR8 respond to guanosine- or uridine-rich singlestranded RNA (ssRNA) from viruses and the synthetic imidazoquinoline compounds imiquimod and R848.
c28 cso30:c:InputProcess connector
c30 cso30:c:InputProcess connector
c31 cso30:c:OutputProcess connector
p11_propro_p11
PMID: 18641647
TLR7 and TLR8 respond to guanosine- or uridine-rich singlestranded RNA (ssRNA) from viruses and the synthetic imidazoquinoline compounds imiquimod and R848.
c29 cso30:c:InputProcess connector
c32 cso30:c:InputProcess connector
c33 cso30:c:OutputProcess connector
p12_propro_p12
PMID: 18641647
TLR7 and TLR8 respond to guanosine- or uridine-rich singlestranded RNA (ssRNA) from viruses and the synthetic imidazoquinoline compounds imiquimod and R848.
c34 cso30:c:InputProcess connector
c37 cso30:c:InputProcess connector
c38 cso30:c:OutputProcess connector
p13_propro_p13
PMID: 18641647
TLR7 and TLR8 respond to guanosine- or uridine-rich singlestranded RNA (ssRNA) from viruses and the synthetic imidazoquinoline compounds imiquimod and R848.
c35 cso30:c:InputProcess connector
c36 cso30:c:InputProcess connector
c39 cso30:c:OutputProcess connector
p14_propro_p14
PMID: 18641647, 17572678
Synthetic ODNs containing CpG dinucleotides can interact directly with the ectodomain of TLR9 and induce conformational changes40 that lead to downstream signalling activation.
c20 cso30:c:InputProcess connector
c41 cso30:c:InputProcess connector
c42 cso30:c:OutputProcess connector
p15_propro_p15
PMID: 18641647, 15229469, 16675322
TLR4 signals through MyD88, TIRAP, TRIF and TRAM; and TLR2 uses both MyD88 and TIRAP.
c43 cso30:c:InputProcess connector
c45 cso30:c:InputProcess connector
c44 cso30:c:OutputProcess connector
p16_propro_p16
PMID: 18641647, 15229469, 16675322
TLR4 signals through MyD88, TIRAP, TRIF and TRAM; and TLR2 uses both MyD88 and TIRAP.
c46 cso30:c:InputProcess connector
c48 cso30:c:InputProcess connector
c47 cso30:c:OutputProcess connector
p17_propro_p17
PMID: 18641647, 15229469, 16675322
TLR4 signals through MyD88, TIRAP, TRIF and TRAM; and TLR2 uses both MyD88 and TIRAP.
c49 cso30:c:InputProcess connector
c50 cso30:c:InputProcess connector
c51 cso30:c:OutputProcess connector
p18_propro_p18
PMID: 18641647, 15229469, 16675322
TLR4 signals through MyD88, TIRAP, TRIF and TRAM; and TLR2 uses both MyD88 and TIRAP.
c52 cso30:c:InputProcess connector
c53 cso30:c:InputProcess connector
c54 cso30:c:OutputProcess connector
p19_propro_p19
PMID: 18641647, 15229469, 16675322
TLR4 signals through MyD88, TIRAP, TRIF and TRAM; and TLR2 uses both MyD88 and TIRAP.
c55 cso30:c:InputProcess connector
c56 cso30:c:InputProcess connector
c57 cso30:c:OutputProcess connector
p20_propro_p20
PMID: 18641647, 15229469, 16675322
TLR4 signals through MyD88, TIRAP, TRIF and TRAM; and TLR2 uses both MyD88 and TIRAP.
c58 cso30:c:InputProcess connector
c60 cso30:c:InputProcess connector
c59 cso30:c:OutputProcess connector
p21_propro_p21
PMID: 18641647
TLR3, which is localized in endosomes, recognizes viral dsRNA and its synthetic mimic polyI:C.
c61 cso30:c:InputProcess connector
c62 cso30:c:InputProcess connector
c63 cso30:c:OutputProcess connector
p22_propro_p22
PMID: 18641647
TLR3, which is localized in endosomes, recognizes viral dsRNA and its synthetic mimic polyI:C.
c64 cso30:c:InputProcess connector
c65 cso30:c:InputProcess connector
c66 cso30:c:OutputProcess connector
p23_propro_p23
PMID: 18641647, 12471095, 12855817
Indeed, TLR3 was shown to associate with TRIF and signal through IRF3, a key factor involved in IFNbeta production.
c67 cso30:c:InputProcess connector
c68 cso30:c:InputProcess connector
c69 cso30:c:OutputProcess connector
p24_propro_p24
PMID: 18641647
Endosomal Toll-like receptor 7 (TLR7), TLR8 and TLR9 recognize RNA and DNA ligands, and signal through a key adaptor MyD88 (myeloid differentiation primary-response gene 88) in the cytosol.
c70 cso30:c:InputProcess connector
c73 cso30:c:InputProcess connector
c74 cso30:c:OutputProcess connector
p25_propro_p25
PMID: 18641647
Endosomal Toll-like receptor 7 (TLR7), TLR8 and TLR9 recognize RNA and DNA ligands, and signal through a key adaptor MyD88 (myeloid differentiation primary-response gene 88) in the cytosol.
c71 cso30:c:InputProcess connector
c75 cso30:c:InputProcess connector
c76 cso30:c:OutputProcess connector
p26_propro_p26
PMID: 18641647
Endosomal Toll-like receptor 7 (TLR7), TLR8 and TLR9 recognize RNA and DNA ligands, and signal through a key adaptor MyD88 (myeloid differentiation primary-response gene 88) in the cytosol.
c72 cso30:c:InputProcess connector
c77 cso30:c:InputProcess connector
c78 cso30:c:OutputProcess connector
p27_propro_p27
PMID: 18641647
MyD88 in turn associates with a signal complex comprised of TRAF6 (tumour-necrosis factor (TNF)-receptor-associated factor 6), BTK (Bruton’s tyrosine kinase), IRAK4 (interleukin- receptor (IL-1R)-associated kinase 4) and IRAK1, which leads to the activation of IRF7 (interferon-regulatory factor 7), NFkappaB (nuclear factorkappaB) and MAPKs (mitogen-activated protein kinases).
c79 cso30:c:InputProcess connector
c80 cso30:c:InputProcess connector
c94 cso30:c:InputProcess connector
c81 cso30:c:InputProcess connector
c88 cso30:c:OutputProcess connector
c91 cso30:c:OutputProcess connector
p28_propro_p28
PMID: 18641647
MyD88 in turn associates with a signal complex comprised of TRAF6 (tumour-necrosis factor (TNF)-receptor-associated factor 6), BTK (Bruton’s tyrosine kinase), IRAK4 (interleukin- receptor (IL-1R)-associated kinase 4) and IRAK1, which leads to the activation of IRF7 (interferon-regulatory factor 7), NFkappaB (nuclear factorkappaB) and MAPKs (mitogen-activated protein kinases).
c82 cso30:c:InputProcess connector
c83 cso30:c:InputProcess connector
c84 cso30:c:InputProcess connector
c95 cso30:c:InputProcess connector
c89 cso30:c:OutputProcess connector
c92 cso30:c:OutputProcess connector
p29_propro_p29
PMID: 18641647
MyD88 in turn associates with a signal complex comprised of TRAF6 (tumour-necrosis factor (TNF)-receptor-associated factor 6), BTK (Bruton’s tyrosine kinase), IRAK4 (interleukin- receptor (IL-1R)-associated kinase 4) and IRAK1, which leads to the activation of IRF7 (interferon-regulatory factor 7), NFkappaB (nuclear factorkappaB) and MAPKs (mitogen-activated protein kinases).
c85 cso30:c:InputProcess connector
c86 cso30:c:InputProcess connector
c87 cso30:c:InputProcess connector
c96 cso30:c:InputProcess connector
c90 cso30:c:OutputProcess connector
c93 cso30:c:OutputProcess connector
p30_propro_p30
PMID: 18641647
Most importantly, IRF7 is activated through TRAF3, IRAK1, IKKalpha (inhibitor of NF-kappaB kinase alpha), osteopontin (OPN) and phosphoinositide 3-kinase (PI3K).
PMID: 18641647
MyD88 in turn associates with a signal complex comprised of TRAF6 (tumour-necrosis factor (TNF)-receptor-associated factor 6), BTK (Bruton’s tyrosine kinase), IRAK4 (interleukin- receptor (IL-1R)-associated kinase 4) and IRAK1, which leads to the activation of IRF7 (interferon-regulatory factor 7), NFkappaB (nuclear factorkappaB) and MAPKs (mitogen-activated protein kinases).
PMID: 18641647, 15361868
IRF7 is activated through ubiquitylation by the ubiquitin E3 ligase activity of TRAF6 (ref. 86) and phosphorylation by IRAK4.
c122 cso30:c:InputProcess connector
c123 cso30:c:OutputProcess connector
c124 cso30:c:OutputProcess connector
c125 cso30:c:OutputProcess connector
c126 cso30:c:OutputProcess connector
c127 cso30:c:OutputProcess connector
c128 cso30:c:OutputProcess connector
p33_propro_p33
PMID: 18641647
MyD88 in turn associates with a signal complex comprised of TRAF6 (tumour-necrosis factor (TNF)-receptor-associated factor 6), BTK (Bruton’s tyrosine kinase), IRAK4 (interleukin- receptor (IL-1R)-associated kinase 4) and IRAK1, which leads to the activation of IRF7 (interferon-regulatory factor 7), NFkappaB (nuclear factorkappaB) and MAPKs (mitogen-activated protein kinases).
PMID: 18641647
The MyD88TRAF6IRAK4 complex then activates IRF7 (interferon-regulatory factor 7), TAK1 (transforminggrowth-factor-beta-activated kinase 1), nuclear factor-kappaB (NF-kappaB) and IRF5 to propagate the downstream signals.
PMID: 18641647
TAK1 triggers the activation of NFkappaB and MAPKs (mitogen-activated protein kinases) and, together with IRF5, leads to the production of pro-inflammatory cytokines and the expression of co-stimulatory molecules.
PMID: 18641647
This presumably activates a different set of signal mediators, particularly NF-kappaB (nuclear factor-kappaB) and probably MAPKs (mitogen-activated protein kinases) and IRF5, and thereby leads to distinct outcomes of pDC activation without high levels of IFN production.
c106 cso30:c:InputProcess connector
c134 cso30:c:InputAssociation connector
c107 cso30:c:OutputProcess connector
p36_propro_p36
PMID: 18641647
MyD88 in turn associates with a signal complex comprised of TRAF6 (tumour-necrosis factor (TNF)-receptor-associated factor 6), BTK (Bruton’s tyrosine kinase), IRAK4 (interleukin- receptor (IL-1R)-associated kinase 4) and IRAK1, which leads to the activation of IRF7 (interferon-regulatory factor 7), NFkappaB (nuclear factorkappaB) and MAPKs (mitogen-activated protein kinases).
PMID: 18641647
TAK1 triggers the activation of NFkappaB and MAPKs (mitogen-activated protein kinases) and, together with IRF5, leads to the production of pro-inflammatory cytokines and the expression of co-stimulatory molecules.
PMID: 18641647
This presumably activates a different set of signal mediators, particularly NF-kappaB (nuclear factor-kappaB) and probably MAPKs (mitogen-activated protein kinases) and IRF5, and thereby leads to distinct outcomes of pDC activation without high levels of IFN production.
c115 cso30:c:InputProcess connector
c133 cso30:c:InputAssociation connector
c116 cso30:c:OutputProcess connector
p39_propro_p39
PMID: 18641647
MyD88 in turn associates with a signal complex comprised of TRAF6 (tumour-necrosis factor (TNF)-receptor-associated factor 6), BTK (Bruton’s tyrosine kinase), IRAK4 (interleukin-1- receptor (IL-1R)-associated kinase 4) and IRAK1, which leads to the activation of IRF7 (interferon-regulatory factor 7), NFkappaB (nuclear factorkappaB) and MAPKs (mitogen-activated protein kinases).
c98 cso30:c:InputProcess connector
c105 cso30:c:InputProcess connector
c108 cso30:c:OutputProcess connector
p42_propro_p42
PMID: 18641647, 15361868
IRF7 is activated through ubiquitylation by the ubiquitin E3 ligase activity of TRAF6 (ref. 86) and phosphorylation by IRAK4.
c109 cso30:c:InputProcess connector
c110 cso30:c:OutputProcess connector
p45_propro_p45
c139 cso30:c:InputProcess connector
c140 cso30:c:OutputProcess connector
c102 cso30:c:OutputProcess connector
p46_propro_p46
PMID: 18641647
MyD88 in turn associates with a signal complex comprised of TRAF6 (tumour-necrosis factor (TNF)-receptor-associated factor 6), BTK (Bruton’s tyrosine kinase), IRAK4 (interleukin-1- receptor (IL-1R)-associated kinase 4) and IRAK1, which leads to the activation of IRF7 (interferon-regulatory factor 7), NFkappaB (nuclear factorkappaB) and MAPKs (mitogen-activated protein kinases).
c97 cso30:c:InputProcess connector
c99 cso30:c:OutputProcess connector
c103 cso30:c:OutputProcess connector
p31_propro_p31
PMID: 18641647
MyD88 in turn associates with a signal complex comprised of TRAF6 (tumour-necrosis factor (TNF)-receptor-associated factor 6), BTK (Bruton’s tyrosine kinase), IRAK4 (interleukin-1- receptor (IL-1R)-associated kinase 4) and IRAK1, which leads to the activation of IRF7 (interferon-regulatory factor 7), NFkappaB (nuclear factorkappaB) and MAPKs (mitogen-activated protein kinases).
c100 cso30:c:InputProcess connector
c101 cso30:c:OutputProcess connector
c104 cso30:c:OutputProcess connector
p32_propro_p32
PMID: 18641647
The MyD88TRAF6IRAK4 complex then activates IRF7 (interferon-regulatory factor 7), TAK1 (transforminggrowth-factor-beta-activated kinase 1), nuclear factor-kappaB (NF-kappaB) and IRF5 to propagate the downstream signals.
c111 cso30:c:InputProcess connector
c112 cso30:c:OutputProcess connector
c113 cso30:c:OutputProcess connector
p34_propro_p34
PMID: 18641647
Most importantly, IRF7 is activated through TRAF3, IRAK1, IKKalpha (inhibitor of NF-kappaB kinase alpha), osteopontin (OPN) and phosphoinositide 3-kinase (PI3K).
c114 cso30:c:InputProcess connector
c117 cso30:c:InputProcess connector
c118 cso30:c:InputProcess connector
c119 cso30:c:InputProcess connector
c121 cso30:c:InputProcess connector
c129 cso30:c:InputProcess connector
c120 cso30:c:OutputProcess connector
p37_propro_p37
PMID: 18641647
MyD88 in turn associates with a signal complex comprised of TRAF6 (tumour-necrosis factor (TNF)-receptor-associated factor 6), BTK (Bruton’s tyrosine kinase), IRAK4 (interleukin- receptor (IL-1R)-associated kinase 4) and IRAK1, which leads to the activation of IRF7 (interferon-regulatory factor 7), NFkappaB (nuclear factorkappaB) and MAPKs (mitogen-activated protein kinases).
PMID: 18641647
TAK1 triggers the activation of NFkappaB and MAPKs (mitogen-activated protein kinases) and, together with IRF5, leads to the production of pro-inflammatory cytokines and the expression of co-stimulatory molecules.
PMID: 18641647
The TLR3TRIF signalling pathway also activates NFkappaB and MAPKs and results in the production of pro-inflammatory cytokines and the expression of co-stimulatory molecules (CD80 and CD86).
PMID: 18641647
Interestingly, when A-type CpG ODNs are disrupted into monomeric structures, they fail to be retained in the early endosome and to induce high amounts of type I IFN production, but instead rapidly traffic to late endosomes and induce maturation and production of IL-6 and TNF.
PMID: 18641647
This presumably activates a different set of signal mediators, particularly NF-kappaB (nuclear factor-kappaB) and probably MAPKs (mitogen-activated protein kinases) and IRF5, and thereby leads to distinct outcomes of pDC activation without high levels of IFN production.
c135 cso30:c:InputProcess connector
c136 cso30:c:OutputProcess connector
p40_propro_p40
PMID: 18641647
The MyD88TRAF6IRAK4 complex then activates IRF7 (interferon-regulatory factor 7), TAK1 (transforminggrowth-factor-beta-activated kinase 1), nuclear factor-kappaB (NF-kappaB) and IRF5 to propagate the downstream signals.
c137 cso30:c:InputProcess connector
c141 cso30:c:InputAssociation connector
c138 cso30:c:OutputProcess connector
p41_propro_p41
PMID: 18641647
Following ubiquitylation and phosphorylation, IRF7 translocates to the nucleus and initiates the transcription of type I interferons (such as IFNalpha, IFNbeta, IFNlambda and IFNomega).
PMID: 18641647
Aggregated self-DNALL37 complexes are retained in the early endosomes of pDCs, and, similar to A-type CpG ODNs, they trigger the TLR9MyD88IRF7 pathway of type I IFN production without inducing pDC maturation.
c142 cso30:c:InputProcess connector
c143 cso30:c:OutputProcess connector
p38_propro_p38
PMID: 18641647
Following ubiquitylation and phosphorylation, IRF7 translocates to the nucleus and initiates the transcription of type I interferons (such as IFNalpha, IFNbeta, IFNlambda and IFNomega).
PMID: 18641647, 16415873
The prolonged retention of multimeric A-type CpG ODNs provides a platform for extended activation of the signal-transducing complex, consisting of MyD88 and IRF7, which leads to robust type I IFN production.
PMID: 18641647
Aggregated self-DNALL37 complexes are retained in the early endosomes of pDCs, and, similar to A-type CpG ODNs, they trigger the TLR9MyD88IRF7 pathway of type I IFN production without inducing pDC maturation.
c148 cso30:c:InputAssociation connector
c144 cso30:c:OutputProcess connector
p43_propro_p43
PMID: 18641647
Following ubiquitylation and phosphorylation, IRF7 translocates to the nucleus and initiates the transcription of type I interferons (such as IFNalpha, IFNbeta, IFNlambda and IFNomega).
PMID: 18641647, 16415873
The prolonged retention of multimeric A-type CpG ODNs provides a platform for extended activation of the signal-transducing complex, consisting of MyD88 and IRF7, which leads to robust type I IFN production.
PMID: 18641647
Aggregated self-DNALL37 complexes are retained in the early endosomes of pDCs, and, similar to A-type CpG ODNs, they trigger the TLR9MyD88IRF7 pathway of type I IFN production without inducing pDC maturation.
c149 cso30:c:InputAssociation connector
c145 cso30:c:OutputProcess connector
p44_propro_p44
PMID: 18641647
Following ubiquitylation and phosphorylation, IRF7 translocates to the nucleus and initiates the transcription of type I interferons (such as IFNalpha, IFNbeta, IFNlambda and IFNomega).
PMID: 18641647, 16415873
The prolonged retention of multimeric A-type CpG ODNs provides a platform for extended activation of the signal-transducing complex, consisting of MyD88 and IRF7, which leads to robust type I IFN production.
PMID: 18641647
Aggregated self-DNALL37 complexes are retained in the early endosomes of pDCs, and, similar to A-type CpG ODNs, they trigger the TLR9MyD88IRF7 pathway of type I IFN production without inducing pDC maturation.
c150 cso30:c:InputAssociation connector
c147 cso30:c:OutputProcess connector
p47_propro_p47
PMID: 18641647
Following ubiquitylation and phosphorylation, IRF7 translocates to the nucleus and initiates the transcription of type I interferons (such as IFNalpha, IFNbeta, IFNlambda and IFNomega).
PMID: 18641647, 16415873
The prolonged retention of multimeric A-type CpG ODNs provides a platform for extended activation of the signal-transducing complex, consisting of MyD88 and IRF7, which leads to robust type I IFN production.
PMID: 18641647
Aggregated self-DNALL37 complexes are retained in the early endosomes of pDCs, and, similar to A-type CpG ODNs, they trigger the TLR9MyD88IRF7 pathway of type I IFN production without inducing pDC maturation.
c151 cso30:c:InputAssociation connector
c146 cso30:c:OutputProcess connector
p35_propro_p35
PMID: 18641647
The MyD88TRAF6IRAK4 complex then activates IRF7 (interferon-regulatory factor 7), TAK1 (transforminggrowth-factor-beta-activated kinase 1), nuclear factor-kappaB (NF-kappaB) and IRF5 to propagate the downstream signals.
c130 cso30:c:InputProcess connector
c132 cso30:c:InputAssociation connector
c131 cso30:c:OutputProcess connector
p48_propro_p48
PMID: 18641647
TAK1 triggers the activation of NFkappaB and MAPKs (mitogen-activated protein kinases) and, together with IRF5, leads to the production of pro-inflammatory cytokines and the expression of co-stimulatory molecules.
PMID: 18641647
Interestingly, when A-type CpG ODNs are disrupted into monomeric structures, they fail to be retained in the early endosome and to induce high amounts of type I IFN production, but instead rapidly traffic to late endosomes and induce maturation and production of IL-6 and TNF.
PMID: 18641647
This presumably activates a different set of signal mediators, particularly NF-kappaB (nuclear factor-kappaB) and probably MAPKs (mitogen-activated protein kinases) and IRF5, and thereby leads to distinct outcomes of pDC activation without high levels of IFN production.
c152 cso30:c:InputProcess connector
c153 cso30:c:OutputProcess connector
p49_propro_p49
PMID: 18641647
Overall, this pathway potently induces the production of high levels of type I IFNs (such as IFNalpha, IFNbeta, IFNlambda and IFNomega), pro-inflammatory cytokines and expression of co-stimulatory molecules.
PMID: 18641647
Interestingly, when A-type CpG ODNs are disrupted into monomeric structures, they fail to be retained in the early endosome and to induce high amounts of type I IFN production, but instead rapidly traffic to late endosomes and induce maturation and production of IL-6 and TNF.
PMID: 18641647, 11160284, 11561001, 7700380
On the other hand, B-type CpG ODNs can activate B cells but only trigger pDCs to produce the pro-inflammatory cytokines TNF and IL-6, and small amounts of IFN, as well as inducing the upregulation of CD80, CD86 and the expression of MHC class II molecules.
c154 cso30:c:InputAssociation connector
c156 cso30:c:OutputProcess connector
p50_propro_p50
PMID: 18641647
Overall, this pathway potently induces the production of high levels of type I IFNs (such as IFNalpha, IFNbeta, IFNlambda and IFNomega), pro-inflammatory cytokines and expression of co-stimulatory molecules.
PMID: 18641647
Interestingly, when A-type CpG ODNs are disrupted into monomeric structures, they fail to be retained in the early endosome and to induce high amounts of type I IFN production, but instead rapidly traffic to late endosomes and induce maturation and production of IL-6 and TNF.
PMID: 18641647, 11160284, 11561001, 7700380
On the other hand, B-type CpG ODNs can activate B cells but only trigger pDCs to produce the pro-inflammatory cytokines TNF and IL-6, and small amounts of IFN, as well as inducing the upregulation of CD80, CD86 and the expression of MHC class II molecules.
c155 cso30:c:InputAssociation connector
c157 cso30:c:OutputProcess connector
p51_propro_p51
PMID: 18641647
Overall, this pathway potently induces the production of high levels of type I IFNs (such as IFNalpha, IFNbeta, IFNlambda and IFNomega), pro-inflammatory cytokines and expression of co-stimulatory molecules.
PMID: 18641647
The TLR3TRIF signalling pathway also activates NFkappaB and MAPKs and results in the production of pro-inflammatory cytokines and the expression of co-stimulatory molecules (CD80 and CD86).
PMID: 18641647, 11160284, 11561001, 7700380
On the other hand, B-type CpG ODNs can activate B cells but only trigger pDCs to produce the pro-inflammatory cytokines TNF and IL-6, and small amounts of IFN, as well as inducing the upregulation of CD80, CD86 and the expression of MHC class II molecules.
c158 cso30:c:InputAssociation connector
c160 cso30:c:OutputProcess connector
p52_propro_p52
PMID: 18641647
Overall, this pathway potently induces the production of high levels of type I IFNs (such as IFNalpha, IFNbeta, IFNlambda and IFNomega), pro-inflammatory cytokines and expression of co-stimulatory molecules.
PMID: 18641647
The TLR3TRIF signalling pathway also activates NFkappaB and MAPKs and results in the production of pro-inflammatory cytokines and the expression of co-stimulatory molecules (CD80 and CD86).
PMID: 18641647, 11160284, 11561001, 7700380
On the other hand, B-type CpG ODNs can activate B cells but only trigger pDCs to produce the pro-inflammatory cytokines TNF and IL-6, and small amounts of IFN, as well as inducing the upregulation of CD80, CD86 and the expression of MHC class II molecules.
c159 cso30:c:InputAssociation connector
c161 cso30:c:OutputProcess connector
p53_propro_p53
PMID: 18641647
Alternatively, the binding of double-stranded RNA (dsRNA) to endosomal TLR3 triggers a signalling pathway mediated by TRIF (Toll/IL-1R (TIR) domain-containing adaptor protein inducing IFNbeta), which involves TRAF3, TBK1 (TANK-binding kinase 1) and IKKepsilon (inhibitor of NFkappaB kinase epsilon).
PMID: 18641647
By coupling with TRAF3, TBK1 and IKKepsilon, IPS1 directly activates IRF3 and NFkappaB through FADD (FAS-associated via death domain), caspase8 and caspase10.
c162 cso30:c:InputAssociation connector
c163 cso30:c:InputProcess connector
c164 cso30:c:OutputProcess connector
p54_propro_p54
PMID: 18641647
Subsequent IRF3 activation leads to IFNbeta production.
c165 cso30:c:InputProcess connector
c167 cso30:c:InputAssociation connector
c166 cso30:c:OutputProcess connector
p55_propro_p55
PMID: 18641647
Subsequent IRF3 activation leads to IFNbeta production.
PMID: 18641647, 17993619
Last, P2Y receptors, a family of G-protein-coupled receptors, downregulate IFNalpha secretion by human pDCs following stimulation by nucleotides such as ATP, ADP and UDP-glucose.
PMID: 18641647, 17993619
The nucleotides that bind to P2Y receptors are also known to be released and to accumulate at sites of cell stress and tissue damage.
PMID: 18641647, 16735691, 17850179
Activation of the BCR-like signalling pathway in pDCs potently suppresses the activation of both TLR7 and TLR9, inhibiting the production of all type I IFNs, as well as TNF and IL-6.
c169 cso30:c:InputAssociation connector
c170 cso30:c:InputAssociation connector
c424 cso30:c:InputInhibitor connector
c435 cso30:c:InputInhibitor connector
c437 cso30:c:InputInhibitor connector
c168 cso30:c:OutputProcess connector
p56_propro_p56
PMID: 18641647
The TLR3TRIF signalling pathway also activates NFkappaB and MAPKs and results in the production of pro-inflammatory cytokines and the expression of co-stimulatory molecules (CD80 and CD86).
c171 cso30:c:InputProcess connector
c173 cso30:c:InputAssociation connector
c172 cso30:c:OutputProcess connector
p57_propro_p57
PMID: 18641647
The TLR3TRIF signalling pathway also activates NFkappaB and MAPKs and results in the production of pro-inflammatory cytokines and the expression of co-stimulatory molecules (CD80 and CD86).
c174 cso30:c:InputProcess connector
c176 cso30:c:InputAssociation connector
c175 cso30:c:OutputProcess connector
p58_propro_p58
PMID: 18641647
The dsRNA receptors RIGI (retinoic-acid-inducible gene I), MDA5 (melanoma differentiation-associated gene 5) and LGP2 (laboratory of genetics and physiology 2) constitute the third nucleic-acid sensor system, exclusively located in the cytoplasm of most cells.
c177 cso30:c:InputProcess connector
c178 cso30:c:InputProcess connector
c179 cso30:c:OutputProcess connector
p59_propro_p59
PMID: 18641647
The dsRNA receptors RIGI (retinoic-acid-inducible gene I), MDA5 (melanoma differentiation-associated gene 5) and LGP2 (laboratory of genetics and physiology 2) constitute the third nucleic-acid sensor system, exclusively located in the cytoplasm of most cells.
c180 cso30:c:InputProcess connector
c181 cso30:c:InputProcess connector
c182 cso30:c:OutputProcess connector
p60_propro_p60
PMID: 18641647
The dsRNA receptors RIGI (retinoic-acid-inducible gene I), MDA5 (melanoma differentiation-associated gene 5) and LGP2 (laboratory of genetics and physiology 2) constitute the third nucleic-acid sensor system, exclusively located in the cytoplasm of most cells.
c183 cso30:c:InputProcess connector
c185 cso30:c:InputProcess connector
c184 cso30:c:OutputProcess connector
p61_propro_p61
PMID: 18641647
RIGI, MDA5 and LGP2 signal through a common adaptor molecule IPS1 (IFNB-promoter stimulator 1), which is associated with the mitochondria.
c186 cso30:c:InputProcess connector
c192 cso30:c:InputProcess connector
c189 cso30:c:OutputProcess connector
p62_propro_p62
PMID: 18641647
RIGI, MDA5 and LGP2 signal through a common adaptor molecule IPS1 (IFNB-promoter stimulator 1), which is associated with the mitochondria.
c187 cso30:c:InputProcess connector
c193 cso30:c:InputProcess connector
c190 cso30:c:OutputProcess connector
p63_propro_p63
PMID: 18641647
RIGI, MDA5 and LGP2 signal through a common adaptor molecule IPS1 (IFNB-promoter stimulator 1), which is associated with the mitochondria.
c188 cso30:c:InputProcess connector
c194 cso30:c:InputProcess connector
c191 cso30:c:OutputProcess connector
p64_propro_p64
PMID: 18641647
By coupling with TRAF3, TBK1 and IKKepsilon, IPS1 directly activates IRF3 and NFkappaB through FADD (FAS-associated via death domain), caspase8 and caspase10.
c196 cso30:c:InputProcess connector
c197 cso30:c:InputProcess connector
c195 cso30:c:OutputProcess connector
p65_propro_p65
PMID: 18641647
By coupling with TRAF3, TBK1 and IKKepsilon, IPS1 directly activates IRF3 and NFkappaB through FADD (FAS-associated via death domain), caspase8 and caspase10.
c198 cso30:c:InputAssociation connector
c199 cso30:c:InputProcess connector
c200 cso30:c:OutputProcess connector
p66_propro_p66
PMID: 18641647
By coupling with TRAF3, TBK1 and IKKepsilon, IPS1 directly activates IRF3 and NFkappaB through FADD (FAS-associated via death domain), caspase8 and caspase10.
c201 cso30:c:InputAssociation connector
c202 cso30:c:InputProcess connector
c203 cso30:c:OutputProcess connector
p68_propro_p68
PMID: 18641647
By coupling with TRAF3, TBK1 and IKKepsilon, IPS1 directly activates IRF3 and NFkappaB through FADD (FAS-associated via death domain), caspase8 and caspase10.
c206 cso30:c:InputAssociation connector
c208 cso30:c:InputProcess connector
c207 cso30:c:OutputProcess connector
p67_propro_p67
PMID: 18641647, 17653195
First, a recently described molecule termed DNA-dependent activator of IRFs (DAI) has been shown in vitro to act as a cytosolic DNA sensor by binding dsDNA and signalling through TBK1 and IRF3 to activate NF-kappaB and induce type I IFN production.
c204 cso30:c:InputProcess connector
c209 cso30:c:InputProcess connector
c205 cso30:c:OutputProcess connector
p69_propro_p69
PMID: 18641647, 17653195
First, a recently described molecule termed DNA-dependent activator of IRFs (DAI) has been shown in vitro to act as a cytosolic DNA sensor by binding dsDNA and signalling through TBK1 and IRF3 to activate NF-kappaB and induce type I IFN production.
c210 cso30:c:InputProcess connector
c212 cso30:c:InputAssociation connector
c211 cso30:c:OutputProcess connector
p70_propro_p70
PMID: 18641647, 17653195
First, a recently described molecule termed DNA-dependent activator of IRFs (DAI) has been shown in vitro to act as a cytosolic DNA sensor by binding dsDNA and signalling through TBK1 and IRF3 to activate NF-kappaB and induce type I IFN production.
c213 cso30:c:InputProcess connector
c215 cso30:c:InputAssociation connector
c214 cso30:c:OutputProcess connector
p71_propro_p71
PMID: 18641647, 17653195
First, a recently described molecule termed DNA-dependent activator of IRFs (DAI) has been shown in vitro to act as a cytosolic DNA sensor by binding dsDNA and signalling through TBK1 and IRF3 to activate NF-kappaB and induce type I IFN production.
c216 cso30:c:InputProcess connector
c218 cso30:c:InputAssociation connector
c217 cso30:c:OutputProcess connector
p72_propro_p72
PMID: 18641647, 17653195
First, a recently described molecule termed DNA-dependent activator of IRFs (DAI) has been shown in vitro to act as a cytosolic DNA sensor by binding dsDNA and signalling through TBK1 and IRF3 to activate NF-kappaB and induce type I IFN production.
PMID: 18641647
This ITAM-mediated pathway potently inhibits type I interferon (IFN) and cytokine production by pDCs in response to Toll-like receptor (TLR) activation.
PMID: 18641647, 16735691, 17850179
Activation of the BCR-like signalling pathway in pDCs potently suppresses the activation of both TLR7 and TLR9, inhibiting the production of all type I IFNs, as well as TNF and IL-6.
c220 cso30:c:InputAssociation connector
c221 cso30:c:InputAssociation connector
c392 cso30:c:InputInhibitor connector
c439 cso30:c:InputInhibitor connector
c219 cso30:c:OutputProcess connector
p73_propro_p73
PMID: 18641647, 18048689
For example, RNAs with short stem-loops can activate IFNinducible dsRNA-dependent protein kinase R (PKR) in a 5'-triphosphate-dependent manner, independent of RIG-I.
c222 cso30:c:InputProcess connector
c224 cso30:c:InputAssociation connector
c225 cso30:c:InputAssociation connector
c223 cso30:c:OutputProcess connector
p74_propro_p74
PMID: 18641647, 17653195
In addition, activation of the ribonuclease L by 2′,5′-linked oligoadenylate leads to the production of small RNA cleavage products from self RNA, which then function to amplify antiviral IFN responses.
c227 cso30:c:InputAssociation connector
c226 cso30:c:OutputProcess connector
c231 cso30:c:OutputProcess connector
p75_propro_p75
PMID: 18641647, 17653195
In addition, activation of the ribonuclease L by 2′,5′-linked oligoadenylate leads to the production of small RNA cleavage products from self RNA, which then function to amplify antiviral IFN responses.
c228 cso30:c:InputProcess connector
c230 cso30:c:InputAssociation connector
c229 cso30:c:OutputProcess connector
p76_propro_p76
PMID: 18641647, 11790540
In most cells, the production of IFN-alpha depends on type I IFN receptor (IFNAR) triggering by IFN-beta, which results in IRF7 induction.
c232 cso30:c:InputProcess connector
c233 cso30:c:OutputProcess connector
p77_propro_p77
PMID: 18641647, 11790540
In most cells, the production of IFN-alpha depends on type I IFN receptor (IFNAR) triggering by IFN-beta, which results in IRF7 induction.
c234 cso30:c:InputProcess connector
c235 cso30:c:InputProcess connector
c236 cso30:c:OutputProcess connector
p78_propro_p78
PMID: 18641647, 11790540
In most cells, the production of IFN-alpha depends on type I IFN receptor (IFNAR) triggering by IFN-beta, which results in IRF7 induction.
PMID: 18641647, 16415873
The prolonged retention of multimeric A-type CpG ODNs provides a platform for extended activation of the signal-transducing complex, consisting of MyD88 and IRF7, which leads to robust type I IFN production.
PMID: 18641647
This ITAM-mediated pathway potently inhibits type I interferon (IFN) and cytokine production by pDCs in response to Toll-like receptor (TLR) activation.
PMID: 18641647, 16735691, 17850179
Activation of the BCR-like signalling pathway in pDCs potently suppresses the activation of both TLR7 and TLR9, inhibiting the production of all type I IFNs, as well as TNF and IL-6.
c238 cso30:c:InputAssociation connector
c394 cso30:c:InputInhibitor connector
c239 cso30:c:InputAssociation connector
c434 cso30:c:InputInhibitor connector
c237 cso30:c:OutputProcess connector
p79_propro_p79
PMID: 18641647, 17702615, 12538667
IRF8 can further amplify the IFN response during the second phase of type I IFN gene transcription in pDCs.
c241 cso30:c:InputAssociation connector
c240 cso30:c:OutputProcess connector
p80_propro_p80
PMID: 18641647, 17360658, 17513736, 15665823
Aside from IRF7, IRF5 directly interacts with MyD88 and mediates the TLR-dependent induction of type I IFNs and pro-inflammatory cytokines, including IL-6 and TNF.
PMID: 18641647, 15665823
However, IRF4 competes with IRF5, but not IRF7, to interact with MyD88, thereby negatively regulating cytokine production induced by TLR stimulation.
c242 cso30:c:InputProcess connector
c243 cso30:c:InputProcess connector
c266 cso30:c:InputInhibitor connector
c244 cso30:c:OutputProcess connector
p81_propro_p81
PMID: 18641647, 17360658, 17513736, 15665823
Aside from IRF7, IRF5 directly interacts with MyD88 and mediates the TLR-dependent induction of type I IFNs and pro-inflammatory cytokines, including IL-6 and TNF.
c249 cso30:c:InputAssociation connector
c245 cso30:c:OutputProcess connector
p82_propro_p82
PMID: 18641647, 17360658, 17513736, 15665823
Aside from IRF7, IRF5 directly interacts with MyD88 and mediates the TLR-dependent induction of type I IFNs and pro-inflammatory cytokines, including IL-6 and TNF.
c250 cso30:c:InputAssociation connector
c246 cso30:c:OutputProcess connector
p83_propro_p83
PMID: 18641647, 17360658, 17513736, 15665823
Aside from IRF7, IRF5 directly interacts with MyD88 and mediates the TLR-dependent induction of type I IFNs and pro-inflammatory cytokines, including IL-6 and TNF.
c251 cso30:c:InputAssociation connector
c247 cso30:c:OutputProcess connector
p84_propro_p84
PMID: 18641647, 17360658, 17513736, 15665823
Aside from IRF7, IRF5 directly interacts with MyD88 and mediates the TLR-dependent induction of type I IFNs and pro-inflammatory cytokines, including IL-6 and TNF.
c252 cso30:c:InputAssociation connector
c248 cso30:c:OutputProcess connector
p85_propro_p85
PMID: 18641647, 17360658, 17513736, 15665823
Aside from IRF7, IRF5 directly interacts with MyD88 and mediates the TLR-dependent induction of type I IFNs and pro-inflammatory cytokines, including IL-6 and TNF.
c255 cso30:c:InputAssociation connector
c254 cso30:c:OutputProcess connector
p86_propro_p86
PMID: 18641647, 17360658, 17513736, 15665823
Aside from IRF7, IRF5 directly interacts with MyD88 and mediates the TLR-dependent induction of type I IFNs and pro-inflammatory cytokines, including IL-6 and TNF.
c253 cso30:c:InputAssociation connector
c256 cso30:c:OutputProcess connector
p87_propro_p87
PMID: 18641647, 17360658, 17513736, 15665823
Aside from IRF7, IRF5 directly interacts with MyD88 and mediates the TLR-dependent induction of type I IFNs and pro-inflammatory cytokines, including IL-6 and TNF.
c258 cso30:c:InputAssociation connector
c257 cso30:c:OutputProcess connector
p88_propro_p88
PMID: 18641647, 17360658, 17513736, 15665823
Aside from IRF7, IRF5 directly interacts with MyD88 and mediates the TLR-dependent induction of type I IFNs and pro-inflammatory cytokines, including IL-6 and TNF.
c260 cso30:c:InputAssociation connector
c259 cso30:c:OutputProcess connector
p89_propro_p89
PMID: 18641647, 17360658, 17513736, 15665823
Aside from IRF7, IRF5 directly interacts with MyD88 and mediates the TLR-dependent induction of type I IFNs and pro-inflammatory cytokines, including IL-6 and TNF.
c261 cso30:c:InputAssociation connector
c262 cso30:c:OutputProcess connector
p90_propro_p90
PMID: 18641647, 15665823
However, IRF4 competes with IRF5, but not IRF7, to interact with MyD88, thereby negatively regulating cytokine production induced by TLR stimulation.
c263 cso30:c:InputProcess connector
c264 cso30:c:InputProcess connector
c265 cso30:c:OutputProcess connector
p91_propro_p91
PMID: 18641647
Resting plasmacytoid dendritic cells (pDCs) predominantly express Toll-like receptor 7 (TLR7) and TLR9, which reside in the endoplasmic reticulum (ER) in association with UNC93B and gp96.
PMID: 18641647, 16415873, 17452530
The delivery of TLRs to endolysosomes and their subsequent proper activation requires UNC93B, an ER-resident transmembrane protein that can specifically interact with TLR3, TLR7 and TLR9.
c267 cso30:c:InputProcess connector
c270 cso30:c:InputProcess connector
c273 cso30:c:InputProcess connector
c276 cso30:c:OutputProcess connector
p92_propro_p92
PMID: 18641647
Resting plasmacytoid dendritic cells (pDCs) predominantly express Toll-like receptor 7 (TLR7) and TLR9, which reside in the endoplasmic reticulum (ER) in association with UNC93B and gp96.
PMID: 18641647, 16415873, 17452530
The delivery of TLRs to endolysosomes and their subsequent proper activation requires UNC93B, an ER-resident transmembrane protein that can specifically interact with TLR3, TLR7 and TLR9.
c268 cso30:c:InputProcess connector
c271 cso30:c:InputProcess connector
c274 cso30:c:InputProcess connector
c277 cso30:c:OutputProcess connector
p93_propro_p93
PMID: 18641647
Resting plasmacytoid dendritic cells (pDCs) predominantly express Toll-like receptor 7 (TLR7) and TLR9, which reside in the endoplasmic reticulum (ER) in association with UNC93B and gp96.
PMID: 18641647, 16415873, 17452530
The delivery of TLRs to endolysosomes and their subsequent proper activation requires UNC93B, an ER-resident transmembrane protein that can specifically interact with TLR3, TLR7 and TLR9.
c269 cso30:c:InputProcess connector
c272 cso30:c:InputProcess connector
c275 cso30:c:InputProcess connector
c278 cso30:c:OutputProcess connector
p99_propro_p99
PMID: 18641647, 11160284, 11561001, 7700380
On the other hand, B-type CpG ODNs can activate B cells but only trigger pDCs to produce the pro-inflammatory cytokines TNF and IL-6, and small amounts of IFN, as well as inducing the upregulation of CD80, CD86 and the expression of MHC class II molecules.
c282 cso30:c:InputAssociation connector
c291 cso30:c:OutputProcess connector
p100_propro_p100
PMID: 18641647, 16415873
The prolonged retention of multimeric A-type CpG ODNs provides a platform for extended activation of the signal-transducing complex, consisting of MyD88 and IRF7, which leads to robust type I IFN production.
c293 cso30:c:InputProcess connector
c294 cso30:c:InputProcess connector
c292 cso30:c:OutputProcess connector
p101_propro_p101
PMID: 18641647, 16415873
The prolonged retention of multimeric A-type CpG ODNs provides a platform for extended activation of the signal-transducing complex, consisting of MyD88 and IRF7, which leads to robust type I IFN production.
c295 cso30:c:InputProcess connector
c297 cso30:c:InputAssociation connector
c296 cso30:c:OutputProcess connector
p102_propro_p102
PMID: 18641647, 16415873
The prolonged retention of multimeric A-type CpG ODNs provides a platform for extended activation of the signal-transducing complex, consisting of MyD88 and IRF7, which leads to robust type I IFN production.
PMID: 18641647
Aggregated self-DNALL37 complexes are retained in the early endosomes of pDCs, and, similar to A-type CpG ODNs, they trigger the TLR9MyD88IRF7 pathway of type I IFN production without inducing pDC maturation.
c298 cso30:c:InputProcess connector
c300 cso30:c:InputAssociation connector
c299 cso30:c:OutputProcess connector
p103_propro_p103
PMID: 18641647, 16415873
The prolonged retention of multimeric A-type CpG ODNs provides a platform for extended activation of the signal-transducing complex, consisting of MyD88 and IRF7, which leads to robust type I IFN production.
PMID: 18641647
Aggregated self-DNALL37 complexes are retained in the early endosomes of pDCs, and, similar to A-type CpG ODNs, they trigger the TLR9MyD88IRF7 pathway of type I IFN production without inducing pDC maturation.
c301 cso30:c:InputProcess connector
c302 cso30:c:OutputProcess connector
c303 cso30:c:OutputProcess connector
c304 cso30:c:OutputProcess connector
c305 cso30:c:OutputProcess connector
p94_propro_p94
PMID: 18641647, 16415873
The prolonged retention of multimeric A-type CpG ODNs provides a platform for extended activation of the signal-transducing complex, consisting of MyD88 and IRF7, which leads to robust type I IFN production.
PMID: 18641647
This ITAM-mediated pathway potently inhibits type I interferon (IFN) and cytokine production by pDCs in response to Toll-like receptor (TLR) activation.
PMID: 18641647, 16735691, 17850179
Activation of the BCR-like signalling pathway in pDCs potently suppresses the activation of both TLR7 and TLR9, inhibiting the production of all type I IFNs, as well as TNF and IL-6.
c279 cso30:c:InputAssociation connector
c393 cso30:c:InputInhibitor connector
c436 cso30:c:InputInhibitor connector
c280 cso30:c:OutputProcess connector
p104_propro_p104
PMID: 18641647, 16415873
The prolonged retention of multimeric A-type CpG ODNs provides a platform for extended activation of the signal-transducing complex, consisting of MyD88 and IRF7, which leads to robust type I IFN production.
PMID: 18641647, 16735691, 17850179
Activation of the BCR-like signalling pathway in pDCs potently suppresses the activation of both TLR7 and TLR9, inhibiting the production of all type I IFNs, as well as TNF and IL6.
c306 cso30:c:InputAssociation connector
c438 cso30:c:InputInhibitor connector
c281 cso30:c:OutputProcess connector
p105_propro_p105
PMID: 18641647, 16415873
The prolonged retention of multimeric A-type CpG ODNs provides a platform for extended activation of the signal-transducing complex, consisting of MyD88 and IRF7, which leads to robust type I IFN production.
PMID: 18641647
This ITAM-mediated pathway potently inhibits type I interferon (IFN) and cytokine production by pDCs in response to Toll-like receptor (TLR) activation.
PMID: 18641647, 16735691, 17850179
Activation of the BCR-like signalling pathway in pDCs potently suppresses the activation of both TLR7 and TLR9, inhibiting the production of all type I IFNs, as well as TNF and IL-6.
c307 cso30:c:InputAssociation connector
c395 cso30:c:InputInhibitor connector
c440 cso30:c:InputInhibitor connector
c308 cso30:c:OutputProcess connector
p106_propro_p106
PMID: 18641647, 15591070, 15815647, 16864658
Conversely, liposome or particle encapsidation of B-type CpG ODNs allows their retention in early endosomes and the subsequent induction of much higher levels of type I IFNs and lower levels of IL-6 and TNF and impaired pDC maturation, which supports the important link between the physical size of TLR9 ligands and their stimulatory capacity.
c311 cso30:c:InputProcess connector
c321 cso30:c:InputAssociation connector
c309 cso30:c:OutputProcess connector
p107_propro_p107
PMID: 18641647
This presumably activates a different set of signal mediators, particularly NF-kappaB (nuclear factor-kappaB) and probably MAPKs (mitogen-activated protein kinases) and IRF5, and thereby leads to distinct outcomes of pDC activation without high levels of IFN production.
c312 cso30:c:InputProcess connector
c314 cso30:c:InputAssociation connector
c313 cso30:c:OutputProcess connector
p108_propro_p108
PMID: 18641647
Interestingly, when A-type CpG ODNs are disrupted into monomeric structures, they fail to be retained in the early endosome and to induce high amounts of type I IFN production, but instead rapidly traffic to late endosomes and induce maturation and production of IL-6 and TNF.
PMID: 18641647
This ITAM-mediated pathway potently inhibits type I interferon (IFN) and cytokine production by pDCs in response to Toll-like receptor (TLR) activation.
PMID: 18641647, 16735691, 17850179
Activation of the BCR-like signalling pathway in pDCs potently suppresses the activation of both TLR7 and TLR9, inhibiting the production of all type I IFNs, as well as TNF and IL-6.
c317 cso30:c:InputAssociation connector
c396 cso30:c:InputInhibitor connector
c441 cso30:c:InputInhibitor connector
c315 cso30:c:OutputProcess connector
p109_propro_p109
PMID: 18641647
Interestingly, when A-type CpG ODNs are disrupted into monomeric structures, they fail to be retained in the early endosome and to induce high amounts of type I IFN production, but instead rapidly traffic to late endosomes and induce maturation and production of IL-6 and TNF.
PMID: 18641647
This ITAM-mediated pathway potently inhibits type I interferon (IFN) and cytokine production by pDCs in response to Toll-like receptor (TLR) activation.
PMID: 18641647, 16735691, 17850179
Activation of the BCR-like signalling pathway in pDCs potently suppresses the activation of both TLR7 and TLR9, inhibiting the production of all type I IFNs, as well as TNF and IL-6.
c318 cso30:c:InputAssociation connector
c397 cso30:c:InputInhibitor connector
c442 cso30:c:InputInhibitor connector
c316 cso30:c:OutputProcess connector
p110_propro_p110
PMID: 18641647, 15591070, 15815647, 16864658
Conversely, liposome or particle encapsidation of B-type CpG ODNs allows their retention in early endosomes and the subsequent induction of much higher levels of type I IFNs and lower levels of IL-6 and TNF and impaired pDC maturation, which supports the important link between the physical size of TLR9 ligands and their stimulatory capacity.
c310 cso30:c:InputProcess connector
c320 cso30:c:InputProcess connector
c319 cso30:c:OutputProcess connector
p111_propro_p111
PMID: 18641647
Interestingly, when A-type CpG ODNs are disrupted into monomeric structures, they fail to be retained in the early endosome and to induce high amounts of type I IFN production, but instead rapidly traffic to late endosomes and induce maturation and production of IL-6 and TNF.
c322 cso30:c:InputProcess connector
c324 cso30:c:InputAssociation connector
c323 cso30:c:OutputProcess connector
p112_propro_p112
PMID: 18641647
This presumably activates a different set of signal mediators, particularly NF-kappaB (nuclear factor-kappaB) and probably MAPKs (mitogen-activated protein kinases) and IRF5, and thereby leads to distinct outcomes of pDC activation without high levels of IFN production.
c325 cso30:c:InputProcess connector
c327 cso30:c:InputAssociation connector
c326 cso30:c:OutputProcess connector
p95_propro_p95
PMID: 18641647
The antimicrobial peptide LL37 is secreted by damaged epithelial cells or deposited by tissue-infiltrating neutrophils. It binds self-DNA fragments released by dying cells to form aggregated and condensed structures that are protected from extracellular nuclease degradation and delivered via lipid rafts from the extracellular environment into the early endosomes of plasmacytoid dendritic cells (pDCs).
c283 cso30:c:InputProcess connector
c284 cso30:c:InputProcess connector
c285 cso30:c:OutputProcess connector
p96_propro_p96
PMID: 18641647
Dying cells also release high-mobility group box 1 protein (HMGB1), which binds aggregated self-DNALL37 complexes and promotes their association with Toll-like receptor 9 (TLR9) in early endosomes by binding to RAGE (receptor for advanced glycation end-products).
PMID: 18641647
Interestingly, in contrast to LL37, HMGB1 can only bind multimeric aggregated DNA structures, such as A-type CpG ODNs, and not monomeric DNA sequences, such as B-type CpG ODNs.
c286 cso30:c:InputProcess connector
c287 cso30:c:InputProcess connector
c288 cso30:c:OutputProcess connector
p97_propro_p97
PMID: 18641647
Dying cells also release high-mobility group box 1 protein (HMGB1), which binds aggregated self-DNALL37 complexes and promotes their association with Toll-like receptor 9 (TLR9) in early endosomes by binding to RAGE (receptor for advanced glycation end-products).
c290 cso30:c:InputProcess connector
c340 cso30:c:InputProcess connector
c328 cso30:c:OutputProcess connector
p98_propro_p98
PMID: 18641647
Dying cells also release high-mobility group box 1 protein (HMGB1), which binds aggregated self-DNALL37 complexes and promotes their association with Toll-like receptor 9 (TLR9) in early endosomes by binding to RAGE (receptor for advanced glycation end-products).
c329 cso30:c:InputProcess connector
c330 cso30:c:InputProcess connector
c331 cso30:c:OutputProcess connector
c332 cso30:c:OutputProcess connector
p113_propro_p113
PMID: 18641647
Aggregated self-DNALL37 complexes are retained in the early endosomes of pDCs, and, similar to A-type CpG ODNs, they trigger the TLR9MyD88IRF7 pathway of type I IFN production without inducing pDC maturation.
c333 cso30:c:InputProcess connector
c334 cso30:c:InputProcess connector
c335 cso30:c:OutputProcess connector
p114_propro_p114
PMID: 18641647
Aggregated self-DNALL37 complexes are retained in the early endosomes of pDCs, and, similar to A-type CpG ODNs, they trigger the TLR9MyD88IRF7 pathway of type I IFN production without inducing pDC maturation.
c336 cso30:c:InputProcess connector
c338 cso30:c:InputAssociation connector
c337 cso30:c:OutputProcess connector
p115_propro_p115
PMID: 18641647
After internalization, the self-DNALL37HMGB1 complex associates with TLR9 in early endosomes by engaging RAGE.
c289 cso30:c:InputProcess connector
c339 cso30:c:OutputProcess connector
p116_propro_p116
PMID: 18641647
DNA-specific IgG antibodies can bind self-DNALL37HMGB1 complexes and potently enhance the internalization of the complex through FcgammaRIIA.
c341 cso30:c:InputProcess connector
c342 cso30:c:InputProcess connector
c343 cso30:c:OutputProcess connector
p117_propro_p117
PMID: 18641647
DNA-specific IgG antibodies can bind self-DNALL37HMGB1 complexes and potently enhance the internalization of the complex through FcgammaRIIA.
c344 cso30:c:InputProcess connector
c345 cso30:c:InputProcess connector
c346 cso30:c:OutputProcess connector
p118_propro_p118
c347 cso30:c:InputProcess connector
c348 cso30:c:InputProcess connector
c349 cso30:c:OutputProcess connector
c350 cso30:c:OutputProcess connector
p119_propro_p119
PMID: 18641647, 11711679
The ongoing production of type I IFNs by pDCs in these patients induces an unabated activation and maturation of mDCs that stimulate autoreactive T cells.
c351 cso30:c:InputAssociation connector
p120_propro_p120
PMID: 18641647, 12932356
Furthermore, pDC-derived type I IFNs, together with IL-6, stimulate the differentiation of autoreactive B cells into autoantibody-secreting plasma cells.
c352 cso30:c:InputAssociation connector
c353 cso30:c:InputAssociation connector
p121_propro_p121
PMID: 18641647, 16330816
However, self-RNA molecules, in particular those rich in uridine or uridine and guanosine (U/UGRNA) and those in small nuclear ribonucleoprotein (snRNP), were shown to trigger pDCs to produce type I IFNs through TLR7 when delivered to endosomes by autoantibodies or liposomes.
c354 cso30:c:InputProcess connector
c355 cso30:c:InputProcess connector
c360 cso30:c:InputAssociation connector
c356 cso30:c:OutputProcess connector
p122_propro_p122
PMID: 18641647, 16330816
However, self-RNA molecules, in particular those rich in uridine or uridine and guanosine (U/UGRNA) and those in small nuclear ribonucleoprotein (snRNP), were shown to trigger pDCs to produce type I IFNs through TLR7 when delivered to endosomes by autoantibodies or liposomes.
PMID: 18641647
This ITAM-mediated pathway potently inhibits type I interferon (IFN) and cytokine production by pDCs in response to Toll-like receptor (TLR) activation.
PMID: 18641647, 16735691, 17850179
Activation of the BCR-like signalling pathway in pDCs potently suppresses the activation of both TLR7 and TLR9, inhibiting the production of all type I IFNs, as well as TNF and IL6.
c357 cso30:c:InputAssociation connector
c359 cso30:c:InputAssociation connector
c391 cso30:c:InputInhibitor connector
c443 cso30:c:InputInhibitor connector
c358 cso30:c:OutputProcess connector
p123_propro_p123
PMID: 18641647, 16735691, 17850179
Both BDCA2 and ILT7 associate with the γchain of the highaffinity Fc receptor for IgE (FcepsilonRIgamma) and activate pDCs through an immunoreceptor-based tyrosine activation motif (ITAM)-mediated signalling pathway.
c362 cso30:c:InputProcess connector
c363 cso30:c:InputProcess connector
c361 cso30:c:OutputProcess connector
p124_propro_p124
PMID: 18641647, 16735691, 17850179
Both BDCA2 and ILT7 associate with the γchain of the highaffinity Fc receptor for IgE (FcepsilonRIgamma) and activate pDCs through an immunoreceptor-based tyrosine activation motif (ITAM)-mediated signalling pathway.
c364 cso30:c:InputProcess connector
c365 cso30:c:InputProcess connector
c366 cso30:c:OutputProcess connector
p125_propro_p125
PMID: 18641647, 15941912
Crosslinking of NKp44, a receptor that signals through the ITAM-bearing adaptor DAP12, inhibits IFNalpha production induced by CpG ODNs.
c367 cso30:c:InputProcess connector
c368 cso30:c:InputProcess connector
c369 cso30:c:OutputProcess connector
p126_propro_p126
PMID: 18641647, 16293595
In mice, antibody crosslinking of Siglec-H (sialicacid-binding immunoglobulin-like lectin H), another DAP12-associated receptor expressed by pDCs, reduces type I IFN production by pDCs in vitro and in vivo.
c370 cso30:c:InputProcess connector
c371 cso30:c:InputProcess connector
c372 cso30:c:OutputProcess connector
p127_propro_p127
PMID: 18641647
These receptor complexes or receptors with intrinsic ITAMs, such as FcgammaRIIA, signal through their ITAMs and activate a B-cell receptor (BCR)-like pathway that involves SRC family protein tyrosine kinases (PTKs), SYK (spleen tyrosine kinase) and the B-cell-specific adaptors BLNK (B-cell linker) and BCAP (B-cell adaptor protein).
c373 cso30:c:InputProcess connector
c381 cso30:c:InputAssociation connector
c374 cso30:c:OutputProcess connector
p128_propro_p128
PMID: 18641647
These receptor complexes or receptors with intrinsic ITAMs, such as FcgammaRIIA, signal through their ITAMs and activate a B-cell receptor (BCR)-like pathway that involves SRC family protein tyrosine kinases (PTKs), SYK (spleen tyrosine kinase) and the B-cell-specific adaptors BLNK (B-cell linker) and BCAP (B-cell adaptor protein).
c375 cso30:c:InputProcess connector
c382 cso30:c:InputAssociation connector
c376 cso30:c:OutputProcess connector
p129_propro_p129
PMID: 18641647
These receptor complexes or receptors with intrinsic ITAMs, such as FcgammaRIIA, signal through their ITAMs and activate a B-cell receptor (BCR)-like pathway that involves SRC family protein tyrosine kinases (PTKs), SYK (spleen tyrosine kinase) and the B-cell-specific adaptors BLNK (B-cell linker) and BCAP (B-cell adaptor protein).
c377 cso30:c:InputProcess connector
c383 cso30:c:InputAssociation connector
c378 cso30:c:OutputProcess connector
p130_propro_p130
PMID: 18641647
These receptor complexes or receptors with intrinsic ITAMs, such as FcgammaRIIA, signal through their ITAMs and activate a B-cell receptor (BCR)-like pathway that involves SRC family protein tyrosine kinases (PTKs), SYK (spleen tyrosine kinase) and the B-cell-specific adaptors BLNK (B-cell linker) and BCAP (B-cell adaptor protein).
c379 cso30:c:InputProcess connector
c384 cso30:c:InputAssociation connector
c380 cso30:c:OutputProcess connector
p131_propro_p131
PMID: 18641647
These receptor complexes or receptors with intrinsic ITAMs, such as FcgammaRIIA, signal through their ITAMs and activate a B-cell receptor (BCR)-like pathway that involves SRC family protein tyrosine kinases (PTKs), SYK (spleen tyrosine kinase) and the B-cell-specific adaptors BLNK (B-cell linker) and BCAP (B-cell adaptor protein).
c385 cso30:c:InputProcess connector
c387 cso30:c:InputAssociation connector
c386 cso30:c:OutputProcess connector
p132_propro_p132
PMID: 18641647
These receptor complexes or receptors with intrinsic ITAMs, such as FcgammaRIIA, signal through their ITAMs and activate a B-cell receptor (BCR)-like pathway that involves SRC family protein tyrosine kinases (PTKs), SYK (spleen tyrosine kinase) and the B-cell-specific adaptors BLNK (B-cell linker) and BCAP (B-cell adaptor protein).
c388 cso30:c:InputProcess connector
c390 cso30:c:InputAssociation connector
c389 cso30:c:OutputProcess connector
p133_propro_p133
PMID: 18641647
These receptor complexes or receptors with intrinsic ITAMs, such as FcgammaRIIA, signal through their ITAMs and activate a B-cell receptor (BCR)-like pathway that involves SRC family protein tyrosine kinases (PTKs), SYK (spleen tyrosine kinase) and the B-cell-specific adaptors BLNK (B-cell linker) and BCAP (B-cell adaptor protein).
c398 cso30:c:InputAssociation connector
c399 cso30:c:InputProcess connector
c400 cso30:c:OutputProcess connector
p134_propro_p134
PMID: 18641647
However, PDC-TREM (triggering receptor expressed on myeloid cells), a newly discovered pDC-specific transmembrane receptor that forms a complex with plexin A1, is activated by its endogenous ligand semaphorin 6D to induce DAP12-mediated activation of PI3K and extracellular-signal-regulated kinase 1 (ERK1) and ERK2, which leads to enhanced levels of type I IFN production.
c401 cso30:c:InputProcess connector
c402 cso30:c:InputProcess connector
c403 cso30:c:OutputProcess connector
p135_propro_p135
PMID: 18641647
However, PDC-TREM (triggering receptor expressed on myeloid cells), a newly discovered pDC-specific transmembrane receptor that forms a complex with plexin A1, is activated by its endogenous ligand semaphorin 6D to induce DAP12-mediated activation of PI3K and extracellular-signal-regulated kinase 1 (ERK1) and ERK2, which leads to enhanced levels of type I IFN production.
c404 cso30:c:InputAssociation connector
c405 cso30:c:InputAssociation connector
c407 cso30:c:InputProcess connector
c406 cso30:c:OutputProcess connector
p136_propro_p136
PMID: 18641647
However, PDC-TREM (triggering receptor expressed on myeloid cells), a newly discovered pDC-specific transmembrane receptor that forms a complex with plexin A1, is activated by its endogenous ligand semaphorin 6D to induce DAP12-mediated activation of PI3K and extracellular-signal-regulated kinase 1 (ERK1) and ERK2, which leads to enhanced levels of type I IFN production.
c408 cso30:c:InputProcess connector
c412 cso30:c:InputAssociation connector
c414 cso30:c:InputAssociation connector
c409 cso30:c:OutputProcess connector
p137_propro_p137
PMID: 18641647
However, PDC-TREM (triggering receptor expressed on myeloid cells), a newly discovered pDC-specific transmembrane receptor that forms a complex with plexin A1, is activated by its endogenous ligand semaphorin 6D to induce DAP12-mediated activation of PI3K and extracellular-signal-regulated kinase 1 (ERK1) and ERK2, which leads to enhanced levels of type I IFN production.
c410 cso30:c:InputProcess connector
c413 cso30:c:InputAssociation connector
c415 cso30:c:InputAssociation connector
c411 cso30:c:OutputProcess connector
p138_propro_p138
PMID: 18641647
However, PDC-TREM (triggering receptor expressed on myeloid cells), a newly discovered pDC-specific transmembrane receptor that forms a complex with plexin A1, is activated by its endogenous ligand semaphorin 6D to induce DAP12-mediated activation of PI3K and extracellular-signal-regulated kinase 1 (ERK1) and ERK2, which leads to enhanced levels of type I IFN production.
c417 cso30:c:InputAssociation connector
c418 cso30:c:InputAssociation connector
c419 cso30:c:InputAssociation connector
c420 cso30:c:InputAssociation connector
c416 cso30:c:OutputProcess connector
p139_propro_p139
PMID: 18641647
However, PDC-TREM (triggering receptor expressed on myeloid cells), a newly discovered pDC-specific transmembrane receptor that forms a complex with plexin A1, is activated by its endogenous ligand semaphorin 6D to induce DAP12-mediated activation of PI3K and extracellular-signal-regulated kinase 1 (ERK1) and ERK2, which leads to enhanced levels of type I IFN production.
c421 cso30:c:InputProcess connector
c422 cso30:c:InputProcess connector
c423 cso30:c:OutputProcess connector
p140_propro_p140
PMID: 18641647, 17993619
The nucleotides that bind to P2Y receptors are also known to be released and to accumulate at sites of cell stress and tissue damage.
c425 cso30:c:InputProcess connector
c426 cso30:c:InputProcess connector
c427 cso30:c:OutputProcess connector
p141_propro_p141
PMID: 18641647, 16330816, 16260486
These self-RNA and autoantibody complexes were also shown to activate autoreactive B cells through the B-cell receptor (BCR) and endosomal TLR7.
c428 cso30:c:InputProcess connector
c430 cso30:c:InputAssociation connector
c429 cso30:c:OutputProcess connector
p142_propro_p142
PMID: 18641647, 16330816, 16260486
These self-RNA and autoantibody complexes were also shown to activate autoreactive B cells through the B-cell receptor (BCR) and endosomal TLR7.
c431 cso30:c:InputProcess connector
c433 cso30:c:InputProcess connector
c432 cso30:c:OutputProcess connector
p143_propro_p143
PMID: 18641647, 11160284
By contrast, myeloid DCs (mDCs) produced type I IFNs and interleukin12 (IL-12) in response to polyI:C but not to CpG-containing DNA.
c445 cso30:c:InputAssociation connector
c446 cso30:c:InputAssociation connector
c444 cso30:c:OutputProcess connector
p144_propro_p144
c447 cso30:c:InputAssociation connector
p145_propro_p145
PMID: 18641647, 11160295, 14971051
Interestingly, at the same time, Klinman and colleagues classified CpG ODNs into two main groups: D-type (now known as A-type) CpG ODNs, which stimulate IFNgamma production by natural killer (NK) cells, and K-type (now known as B-type) CpG ODNs, which stimulate B-cell proliferation and B-cell IL-6 and antibody production.
c448 cso30:c:InputAssociation connector
c450 cso30:c:InputAssociation connector
c449 cso30:c:OutputProcess connector
p146_propro_p146
PMID: 18641647, 11160295, 14971051
Interestingly, at the same time, Klinman and colleagues classified CpG ODNs into two main groups: D-type (now known as A-type) CpG ODNs, which stimulate IFNgamma production by natural killer (NK) cells, and K-type (now known as B-type) CpG ODNs, which stimulate B-cell proliferation and B-cell IL-6 and antibody production.
c451 cso30:c:InputAssociation connector
c453 cso30:c:InputAssociation connector
c452 cso30:c:OutputProcess connector
LPS_enti_MO000016882
LPS
TLR4_enti_e12
TLR4
TLR5_enti_e13
TLR5
LPS: TLR4_enti_e14
LPS: TLR4
flagellin: TLR5_enti_e15
flagellin: TLR5
flagellin_enti_e16
flagellin
Lp_enti_e17
Lp
TLR1: TLR2_enti_e18
TLR1: TLR2
Lp: TLR1: TLR2_enti_e19
Lp: TLR1: TLR2
TLR6: TLR2_enti_e21
TLR6: TLR2
PGN: TLR6: TLR2_enti_e22
PGN: TLR6: TLR2
PGN_enti_MO000042032
PGN
TLR8_enti_MO000042007
TLR8
TLR9_enti_MO000042012
TLR9
TLR7_enti_MO000042126
TLR7
TLR3_enti_MO000019398
TLR3
MyD88_enti_MO000016573
MyD88
IRAK_enti_MO000000213
IRAK
IRAK-4_enti_MO000039077
IRAK-4
TRAF6_enti_MO000000212
TRAF6
dsRNA_enti_MO000022224
dsRNA
dsRNA:TLR3_enti_MO000041446
dsRNA:TLR3
dsRNA:TLR3:TRIF_enti_MO000041437
dsRNA:TLR3:TRIF
Btk_enti_MO000001935
Btk
IRF-7_enti_MO000007702
IRF-7
IRF-7{p}_enti_MO000041457
IRF-7{p}
IRF-3_enti_MO000007694
IRF-3
IRF-3{p}_enti_MO000041456
IRF-3{p}
IRF-4_enti_MO000007697
IRF-4
IRF-8_enti_MO000007185
IRF-8
ssRNA_enti_e23
ssRNA
TBK1_enti_MO000019331
TBK1
ssRNA: TLR7_enti_e24
ssRNA: TLR7
ssRNA: TLR8_enti_e25
ssRNA: TLR8
p50:RelA-p65:IkappaB-alpha{p}_enti_MO000000254
p50:RelA-p65:IkappaB-alpha{p}
p50:RelA-p65{activated}_enti_MO000016632
p50:RelA-p65{activated}
p50:RelA-p65:IkappaB-alpha_enti_MO000038724
p50:RelA-p65:IkappaB-alpha
MDA-5_enti_MO000103999
MDA-5
CpG DNA: TLR9_enti_e26
CpG DNA: TLR9
TRIF_enti_MO000041125
TRIF
IPS1_enti_MO000094908
IPS1
IFN-alpha1_enti_G016992
IFN-alpha1
IFNalpha1_enti_MO000016659
IFNalpha1
IFNbeta_enti_MO000016660
IFNbeta
IFN-beta_enti_G010228
IFN-beta
imiquimod_enti_e27
imiquimod
IL-6_enti_G010262
IL-6
IL-6_enti_MO000007384
IL-6
TNF-alpha_enti_G010329
TNF-alpha
TNF-alpha_enti_MO000000289
TNF-alpha
imidazoquinoline: TLR7_enti_e28
imidazoquinoline: TLR7
imidazoquinoline: TLR8_enti_e29
imidazoquinoline: TLR8
MAPKs_enti_MO000000077
MAPKs
CD80_enti_G012224
CD80
CD86_enti_G010859
CD86
TRAF3_enti_MO000016963
TRAF3
OPN_enti_MO000061307
OPN
R-848_enti_e30
R-848
R-848: TLR8_enti_e31
R-848: TLR8
R-848: TLR7_enti_e32
R-848: TLR7
TAK1_enti_MO000016574
TAK1
guanosine analogues_enti_e33
guanosine analogues
guanosine analogues: TLR7_enti_e34
guanosine analogues: TLR7
guanosine analogues: TLR8_enti_e35
guanosine analogues: TLR8
CpG ss-DNA _enti_e36
CpG ss-DNA
LL37_enti_MO000000311
LL37
IKK-alpha_enti_MO000000210
IKK-alpha
CpG ODN_enti_e20
CpG ODN
CpG ODN: TLR9_enti_e37
CpG ODN: TLR9
LPS: TLR4: MAL_enti_e38
LPS: TLR4: MAL
MAL_enti_MO000068831
MAL
LPS: TLR4: MAL: MyD88_enti_e39
LPS: TLR4: MAL: MyD88
LPS: TLR4: TRAM_enti_e40
LPS: TLR4: TRAM
LPS: TLR4: TRAM: TRIF_enti_e41
LPS: TLR4: TRAM: TRIF
Lp: TLR1: TLR2: MAL_enti_e42
Lp: TLR1: TLR2: MAL
Lp: TLR1: TLR2: MAL: MyD88_enti_e43
Lp: TLR1: TLR2: MAL: MyD88
TRAM_enti_MO000041132
TRAM
poly I:C: TLR3_enti_e44
poly I:C: TLR3
Poly I:C: TLR3_enti_e45
Poly I:C: TLR3
ssRNA: TLR7: MyD88_enti_e46
ssRNA: TLR7: MyD88
ssRNA: TLR8: MyD88_enti_e47
ssRNA: TLR8: MyD88
CpG DNA: TLR9: MyD88_enti_e48
CpG DNA: TLR9: MyD88
ssRNA: TLR7: MyD88: IRAK-1: IRAK-4: TRAF6: BTK_enti_e49
ssRNA: TLR7: MyD88: IRAK-1: IRAK-4: TRAF6: BTK
ssRNA: TLR8: MyD88: IRAK-1: IRAK-4: TRAF6: BTK_enti_e63
ssRNA: TLR8: MyD88: IRAK-1: IRAK-4: TRAF6: BTK
CpG DNA: TLR9: MyD88: IRAK-1: IRAK-4: TRAF6: BTK_enti_e64
CpG DNA: TLR9: MyD88: IRAK-1: IRAK-4: TRAF6: BTK
MAPKs{activated}_enti_e65
MAPKs{activated}
IRAK-1: IRAK4:TRAF6: BTK{activated}_enti_e72
IRAK-1: IRAK4:TRAF6: BTK{activated}
IRAK-1: IRAK4:TRAF6: BTK: IRF-7_enti_e66
IRAK-1: IRAK4:TRAF6: BTK: IRF-7
IRAK-1: IRAK4:TRAF6: BTK: IRF-7{ub}_enti_e67
IRAK-1: IRAK4:TRAF6: BTK: IRF-7{ub}
IRAK1: IRF-7{ub}_enti_e69
IRAK1: IRF-7{ub}
IRAK-1: TRAF6: BTK_enti_e70
IRAK-1: TRAF6: BTK
IRAK1: IRF-7{ub}: TRAF3: TABK1: IKK-alpha: OPN: PI3K_enti_e68
IRAK1: IRF-7{ub}: TRAF3: TABK1: IKK-alpha: OPN: PI3K
PI3K_enti_MO000000030
PI3K
TAK1{activated}_enti_e71
TAK1{activated}
IRF-5_enti_MO000007700
IRF-5
IRF-5{activated}_enti_e73
IRF-5{activated}
IRF-7{ub}{p}_enti_e74
IRF-7{ub}{p}
IFNW1_enti_G012384
IFNW1
IFNL_enti_e75
IFNL
p50:RelA-p65{activated}_enti_e77
p50:RelA-p65{activated}
TRAF3: TBK1: IKK-i_enti_e76
TRAF3: TBK1: IKK-i
TRAF3: TBK1: IKK-i{activated}_enti_e78
TRAF3: TBK1: IKK-i{activated}
RIG-1_enti_e79
RIG-1
dsRNA_enti_e80
dsRNA
dsRNA: RIG-1_enti_e81
dsRNA: RIG-1
dsRNA: MDA-5_enti_e82
dsRNA: MDA-5
dsRNA: LGP2_enti_e83
dsRNA: LGP2
LGP2_enti_e84
LGP2
dsRNA: RIG-1: IPS1_enti_e94
dsRNA: RIG-1: IPS1
dsRNA: MDA-5: IPS1_enti_e95
dsRNA: MDA-5: IPS1
dsRNA: LGP2: IPS1_enti_e96
dsRNA: LGP2: IPS1
dsRNA: RIG1: IPS1: TRAF3: TBK1: IKK-i_enti_e97
dsRNA: RIG1: IPS1: TRAF3: TBK1: IKK-i
FADD: caspase-8_enti_e98
FADD: caspase-8
FADD: caspase-8{activated}_enti_e99
FADD: caspase-8{activated}
p50:RelA-p65{activated}_enti_e100
p50:RelA-p65{activated}
DAI_enti_MO000061425
DAI
dsRNA: DAI_enti_e101
dsRNA: DAI
TBK1{activated}_enti_e102
TBK1{activated}
IFN Type I_enti_MO000016658
IFN Type I
IFN Type I_enti_e103
IFN Type I
PKR_enti_MO000008179
PKR
PKR{activated}_enti_e104
PKR{activated}
5'-triphosphate_enti_e105
5'-triphosphate
self RNA_enti_e106
self RNA
RNASEL{activated}_enti_MO000061281
RNASEL{activated}
RNASEL_enti_e107
RNASEL
2', 5'--linked oligoadenylate_enti_e108
2', 5'--linked oligoadenylate
small RNA cleavage products_enti_e109
small RNA cleavage products
IFNAR_enti_e110
IFNAR
IFNbeta_enti_e111
IFNbeta
IFN beta: IFNAR_enti_e112
IFN beta: IFNAR
MyD88: IRF-5_enti_e113
MyD88: IRF-5
CD40_enti_G010691
CD40
MyD88: IRF-4_enti_e114
MyD88: IRF-4
UNC93B_enti_e115
UNC93B
gp96_enti_e119
gp96
TLR3: UNC93B: gp96_enti_e116
TLR3: UNC93B: gp96
TLR7: UNC93B: gp96_enti_e117
TLR7: UNC93B: gp96
TLR9: UNC93B: gp96_enti_e118
TLR9: UNC93B: gp96
A type CpG ODN: TLR9_enti_e120
A type CpG ODN: TLR9
Type B CpG ODN: TLR9_enti_e121
Type B CpG ODN: TLR9
MHC_enti_G010240
MHC
A type CpG ODN: TLR9: MyD88_enti_e122
A type CpG ODN: TLR9: MyD88
IRAK-4: TRAF6_enti_e123
IRAK-4: TRAF6
IRAK-4: TRAF6{activated}_enti_e124
IRAK-4: TRAF6{activated}
IRAK-1: TRAF3: OPN: IRF-7_enti_e125
IRAK-1: TRAF3: OPN: IRF-7
IRAK-1: TRAF3: OPN: IRF-7_enti_e126
IRAK-1: TRAF3: OPN: IRF-7
IFNL_enti_e127
IFNL
IFNW1_enti_e128
IFNW1
IRAK4:TRAF6: BTK_enti_e129
IRAK4:TRAF6: BTK
IRAK4:TRAF6: BTK_enti_e130
IRAK4:TRAF6: BTK
Type B CpG ODN: TLR9: MyD88_enti_e131
Type B CpG ODN: TLR9: MyD88
self DNA_enti_e132
self DNA
LL37: self DNA_enti_e133
LL37: self DNA
HMGB1_enti_e134
HMGB1
LL37: self DNA: HMGB1_enti_e135
LL37: self DNA: HMGB1
RAGE_enti_e136
RAGE
LL37: self DNA: HMGB1: RAGE_enti_e137
LL37: self DNA: HMGB1: RAGE
LL37: self DNA: HMGB1: TLR9_enti_e138
LL37: self DNA: HMGB1: TLR9
LL37: self DNA: HMGB1: TLR9: MyD88_enti_e139
LL37: self DNA: HMGB1: TLR9: MyD88
LL37: self DNA: HMGB1_enti_e140
LL37: self DNA: HMGB1
DNA-specific IgG antibody_enti_e141
DNA-specific IgG antibody
LL37: self DNA: HMGB1: DNA-specific IgG antibody_enti_e142
LL37: self DNA: HMGB1: DNA-specific IgG antibody
FCgammaRIIA_enti_e143
FCgammaRIIA
LL37: self DNA: HMGB1: DNA-specific IgG antibody: FCgammaRIIA_enti_e144
LL37: self DNA: HMGB1: DNA-specific IgG antibody: FCgammaRIIA
LL37: self DNA: HMGB1: DNA-specific IgG antibody: TLR9_enti_e145
LL37: self DNA: HMGB1: DNA-specific IgG antibody: TLR9
snRNA_enti_e146
snRNA
snRNA: TLR7_enti_e147
snRNA: TLR7
auto-antibody_enti_e148
auto-antibody
BDCA2ligand: BDCA2_enti_e149
BDCA2ligand: BDCA2
ILT7 ligand: ILT7_enti_e150
ILT7 ligand: ILT7
BDCA2ligand: BDCA2: IgE: FCepsilonRIgamma_enti_e151
BDCA2ligand: BDCA2: IgE: FCepsilonRIgamma
IgE: FCepsilonRIgamma_enti_e152
IgE: FCepsilonRIgamma
ILT7 ligand: ILT7: IgE: FCepsilonRIgamma_enti_e153
ILT7 ligand: ILT7: IgE: FCepsilonRIgamma
ligand: DAP12_enti_e154
ligand: DAP12
ligand: NKp44_enti_e155
ligand: NKp44
ligand: Siglec-H_enti_e156
ligand: Siglec-H
ligand: NKp44: ligand: DAP12_enti_e157
ligand: NKp44: ligand: DAP12
ligand: Siglec-H: ligand: DAP12_enti_e158
ligand: Siglec-H: ligand: DAP12
PTKs_enti_e159
PTKs
PTKs{activated}_enti_e160
PTKs{activated}
Syk{activated}_enti_e161
Syk{activated}
Syk_enti_e162
Syk
BLNK: BCAP_enti_e163
BLNK: BCAP
BLNK: BCAP{activated}_enti_e164
BLNK: BCAP{activated}
FcgammaRIIA_enti_e165
FcgammaRIIA
PDC-TREM: plexin A1_enti_e166
PDC-TREM: plexin A1
semaphorin 6D_enti_e167
semaphorin 6D
semaphorin 6D: PDC-TREM: plexin A1_enti_e168
semaphorin 6D: PDC-TREM: plexin A1
PI3K{activated}_enti_e169
PI3K{activated}
ERK1_enti_e170
ERK1
ERK2_enti_e171
ERK2
ERK1{activated}_enti_e172
ERK1{activated}
ERK2{activated}_enti_e173
ERK2{activated}
PDC-TREM_enti_e174
PDC-TREM
plexin A1_enti_e175
plexin A1
nucleortide: P2Y_enti_e176
nucleortide: P2Y
ADP_enti_e177
ADP
P2Y_enti_e178
P2Y
ligand: BCR_enti_e179
ligand: BCR
ligand: BCR{activated}_enti_e180
ligand: BCR{activated}
self RNA_enti_e181
self RNA
self RNA: TLR7_enti_e182
self RNA: TLR7
IL-12_enti_e183
IL-12
IL-12_enti_e184
IL-12
IFN-gamma_enti_e185
IFN-gamma
IFN-gamma_enti_e186
IFN-gamma
antibody_enti_e187
antibody
antibody_enti_e188
antibody