_enti_e7
_enti_e8
_enti_e9
_enti_e1
_enti_e10
_enti_e4
_enti_e3
_enti_e2
_enti_e55
_enti_e53
_enti_e59
_enti_e52
_enti_e51
_enti_e54
_enti_e56
_enti_e50
_enti_e61
_enti_e58
_enti_e57
_enti_e60
_enti_e62
g2_fact_g2
g1_fact_g14
g1_fact_g1
g2_fact_g12
g2_fact_g13
p1_propro_p1
PMID: 16419614
The host defence against microorganisms mediated by TLRs relies mainly on signalling pathways induced by a common Toll-interleukin 1 receptor (TIR) domain and shows a high homology to that of the IL-1R (IL-1 receptor) family.
c1 cso30:c:InputProcess connector
c2 cso30:c:InputProcess connector
c3 cso30:c:OutputProcess connector
p2_propro_p2
PMID: 16419614, 11544529, 11526399
In the process of analysing the MyD88-independent activation of the LPS-TLR4 signalling a novel adaptor protein named TIRAP or Mal was discovered (Fitzgerald et al. 2001; Horng et al., 2001).
c4 cso30:c:InputProcess connector
c5 cso30:c:InputProcess connector
c6 cso30:c:OutputProcess connector
p3_propro_p3
PMID: 16419614, 11544529, 11526399
In the process of analysing the MyD88-independent activation of the LPS-TLR4 signalling a novel adaptor protein named TIRAP or Mal was discovered (Fitzgerald et al. 2001; Horng et al., 2001).
c7 cso30:c:InputProcess connector
c8 cso30:c:InputProcess connector
c9 cso30:c:OutputProcess connector
p4_propro_p4
PMID: 16419614
Hence, in LPS signalling, the TLR4 recruits two types of adaptors, TIRAP and TRAM, to its cytoplasmic domain that are indirectly connected to two effec-tive adaptors, MyD88 and TRIF, respectively.
c10 cso30:c:InputProcess connector
c11 cso30:c:InputProcess connector
c12 cso30:c:OutputProcess connector
p5_propro_p5
PMID: 16419614
NK cells are major players in the antiviral immune response and express TLR3 and are activated directly in response to poly(I:C).
c13 cso30:c:InputProcess connector
c14 cso30:c:InputProcess connector
c15 cso30:c:OutputProcess connector
p6_propro_p6
PMID: 16419614, 11489966
Accordingly, TLR5, the receptor for flagellin, is exclusively expressed on the basolateral, but not the apical surface of the intestinal epithelial cells (Gewirtz et al., 2001).
c16 cso30:c:InputProcess connector
c17 cso30:c:InputProcess connector
c18 cso30:c:OutputProcess connector
p7_propro_p7
PMID: 16419614
Renal inflammation evoked by ischaemia markedly enhanced synthesis of TLR2 and TLR4 mRNA followed by significant elevation of protein expression in the distal tubular epithelium, the thin limb of Henle’s loop and collecting ducts. This phenomenon was shown to be completely dependent on the action of IFN-gamma and TNF.
PMID: 16419614
Preincubation with TNF or IFN-gamma significantly induces endothelial TLR2 expression.
c25 cso30:c:InputAssociation connector
c19 cso30:c:OutputProcess connector
p8_propro_p8
PMID: 16419614
Renal inflammation evoked by ischaemia markedly enhanced synthesis of TLR2 and TLR4 mRNA followed by significant elevation of protein expression in the distal tubular epithelium, the thin limb of Henle’s loop and collecting ducts. This phenomenon was shown to be completely dependent on the action of IFN-gamma and TNF.
PMID: 16419614
Preincubation with TNF or IFN-gamma significantly induces endothelial TLR2 expression.
c23 cso30:c:InputAssociation connector
c20 cso30:c:OutputProcess connector
p9_propro_p9
PMID: 16419614
Renal inflammation evoked by ischaemia markedly enhanced synthesis of TLR2 and TLR4 mRNA followed by significant elevation of protein expression in the distal tubular epithelium, the thin limb of Henle’s loop and collecting ducts. This phenomenon was shown to be completely dependent on the action of IFN-gamma and TNF.
c24 cso30:c:InputAssociation connector
c21 cso30:c:OutputProcess connector
p10_propro_p10
PMID: 16419614
Renal inflammation evoked by ischaemia markedly enhanced synthesis of TLR2 and TLR4 mRNA followed by significant elevation of protein expression in the distal tubular epithelium, the thin limb of Henle’s loop and collecting ducts. This phenomenon was shown to be completely dependent on the action of IFN-gamma and TNF.
c26 cso30:c:InputAssociation connector
c22 cso30:c:OutputProcess connector
p11_propro_p11
PMID: 16419614
The host defence against microorganisms mediated by TLRs relies mainly on signalling pathways induced by a common Toll-interleukin 1 receptor (TIR) domain and shows a high homology to that of the IL-1R (IL-1 receptor) family.
c27 cso30:c:InputProcess connector
c29 cso30:c:InputProcess connector
c28 cso30:c:OutputProcess connector
p12_propro_p12
PMID: 16419614
Both TLRs and IL-1R interact with the intracellular adaptor protein MyD88 (myeloid differentiation factor).
c30 cso30:c:InputProcess connector
c31 cso30:c:InputProcess connector
c32 cso30:c:OutputProcess connector
p13_propro_p13
PMID: 16419614
Both TLRs and IL-1R interact with the intracellular adaptor protein MyD88 (myeloid differentiation factor).
c33 cso30:c:InputProcess connector
c34 cso30:c:InputProcess connector
c35 cso30:c:OutputProcess connector
p14_propro_p14
PMID: 16419614
MyD88 afterwards recruits the serine/threonine kinase IRAK.
PMID: 16419614
Before IL-1 treatment, Tollip is present in a complex with IRAK. Following the IL-1 stimulation, the recruitment of Tollip-IRAK complexes to the activated IL-1R occurs through the association of Tollip with IL-1R.
c38 cso30:c:InputProcess connector
c36 cso30:c:InputProcess connector
c37 cso30:c:OutputProcess connector
p15_propro_p15
PMID: 16419614
MyD88 afterwards recruits the serine/threonine kinase IRAK.
PMID: 16419614
Before IL-1 treatment, Tollip is present in a complex with IRAK. Following the IL-1 stimulation, the recruitment of Tollip-IRAK complexes to the activated IL-1R occurs through the association of Tollip with IL-1R.
c40 cso30:c:InputProcess connector
c39 cso30:c:InputProcess connector
c41 cso30:c:OutputProcess connector
p16_propro_p16
PMID: 16419614
This, similarly to MyD88, contains DD and upon recruitment to MyD88 via DD-domain interactions is phosphorylated and subsequently associated with TRAF-6.
c43 cso30:c:InputProcess connector
c274 cso30:c:InputProcess connector
c44 cso30:c:OutputProcess connector
p17_propro_p17
PMID: 16419614
This, similarly to MyD88, contains DD and upon recruitment to MyD88 via DD-domain interactions is phosphorylated and subsequently associated with TRAF-6.
c42 cso30:c:InputProcess connector
c280 cso30:c:InputProcess connector
c45 cso30:c:OutputProcess connector
p18_propro_p18
PMID: 16419614
This, similarly to MyD88, contains DD and upon recruitment to MyD88 via DD-domain interactions is phosphorylated and subsequently associated with TRAF-6.
PMID: 16419614, 10854325
Co-recruited MyD88 then triggers IRAK autophosphorylation, which in turn leads to rapid dissociation of IRAK from Tollip (Burns et al., 2000).
c46 cso30:c:InputProcess connector
c47 cso30:c:OutputProcess connector
p19_propro_p19
PMID: 16419614
This, similarly to MyD88, contains DD and upon recruitment to MyD88 via DD-domain interactions is phosphorylated and subsequently associated with TRAF-6.
PMID: 16419614, 10854325
Co-recruited MyD88 then triggers IRAK autophosphorylation, which in turn leads to rapid dissociation of IRAK from Tollip (Burns et al., 2000).
c48 cso30:c:InputProcess connector
c49 cso30:c:OutputProcess connector
p20_propro_p20
PMID: 16419614, 9374458
Its activation in turn leads to initiation of two distinct downstream pathways resulting in activation of NF-kappaB and AP-1 transcription factors (Muzio et al., 1997; 1998).
c50 cso30:c:InputProcess connector
c54 cso30:c:InputAssociation connector
c51 cso30:c:OutputProcess connector
p21_propro_p21
PMID: 16419614, 9374458
Its activation in turn leads to initiation of two distinct downstream pathways resulting in activation of NF-kappaB and AP-1 transcription factors (Muzio et al., 1997; 1998).
c52 cso30:c:InputProcess connector
c55 cso30:c:InputAssociation connector
c53 cso30:c:OutputProcess connector
p24_propro_p24
PMID: 16419614
Hence, in LPS signalling, the TLR4 recruits two types of adaptors, TIRAP and TRAM, to its cytoplasmic domain that are indirectly connected to two effec-tive adaptors, MyD88 and TRIF, respectively.
c62 cso30:c:InputProcess connector
c63 cso30:c:InputProcess connector
c64 cso30:c:OutputProcess connector
p25_propro_p25
PMID: 16419614
Hence, in LPS signalling, the TLR4 recruits two types of adaptors, TIRAP and TRAM, to its cytoplasmic domain that are indirectly connected to two effec-tive adaptors, MyD88 and TRIF, respectively.
c65 cso30:c:InputProcess connector
c66 cso30:c:InputProcess connector
c67 cso30:c:OutputProcess connector
p26_propro_p26
PMID: 16419614, 10854325
Co-recruited MyD88 then triggers IRAK autophosphorylation, which in turn leads to rapid dissociation of IRAK from Tollip (Burns et al., 2000).
c70 cso30:c:InputProcess connector
c71 cso30:c:OutputProcess connector
c81 cso30:c:OutputProcess connector
p27_propro_p27
PMID: 16419614, 10854325
Co-recruited MyD88 then triggers IRAK autophosphorylation, which in turn leads to rapid dissociation of IRAK from Tollip (Burns et al., 2000).
c68 cso30:c:InputProcess connector
c69 cso30:c:OutputProcess connector
c80 cso30:c:OutputProcess connector
p28_propro_p28
PMID: 16419614
The inhibition of NF-kappaB activation in response to IL-1, as well as TLR2 and TLR4 ligands (Fig. 1), is mediated through the ability of Tollip to suppress the activity of IRAK.
c72 cso30:c:InputProcess connector
c74 cso30:c:InputProcess connector
c73 cso30:c:OutputProcess connector
p29_propro_p29
PMID: 16419614, 10854325
Co-recruited MyD88 then triggers IRAK autophosphorylation, which in turn leads to rapid dissociation of IRAK from Tollip (Burns et al., 2000).
c75 cso30:c:InputProcess connector
c76 cso30:c:OutputProcess connector
p30_propro_p30
PMID: 16419614, 10854325
Co-recruited MyD88 then triggers IRAK autophosphorylation, which in turn leads to rapid dissociation of IRAK from Tollip (Burns et al., 2000).
c77 cso30:c:InputProcess connector
c78 cso30:c:OutputProcess connector
c79 cso30:c:OutputProcess connector
p32_propro_p32
PMID: 16419614
This, similarly to MyD88, contains DD and upon recruitment to MyD88 via DD-domain interactions is phosphorylated and subsequently associated with TRAF-6
c86 cso30:c:InputProcess connector
c82 cso30:c:InputProcess connector
c87 cso30:c:OutputProcess connector
p31_propro_p31
c83 cso30:c:InputProcess connector
c85 cso30:c:InputAssociation connector
c84 cso30:c:OutputProcess connector
p33_propro_p33
PMID: 16419614
TIRAP/Mal forms dimers with MyD88 followed by association with IRAK and activation of NF-kappaB (Fig. 1).
c88 cso30:c:InputProcess connector
c90 cso30:c:InputAssociation connector
c89 cso30:c:OutputProcess connector
p34_propro_p34
PMID: 16419614
TIRAP/Mal forms dimers with MyD88 followed by association with IRAK and activation of NF-kappaB (Fig. 1).
c91 cso30:c:InputProcess connector
c93 cso30:c:InputAssociation connector
c92 cso30:c:OutputProcess connector
p35_propro_p35
PMID: 16419614
TIRAP/Mal forms dimers with MyD88 followed by association with IRAK and activation of NF-kappaB (Fig. 1).
c94 cso30:c:InputProcess connector
c96 cso30:c:InputAssociation connector
c95 cso30:c:OutputProcess connector
p36_propro_p36
PMID: 16419614
TIRAP/Mal forms dimers with MyD88 followed by association with IRAK and activation of NF-kappaB (Fig. 1).
c97 cso30:c:InputAssociation connector
c98 cso30:c:InputProcess connector
c99 cso30:c:OutputProcess connector
p37_propro_p37
PMID: 16419614, 12447441
Further data suggest that TIRAP/Mal is not specific to TLR4 signalling and that it takes part in the TLR2 signalling as well; however, it does not participate in the MyD88- independent pathway (Yamamoto et al., 2002).
c100 cso30:c:InputProcess connector
c102 cso30:c:InputProcess connector
c103 cso30:c:OutputProcess connector
p38_propro_p38
PMID: 16419614, 12447441
Further data suggest that TIRAP/Mal is not specific to TLR4 signalling and that it takes part in the TLR2 signalling as well; however, it does not participate in the MyD88- independent pathway (Yamamoto et al., 2002).
c101 cso30:c:InputProcess connector
c104 cso30:c:InputProcess connector
c105 cso30:c:OutputProcess connector
p39_propro_p39
PMID: 16419614, 12447441
Further data suggest that TIRAP/Mal is not specific to TLR4 signalling and that it takes part in the TLR2 signalling as well; however, it does not parti
c107 cso30:c:InputProcess connector
c106 cso30:c:InputProcess connector
c108 cso30:c:OutputProcess connector
p40_propro_p40
PMID: 16419614
The inhibition of NF-kappaB activation in response to IL-1, as well as TLR2 and TLR4 ligands (Fig. 1), is mediated through the ability of Tollip to suppress the activity of IRAK.
c109 cso30:c:InputProcess connector
c110 cso30:c:InputProcess connector
c111 cso30:c:OutputProcess connector
p41_propro_p41
PMID: 16419614, 10854325
Co-recruited MyD88 then triggers IRAK autophosphorylation, which in turn leads to rapid dissociation of IRAK from Tollip (Burns et al., 2000).
c112 cso30:c:InputProcess connector
c113 cso30:c:OutputProcess connector
p42_propro_p42
PMID: 16419614, 10854325
Co-recruited MyD88 then triggers IRAK autophosphorylation, which in turn leads to rapid dissociation of IRAK from Tollip (Burns et al., 2000).
c114 cso30:c:InputProcess connector
c115 cso30:c:OutputProcess connector
c116 cso30:c:OutputProcess connector
p43_propro_p43
PMID: 16419614
This, similarly to MyD88, contains DD and upon recruitment to MyD88 via DD-domain interactions is phosphorylated and subsequently associated with TRAF-6.
c117 cso30:c:InputProcess connector
c119 cso30:c:InputProcess connector
c118 cso30:c:OutputProcess connector
p44_propro_p44
PMID: 16419614
The inhibition of NF-kappaB activation in response to IL-1, as well as TLR2 and TLR4 ligands (Fig. 1), is mediated through the ability of Tollip to suppress the activity of IRAK.
c120 cso30:c:InputProcess connector
c122 cso30:c:InputAssociation connector
c121 cso30:c:OutputProcess connector
p45_propro_p45
PMID: 16419614, 11607032
Similarly to LPS, the dsRNA stimulation of TLR3 in the MyD88- deficient cells induced activation of NF-kappaB, but no production of inflammatory cytokines (Alexopoulou et al.,2001).
c123 cso30:c:InputProcess connector
c124 cso30:c:InputProcess connector
c125 cso30:c:OutputProcess connector
p46_propro_p46
PMID: 16419614, 12539043, 14519765
Thus, dsRNA-TLR3-dependent production of IFN-beta is mediated mainly by TRIF/TICAM-1.
c127 cso30:c:InputProcess connector
c129 cso30:c:InputProcess connector
c130 cso30:c:OutputProcess connector
p47_propro_p47
PMID: 16419614
TRIF physically associates with TLR3 and IRF-3 in response to poly(I:C).
c126 cso30:c:InputProcess connector
c128 cso30:c:InputProcess connector
c131 cso30:c:OutputProcess connector
p48_propro_p48
PMID: 16419614
TRIF physically associates with TLR3 and IRF-3 in response to poly(I:C).
c132 cso30:c:InputProcess connector
c133 cso30:c:InputProcess connector
c134 cso30:c:OutputProcess connector
p49_propro_p49
PMID: 16419614
In these experiments, TRIF was found to recruit TRAF-6 to TLR3 through its TRAF6-binding site.
c135 cso30:c:InputProcess connector
c137 cso30:c:InputProcess connector
c136 cso30:c:OutputProcess connector
p50_propro_p50
PMID: 16419614, 14982987
Furthermore, mutation of the TRAF6-binding site of TRIF only abolished its ability to activate NF-kappaB but not IRF3, suggesting that TLR3-mediated activation of NF-kappaB and IRF3 might bifurcate at TRIF (Jiang et al., 2004).
c138 cso30:c:InputProcess connector
c140 cso30:c:InputAssociation connector
c139 cso30:c:OutputProcess connector
p51_propro_p51
PMID: 16419614
Recently, two IKK-related kinases, inducible IkappaB kinase (IKK-i) and TANK-binding kinase 1 (TBK1), were suggested to act as IRF-3 kinases and to be involved in IFN-beta production in TLR signalling and viral infection (Fig. 1, Fig. 2b).
PMID: 16419614
Thus, viral infection or dsRNA stimulation via TLR3 as well as LPS stimulation via TLR4 induces phosphorylation and subsequent activation of IRF-3 and its translocation to the nucleus, thereby leading to the IFN-beta gene expression.
c141 cso30:c:InputProcess connector
c145 cso30:c:InputAssociation connector
c147 cso30:c:InputAssociation connector
c148 cso30:c:InputAssociation connector
c142 cso30:c:OutputProcess connector
p52_propro_p52
PMID: 16419614
Restricted to the TLR4 pathway, TRAM activates IRF-3, IRF-7, and NF-kappaB-dependent signalling pathways in MyD88-independent manner (Figs. 1, 2a).
PMID: 16419614
Recently, two IKK-related kinases, inducible IkappaB kinase (IKK-i) and TANK-binding kinase 1 (TBK1), were suggested to act as IRF-3 kinases and to be involved in IFN-beta production in TLR signalling and viral infection (Fig. 1, Fig. 2b).
PMID: 16419614
Thus, viral infection or dsRNA stimulation via TLR3 as well as LPS stimulation via TLR4 induces phosphorylation and subsequent activation of IRF-3 and its translocation to the nucleus, thereby leading to the IFN-beta gene expression.
c143 cso30:c:InputProcess connector
c146 cso30:c:InputAssociation connector
c149 cso30:c:InputAssociation connector
c150 cso30:c:InputAssociation connector
c144 cso30:c:OutputProcess connector
p53_propro_p53
PMID: 16419614
Restricted to the TLR4 pathway, TRAM activates IRF-3, IRF-7, and NF-kappaB-dependent signalling pathways in MyD88-independent manner (Figs. 1, 2a).
c151 cso30:c:InputProcess connector
c153 cso30:c:InputAssociation connector
c152 cso30:c:OutputProcess connector
p54_propro_p54
PMID: 16419614
Restricted to the TLR4 pathway, TRAM activates IRF-3, IRF-7, and NF-kappaB-dependent signalling pathways in MyD88-independent manner (Figs. 1, 2a).
c154 cso30:c:InputProcess connector
c156 cso30:c:InputAssociation connector
c155 cso30:c:OutputProcess connector
p55_propro_p55
PMID: 16419614
Thus, viral infection or dsRNA stimulation via TLR3 as well as LPS stimulation via TLR4 induces phosphorylation and subsequent activation of IRF-3 and its translocation to the nucleus, thereby leading to the IFN-beta gene expression.
c157 cso30:c:InputProcess connector
c158 cso30:c:OutputProcess connector
p56_propro_p56
PMID: 16419614
Thus, viral infection or dsRNA stimulation via TLR3 as well as LPS stimulation via TLR4 induces phosphorylation and subsequent activation of IRF-3 and its translocation to the nucleus, thereby leading to the IFN-beta gene expression.
PMID: 16419614
Activated by TLR3 and TLR4, IRF-3 binds the interferon-sensitive response element (ISRE) in DNA and induces expression of the IFN-beta gene.
c261 cso30:c:InputAssociation connector
c159 cso30:c:OutputProcess connector
p57_propro_p57
PMID: 16419614
Activated by TLR3 and TLR4, IRF-3 binds the interferon-sensitive response element (ISRE) in DNA and induces expression of the IFN-beta gene.
c160 cso30:c:InputProcess connector
c161 cso30:c:InputProcess connector
c162 cso30:c:OutputProcess connector
p58_propro_p58
PMID: 16419614, 11790540, 15800576
IRF-7 is also induced by viral infection and is critically involved in the system of IFN-alpha/beta gene induction (Taniguchi et al., 2002, Honda et al., 2005).
c164 cso30:c:InputAssociation connector
c165 cso30:c:OutputProcess connector
p59_propro_p59
PMID: 16419614, 11790540, 15800576
IRF-7 is also induced by viral infection and is critically involved in the system of IFN-alpha/beta gene induction (Taniguchi et al., 2002, Honda et al., 2005).
c166 cso30:c:InputAssociation connector
c167 cso30:c:OutputProcess connector
p60_propro_p60
PMID: 16419614
In the TLR2-mediated signalling, stimulation of human monocytes by S. aureus induces a fast and transient activation of the Rho GTPases Rac1 and Cdc42 followed by the recruitment of active Rac1 and phosphatidylinositol-3 kinase (PI3K) to the TLR2 cytosolic domain.
c168 cso30:c:InputProcess connector
c169 cso30:c:InputProcess connector
c171 cso30:c:InputProcess connector
c170 cso30:c:OutputProcess connector
p61_propro_p61
PMID: 16419614, 11101877
This in turn activates Akt kinase that induces activation and translocation of the p65 subunit of NF-kappaB into the cell nucleus in a process that is independent of IkappaB degradation.
c175 cso30:c:InputAssociation connector
c176 cso30:c:InputProcess connector
c177 cso30:c:OutputProcess connector
p62_propro_p62
PMID: 16419614, 11101877
This in turn activates Akt kinase that induces activation and translocation of the p65 subunit of NF-kappaB into the cell nucleus in a process that is independent of IkappaB degradation.
c172 cso30:c:InputProcess connector
c174 cso30:c:InputAssociation connector
c173 cso30:c:OutputProcess connector
p63_propro_p63
PMID: 16419614, 11101877
This in turn activates Akt kinase that induces activation and translocation of the p65 subunit of NF-kappaB into the cell nucleus in a process that is independent of IkappaB degradation.
c178 cso30:c:InputProcess connector
c179 cso30:c:OutputProcess connector
p64_propro_p64
PMID: 16419614
NK cells also seem to be able to respond directly to other viral TLR stimuli, such as CpG DNA.
c180 cso30:c:InputProcess connector
c181 cso30:c:InputProcess connector
c182 cso30:c:OutputProcess connector
p65_propro_p65
PMID: 16419614
However, all these effects are MyD88-dependent.
c183 cso30:c:InputProcess connector
c185 cso30:c:InputProcess connector
c184 cso30:c:OutputProcess connector
p67_propro_p67
PMID: 16419614
Similar to the LPS response, TLR9 signalling can also induce expression of IFN-beta and IFN-inducible genes, and upregulation of CD40.
c189 cso30:c:InputAssociation connector
c186 cso30:c:OutputProcess connector
p68_propro_p68
PMID: 16419614
Similar to the LPS response, TLR9 signalling can also induce expression of IFN-beta and IFN-inducible genes, and upregulation of CD40.
c190 cso30:c:InputAssociation connector
c191 cso30:c:OutputProcess connector
p66_propro_p66
PMID: 16419614
Similar to the LPS response, TLR9 signalling can also induce expression of IFN-beta and IFN-inducible genes, and upregulation of CD40.
c188 cso30:c:InputAssociation connector
c187 cso30:c:OutputProcess connector
p22_propro_p22
PMID: 16419614, 9374458
Its activation in turn leads to initiation of two distinct downstream pathways resulting in activation of NF-kappaB and AP-1 transcription factors (Muzio et al., 1997; 1998).
PMID: 16419614, 7622446
The activation of the AP-1 is induced through phosphorylation by the MAP kinases such as JNK and ERK, respectively, that are activated by means of TLR or IL-1R engagement (Karin, 1995).
c57 cso30:c:InputProcess connector
c204 cso30:c:InputAssociation connector
c56 cso30:c:OutputProcess connector
p69_propro_p69
PMID: 16419614, 10626894
Not just a bacterial, but also a viral infection or dsRNA induce JNK kinase, leading to stimulation of AP-1 (Chu et al., 1999).
c194 cso30:c:InputProcess connector
c199 cso30:c:InputAssociation connector
c195 cso30:c:OutputProcess connector
p70_propro_p70
PMID: 16419614, 1744583, 10318814
TLR4 ligand LPS and various TLR2 ligands rapidly activated JNK kinases, which was followed by activation of the AP-1 transcription factor (Mackman et al., 1991; Gupta et al., 1999).
c196 cso30:c:InputProcess connector
c200 cso30:c:InputAssociation connector
c197 cso30:c:OutputProcess connector
p71_propro_p71
PMID: 16419614, 7622446
The activation of the AP-1 is induced through phosphorylation by the MAP kinases such as JNK and ERK, respectively, that are activated by means of TLR or IL-1R engagement (Karin, 1995).
c192 cso30:c:InputProcess connector
c198 cso30:c:InputAssociation connector
c193 cso30:c:OutputProcess connector
p72_propro_p72
PMID: 16419614, 7622446
The activation of the AP-1 is induced through phosphorylation by the MAP kinases such as JNK and ERK, respectively, that are activated by means of TLR or IL-1R engagement (Karin, 1995).
c201 cso30:c:InputProcess connector
c203 cso30:c:InputAssociation connector
c202 cso30:c:OutputProcess connector
p73_propro_p73
PMID: 16419614, 7622446
The activation of the AP-1 is induced through phosphorylation by the MAP kinases such as JNK and ERK, respectively, that are activated by means of TLR or IL-1R engagement (Karin, 1995).
c60 cso30:c:InputAssociation connector
c208 cso30:c:InputProcess connector
c209 cso30:c:OutputProcess connector
p74_propro_p74
PMID: 16419614, 7622446
The activation of the AP-1 is induced through phosphorylation by the MAP kinases such as JNK and ERK, respectively, that are activated by means of TLR or IL-1R engagement (Karin, 1995).
c61 cso30:c:InputAssociation connector
c206 cso30:c:InputProcess connector
c207 cso30:c:OutputProcess connector
p23_propro_p23
PMID: 16419614, 12829592
The agonists of all TLRs expressed in neutrophils triggered cytokine release, superoxide generation, L-selectin shedding and increased phagocytosis of opsonised latex beads (Hayashi et al., 2003).
c59 cso30:c:InputAssociation connector
c210 cso30:c:InputAssociation connector
c58 cso30:c:OutputProcess connector
p75_propro_p75
PMID: 16419614, 12829592
The agonists of all TLRs expressed in neutrophils triggered cytokine release, superoxide generation, L-selectin shedding and increased phagocytosis of opsonised latex beads (Hayashi et al., 2003).
c205 cso30:c:InputAssociation connector
c211 cso30:c:OutputProcess connector
p76_propro_p76
PMID: 16419614, 15995707
Indeed, recently it was found that agonists of TLR3 and TLR4 had acted in synergy with agonists of TLR8 in inducing IL-12, IL-23 and Delta-4 in amounts that were 50- to 100-fold higher than those induced by optimal concentrations of single agonists leading to enhanced and sustained TH1- polarizing capacity (Napolitani et al., 2005).
c215 cso30:c:InputAssociation connector
c216 cso30:c:InputAssociation connector
c217 cso30:c:InputAssociation connector
c212 cso30:c:OutputProcess connector
p77_propro_p77
PMID: 16419614, 15995707
Indeed, recently it was found that agonists of TLR3 and TLR4 had acted in synergy with agonists of TLR8 in inducing IL-12, IL-23 and Delta-4 in amounts that were 50- to 100-fold higher than those induced by optimal concentrations of single agonists leading to enhanced and sustained TH1- polarizing capacity (Napolitani et al., 2005).
c218 cso30:c:InputAssociation connector
c219 cso30:c:InputAssociation connector
c220 cso30:c:InputAssociation connector
c213 cso30:c:OutputProcess connector
p78_propro_p78
PMID: 16419614, 15995707
Indeed, recently it was found that agonists of TLR3 and TLR4 had acted in synergy with agonists of TLR8 in inducing IL-12, IL-23 and Delta-4 in amounts that were 50- to 100-fold higher than those induced by optimal concentrations of single agonists leading to enhanced and sustained TH1- polarizing capacity (Napolitani et al., 2005).
c221 cso30:c:InputAssociation connector
c222 cso30:c:InputAssociation connector
c223 cso30:c:InputAssociation connector
c214 cso30:c:OutputProcess connector
p79_propro_p79
PMID: 16419614
Initially, NF-kappaB (nuclear factorkappa B) was found to be essential for the transcription of immunoglobulin light chain genes in B cells.
c224 cso30:c:InputAssociation connector
c225 cso30:c:OutputProcess connector
p81_propro_p81
PMID: 16419614
NF-IL6 (nuclear factor-IL6) specifically binds to an IL-1-responsive element in the IL-6 gene.
c226 cso30:c:InputProcess connector
c227 cso30:c:InputProcess connector
c228 cso30:c:OutputProcess connector
p80_propro_p80
PMID: 16419614, 2112087
Interestingly, NF-IL6 was shown to bind to regulatory regions of various acute-phase protein and several other cytokine genes such as TNF, IL-8 and G-CSF, implying that NF-IL6 has a role in the regulation ot only of the IL-6 gene, but also of several other genes involved in acute-phase reaction, inflammation and haematopoiesis (Akira et al., 1990).
c229 cso30:c:InputProcess connector
c231 cso30:c:InputProcess connector
c230 cso30:c:OutputProcess connector
p82_propro_p82
PMID: 16419614
The NF-IL6 mRNA was induced by the stimulation with LPS, IL-1 or IL-6.
c233 cso30:c:InputAssociation connector
c236 cso30:c:OutputProcess connector
p83_propro_p83
PMID: 16419614
The NF-IL6 mRNA was induced by the stimulation with LPS, IL-1 or IL-6.
c163 cso30:c:InputAssociation connector
c237 cso30:c:OutputProcess connector
p84_propro_p84
PMID: 16419614
The NF-IL6 mRNA was induced by the stimulation with LPS, IL-1 or IL-6.
c234 cso30:c:InputAssociation connector
c235 cso30:c:OutputProcess connector
p85_propro_p85
PMID: 16419614, 2112087
Interestingly, NF-IL6 was shown to bind to regulatory regions of various acute-phase protein and several other cytokine genes such as TNF, IL-8 and G-CSF, implying that NF-IL6 has a role in the regulation ot only of the IL-6 gene, but also of several other genes involved in acute-phase reaction, inflammation and haematopoiesis (Akira et al., 1990).
c238 cso30:c:InputProcess connector
c239 cso30:c:InputProcess connector
c243 cso30:c:OutputProcess connector
p86_propro_p86
PMID: 16419614, 2112087
Interestingly, NF-IL6 was shown to bind to regulatory regions of various acute-phase protein and several other cytokine genes such as TNF, IL-8 and G-CSF, implying that NF-IL6 has a role in the regulation ot only of the IL-6 gene, but also of several other genes involved in acute-phase reaction, inflammation and haematopoiesis (Akira et al., 1990).
c240 cso30:c:InputProcess connector
c241 cso30:c:InputProcess connector
c242 cso30:c:OutputProcess connector
p87_propro_p87
PMID: 16419614, 8336793
LPS or inflammatory cytokine stimulation of macrophages and hepatocytes activated MAP kinases that in turn phosphorylated NF-IL6, enhancing its transcriptional efficacy (Trautwein et al., 1993).
c244 cso30:c:InputAssociation connector
c245 cso30:c:InputProcess connector
c246 cso30:c:OutputProcess connector
p88_propro_p88
PMID: 16419614, 8336793
LPS or inflammatory cytokine stimulation of macrophages and hepatocytes activated MAP kinases that in turn phosphorylated NF-IL6, enhancing its transcriptional efficacy (Trautwein et al., 1993).
c247 cso30:c:InputProcess connector
c249 cso30:c:InputAssociation connector
c248 cso30:c:OutputProcess connector
p89_propro_p89
PMID: 16419614, 7530603
The NF-IL6 deficient mice were highly susceptible to infection with Listeria monocytogenes; moreover NF-IL6 was essential for the induction of G-CSF in macrophages.
c250 cso30:c:InputAssociation connector
c251 cso30:c:OutputProcess connector
p90_propro_p90
PMID: 16419614, 12023384
NF-IL6-deficient murine macrophages in stimulation with LPS displayed impaired expression of membrane-bound glutathione-dependent PGE2 synthase or Cox-2.
c252 cso30:c:InputAssociation connector
c256 cso30:c:InputAssociation connector
c254 cso30:c:OutputProcess connector
p91_propro_p91
PMID: 16419614, 12023384
NF-IL6-deficient murine macrophages in stimulation with LPS displayed impaired expression of membrane-bound glutathione-dependent PGE2 synthase or Cox-2.
c253 cso30:c:InputAssociation connector
c257 cso30:c:InputAssociation connector
c255 cso30:c:OutputProcess connector
p92_propro_p92
PMID: 16419614, 14557267
The results therefore indicate that IRF-3-mediated activation of the ISRE by TLR4 requires the p65 subunit of NF-kappaB.
c258 cso30:c:InputProcess connector
c260 cso30:c:InputAssociation connector
c259 cso30:c:OutputProcess connector
p93_propro_p93
PMID: 16419614
IL-1 and LPS stimulation induce activation of the STAT family of transcription factors, which consists of seven members.
c270 cso30:c:InputProcess connector
c279 cso30:c:InputAssociation connector
c271 cso30:c:OutputProcess connector
p94_propro_p94
PMID: 16419614, 9649436
Bacterial infection of macrophages or treatment with LPS resulted in rapid STAT1 serine phosphorylation, independent of concomitant tyrosine phosphorylation.
PMID: 16419614, 9794412
Other studies proved that LPS stimulation of macrophages using the MyD88-independent pathway and IRF-3-induced expression of IFN-beta, which then induced expression of IFN-regulated genes through activation of STAT1.
c232 cso30:c:InputProcess connector
c263 cso30:c:InputAssociation connector
c277 cso30:c:InputAssociation connector
c262 cso30:c:OutputProcess connector
p95_propro_p95
PMID: 16419614, 12356687
LPS-induced expression of IRF-1, iNOS and IFN-inducible genes such as IP-10 was severely impaired in STAT1-deficient murine macrophages, suggesting that STAT1 may play a role in the response to LPS.
c265 cso30:c:InputAssociation connector
c266 cso30:c:OutputProcess connector
p96_propro_p96
PMID: 16419614, 12356687
LPS-induced expression of IRF-1, iNOS and IFN-inducible genes such as IP-10 was severely impaired in STAT1-deficient murine macrophages, suggesting that STAT1 may play a role in the response to LPS.
c264 cso30:c:InputAssociation connector
c267 cso30:c:OutputProcess connector
p97_propro_p97
PMID: 16419614, 12356687
LPS-induced expression of IRF-1, iNOS and IFN-inducible genes such as IP-10 was severely impaired in STAT1-deficient murine macrophages, suggesting that STAT1 may play a role in the response to LPS.
c269 cso30:c:InputAssociation connector
c268 cso30:c:OutputProcess connector
p98_propro_p98
PMID: 16419614
IL-1 and LPS stimulation induce activation of the STAT family of transcription factors, which consists of seven members.
c272 cso30:c:InputProcess connector
c278 cso30:c:InputAssociation connector
c273 cso30:c:OutputProcess connector
p99_propro_p99
c275 cso30:c:InputAssociation connector
c276 cso30:c:OutputProcess connector
TLR4_enti_MO000019394
TLR4
TLRs_enti_MO000019395
TLRs
TLR3_enti_MO000019398
TLR3
TLR5_enti_MO000019399
TLR5
TLR9_enti_MO000042012
TLR9
TLR ligand_enti_e5
TLR ligand
LPS_enti_MO000016882
LPS
dsRNA_enti_MO000022224
dsRNA
TLR ligand: TLR_enti_e6
TLR ligand: TLR
MyD88_enti_MO000016573
MyD88
TRAF6_enti_MO000000212
TRAF6
TRIF_enti_MO000041125
TRIF
TRAM_enti_MO000041132
TRAM
LPS: TLR4_enti_e12
LPS: TLR4
LPS: TLR4: TIRAP_enti_e11
LPS: TLR4: TIRAP
Tollip:IRAK_enti_MO000039097
Tollip:IRAK
Tollip_enti_MO000019406
Tollip
TIRAP_enti_MO000022528
TIRAP
LPS: TLR4: TIRAP: MyD88_enti_e13
LPS: TLR4: TIRAP: MyD88
IL-1: IL-1R: MyD88: IRAK {p}: Tollip_enti_e14
IL-1: IL-1R: MyD88: IRAK {p}: Tollip
polyI:C_enti_e15
polyI:C
polyI:C: TLR3_enti_e16
polyI:C: TLR3
IRF-3_enti_MO000007694
IRF-3
IRF-3{p}_enti_MO000041456
IRF-3{p}
flagellin_enti_MO000022185
flagellin
flagellin: TLR5_enti_e17
flagellin: TLR5
TLR2_enti_G010962
TLR2
Tlr4_enti_G010693
Tlr4
IFNgamma_enti_MO000016665
IFNgamma
TNF-alpha_enti_MO000000289
TNF-alpha
IL-1R_enti_e18
IL-1R
IL-1: IL-1R_enti_e19
IL-1: IL-1R
IL-1_enti_MO000000214
IL-1
TLR ligand: TLR: MyD88_enti_e20
TLR ligand: TLR: MyD88
IL-1: IL-1R: MyD88_enti_e21
IL-1: IL-1R: MyD88
NF-kappaB_enti_MO000000058
NF-kappaB
AP-1_enti_MO000000276
AP-1
IFNbeta_enti_MO000016660
IFNbeta
TLR ligand: TLR: MyD88: IRAK: Tollip_enti_e22
TLR ligand: TLR: MyD88: IRAK: Tollip
IL-1: IL-1R: MyD88: IRAK: Tollip_enti_e23
IL-1: IL-1R: MyD88: IRAK: Tollip
TLR ligand: TLR: MyD88: IRAK {p}: TRAF6_enti_e24
TLR ligand: TLR: MyD88: IRAK {p}: TRAF6
IL-1: IL-1R: MyD88: IRAK {p}: TRAF6_enti_e25
IL-1: IL-1R: MyD88: IRAK {p}: TRAF6
IFN-beta_enti_G010228
IFN-beta
TLR ligand: TLR: MyD88: IRAK {p}: Tollip_enti_e27
TLR ligand: TLR: MyD88: IRAK {p}: Tollip
NF-kappaB {activated}_enti_e26
NF-kappaB {activated}
AP-1 {activated}_enti_e28
AP-1 {activated}
LPS: TLR4: TRAM_enti_e29
LPS: TLR4: TRAM
LPS: TLR4: TRAM: TRIF_enti_e30
LPS: TLR4: TRAM: TRIF
TLR ligand: TLR: MyD88: IRAK {p}_enti_e31
TLR ligand: TLR: MyD88: IRAK {p}
IL-1: IL-1R: MyD88: IRAK {p}_enti_e32
IL-1: IL-1R: MyD88: IRAK {p}
LPS: TLR4: TIRAP: MyD88: IRAK: Tollip_enti_e33
LPS: TLR4: TIRAP: MyD88: IRAK: Tollip
LPS: TLR4: TIRAP: MyD88: IRAK [p}: Tollip_enti_e34
LPS: TLR4: TIRAP: MyD88: IRAK [p}: Tollip
TBK1_enti_MO000019331
TBK1
LPS: TLR4: TIRAP: MyD88: IRAK [p}_enti_e35
LPS: TLR4: TIRAP: MyD88: IRAK [p}
LPS: TLR4: TIRAP: MyD88: IRAK [p}: IRAK4: TRAF6_enti_e37
LPS: TLR4: TIRAP: MyD88: IRAK [p}: IRAK4: TRAF6
TAK1_enti_MO000016574
TAK1
TAK1 {activated}_enti_e36
TAK1 {activated}
IKK-alpha:IKK-beta:IKK-gamma_enti_e38
IKK-alpha:IKK-beta:IKK-gamma
IKK-alpha:IKK-beta:IKK-gamma {activated}_enti_e39
IKK-alpha:IKK-beta:IKK-gamma {activated}
IkappaB_enti_MO000000215
IkappaB
IkappaB {activated}_enti_e40
IkappaB {activated}
TLR1: TLR2_enti_e41
TLR1: TLR2
BLPs: TLR1: TLR2: TIRAP_enti_e43
BLPs: TLR1: TLR2: TIRAP
BLPs: TLR1: TLR2_enti_e44
BLPs: TLR1: TLR2
BLPs_enti_e45
BLPs
BLPs: TLR1: TLR2: TIRAP: MyD88_enti_e46
BLPs: TLR1: TLR2: TIRAP: MyD88
BLPs: TLR1: TLR2: TIRAP: MyD88: IRAK: Tollip_enti_e47
BLPs: TLR1: TLR2: TIRAP: MyD88: IRAK: Tollip
BLPs: TLR1: TLR2: TIRAP: MyD88: IRAK {p}: Tollip_enti_e48
BLPs: TLR1: TLR2: TIRAP: MyD88: IRAK {p}: Tollip
BLPs: TLR1: TLR2: TIRAP: MyD88: IRAK {p}_enti_e49
BLPs: TLR1: TLR2: TIRAP: MyD88: IRAK {p}
BLPs: TLR1: TLR2: TIRAP: MyD88: IRAK {p}: TRAF6_enti_e42
BLPs: TLR1: TLR2: TIRAP: MyD88: IRAK {p}: TRAF6
dsRNA: TLR3_enti_e63
dsRNA: TLR3
dsRNA: TLR3: TRIF_enti_e64
dsRNA: TLR3: TRIF
polyI:C: TLR3: TRIF_enti_e65
polyI:C: TLR3: TRIF
polyI:C: TLR3: TRIF: IRF-3_enti_e66
polyI:C: TLR3: TRIF: IRF-3
dsRNA: TLR3: TRIF: TRAF6_enti_e67
dsRNA: TLR3: TRIF: TRAF6
IKK-i_enti_MO000016608
IKK-i
IRF-7_enti_MO000007702
IRF-7
IRF-7 [activated}_enti_e68
IRF-7 [activated}
IRF-3{p} [nucleus}_enti_e69
IRF-3{p} [nucleus}
ISRE_enti_e70
ISRE
ISRE: IRF-3{p} {nucleus}_enti_e71
ISRE: IRF-3{p} {nucleus}
IFN-alpha_enti_e72
IFN-alpha
Rac1 [activated}_enti_MO000000166
Rac1 [activated}
BLPs: TLR1: TLR2: TIRAP: MyD88: Rac1 {activated}: PI3K_enti_e73
BLPs: TLR1: TLR2: TIRAP: MyD88: Rac1 {activated}: PI3K
PI3K_enti_MO000000030
PI3K
RelA-p65_enti_MO000000193
RelA-p65
RelA-p65 {activated}_enti_e74
RelA-p65 {activated}
AKT_enti_MO000000048
AKT
AKT {activated}_enti_e75
AKT {activated}
RelA-p65 {nucleus} _enti_e76
RelA-p65 {nucleus}
CpG DNA_enti_e77
CpG DNA
CpG DNA: TLR9_enti_e78
CpG DNA: TLR9
CpG DNA: TLR9: MyD88_enti_e79
CpG DNA: TLR9: MyD88
IFN inducible genes_enti_e80
IFN inducible genes
CD40_enti_MO000016922
CD40
JNK_enti_MO000000023
JNK
JNK {activated}_enti_e81
JNK {activated}
ERK_enti_MO000000011
ERK
ERK {activated}_enti_e82
ERK {activated}
IL-6_enti_MO000007384
IL-6
cytokines_enti_MO000019387
cytokines
cytokines_enti_e83
cytokines
superoxide_enti_MO000021062
superoxide
TLR agonist_enti_e84
TLR agonist
IL-12 p40_enti_G010657
IL-12 p40
IL23_enti_e85
IL23
Delta-4_enti_e86
Delta-4
TLR3 agonist_enti_e87
TLR3 agonist
TLR4 agonist_enti_e88
TLR4 agonist
TLR8 agonist_enti_e89
TLR8 agonist
immunoglobulin light chain genes_enti_e90
immunoglobulin light chain genes
NF-IL6 {p}_enti_e91
NF-IL6 {p}
IL-6_enti_e92
IL-6
IL-6: NF-IL6_enti_e93
IL-6: NF-IL6
TNF: NF-IL6_enti_e94
TNF: NF-IL6
TNF_enti_e95
TNF
NF-IL6_enti_e96
NF-IL6
IL-8_enti_e97
IL-8
G-CSF_enti_e98
G-CSF
IL-8: NFIL6_enti_e99
IL-8: NFIL6
G-CSF: NF-IL6_enti_e100
G-CSF: NF-IL6
MAPK{p}_enti_MO000000342
MAPK{p}
MAPK_enti_MO000016894
MAPK
NF-IL6_enti_e101
NF-IL6
G-CSF_enti_G010291
G-CSF
PGE2_enti_e102
PGE2
COX2_enti_G029941
COX2
ISRE {activated}: IRF-3{p} {nucleus}_enti_e103
ISRE {activated}: IRF-3{p} {nucleus}
STAT1_enti_MO000013119
STAT1
STATs_enti_MO000016656
STATs
STAT1{p}_enti_MO000019704
STAT1{p}
IRF-1_enti_G010384
IRF-1
iNOS_enti_G010514
iNOS
IP-10_enti_e104
IP-10
STATs {activated}_enti_e105
STATs {activated}