_enti_e8
_enti_e1
_enti_e4
_enti_e3
_enti_e2
_enti_e55
_enti_e53
_enti_e59
_enti_e52
_enti_e56
_enti_e54
_enti_e50
_enti_e51
_enti_e58
_enti_e57
_enti_e61
_enti_e60
_enti_e62
g1_fact_g1
g2_fact_g12
g2_fact_g13
g1_fact_g14
p1_propro_p1
PMID: 16723122,10225417
ROS are generated
through multiple sources in the cell, such as the electron
transport chain in mitochondria, ionizing radiations and
through enzymes producing superoxide anion such as
phagocytic and non-phagocytic NADPH oxidases , lipoxygenases
and cycloxygenases.
c1 cso30:c:InputAssociation connector
c2 cso30:c:OutputProcess connector
p1_propro_p2
PMID: 16723122,6254151
ROS are generated
through multiple sources in the cell, such as the electron
transport chain in mitochondria, ionizing radiations and
through enzymes producing superoxide anion such as
phagocytic and non-phagocytic NADPH oxidases , lipoxygenases
and cycloxygenases.
c3 cso30:c:InputAssociation connector
c4 cso30:c:OutputProcess connector
p1_propro_p3
PMID: 16723122,10029572,10488060,12147646
ROS are generated
through multiple sources in the cell, such as the electron
transport chain in mitochondria, ionizing radiations and
through enzymes producing superoxide anion such as
phagocytic and non-phagocytic NADPH oxidases , lipoxygenases
and cycloxygenases.
c5 cso30:c:InputAssociation connector
c6 cso30:c:OutputProcess connector
p1_propro_p4
PMID: 16723122,10029572,10488060,12147646
ROS are generated
through multiple sources in the cell, such as the electron
transport chain in mitochondria, ionizing radiations and
through enzymes producing superoxide anion such as
phagocytic and non-phagocytic NADPH oxidases , lipoxygenases
and cycloxygenases.
c7 cso30:c:InputAssociation connector
c8 cso30:c:OutputProcess connector
p6_propro_p6
PMID: 16723122
In
the resting state, NF-kB is sequestered in the cytoplasm of the
cell through its tight associationwith inhibitory proteins called
IkBs
c11 cso30:c:InputProcess connector
c12 cso30:c:InputProcess connector
c13 cso30:c:OutputProcess connector
p7_propro_p7
PMID; 16723122,12421671,10795740
The classical NF-kB-activating pathway is induced by a variety
of innate and adaptative immunity mediators, such as proinflammatory
cytokines (TNFa, IL-1b, Toll-like receptors
(TLRs) and antigen receptors (TCR, BCR)
ligation
PMID: 16723122,9915703
The ligation of TNFR1 by
trimeric TNFa leads to the aggregation of the receptor and
dissociation of silencer of death domain (SODD), an inhibitor
of TNFR1 activity, which allows binding of TNFR-associated
death domain protein (TRADD protein)
c14 cso30:c:InputProcess connector
c15 cso30:c:InputProcess connector
c16 cso30:c:OutputProcess connector
c209 cso30:c:OutputProcess connector
p8_propro_p8
PMID: 16723122,9657155,9346241
Whereas all these NF-kB inducers signal through different
receptors and adaptor proteins, they all converge to the
activation of the so called IkB-kinase (IKK) complex, which
includes the scaffold protein NF-kB essential modulator
(NEMO, also called IKKg, IKKa and IKKb kinases.
c29 cso30:c:InputAssociation connector
c30 cso30:c:InputProcess connector
c31 cso30:c:OutputProcess connector
p7_propro_p9
PMID; 16723122,12421671,10795740
The classical NF-kB-activating pathway is induced by a variety
of innate and adaptative immunity mediators, such as proinflammatory
cytokines (TNFa, IL-1b, Toll-like receptors
(TLRs) and antigen receptors (TCR, BCR) ligation
c17 cso30:c:InputProcess connector
c18 cso30:c:InputProcess connector
c19 cso30:c:OutputProcess connector
p7_propro_p10
PMID; 16723122,16343886
The classical NF-kB-activating pathway is induced by a variety
of innate and adaptative immunity mediators, such as proinflammatory
cytokines (TNFa, IL-1b, Toll-like receptors
(TLRs) and antigen receptors (TCR, BCR) ligation
c20 cso30:c:InputProcess connector
c21 cso30:c:InputProcess connector
c22 cso30:c:OutputProcess connector
p7_propro_p11
PMID; 16723122,15134788,15145317,16439988
The classical NF-kB-activating pathway is induced by a variety
of innate and adaptative immunity mediators, such as proinflammatory
cytokines (TNFa, IL-1b, Toll-like receptors
(TLRs) and antigen receptors (TCR, BCR) ligation
c23 cso30:c:InputProcess connector
c24 cso30:c:InputProcess connector
c25 cso30:c:OutputProcess connector
p7_propro_p12
PMID; 16723122,12421671,10795740
The classical NF-kB-activating pathway is induced by a variety
of innate and adaptative immunity mediators, such as proinflammatory
cytokines (TNFa, IL-1b, Toll-like receptors
(TLRs) and antigen receptors (TCR, BCR) ligation
c26 cso30:c:InputProcess connector
c27 cso30:c:InputProcess connector
c28 cso30:c:OutputProcess connector
p8_propro_p13
PMID: 16723122,9657155,9346241
Whereas all these NF-kB inducers signal through different
receptors and adaptor proteins, they all converge to the
activation of the so called IkB-kinase (IKK) complex, which
includes the scaffold protein NF-kB essential modulator
(NEMO, also called IKKg, IKKa and IKKb kinases.
c32 cso30:c:InputAssociation connector
c33 cso30:c:InputProcess connector
c34 cso30:c:OutputProcess connector
p8_propro_p14
PMID: 16723122,9657155,9346241
Whereas all these NF-kB inducers signal through different
receptors and adaptor proteins, they all converge to the
activation of the so called IkB-kinase (IKK) complex, which
includes the scaffold protein NF-kB essential modulator
(NEMO, also called IKKg, IKKa and IKKb kinases.
c35 cso30:c:InputProcess connector
c37 cso30:c:InputAssociation connector
c36 cso30:c:OutputProcess connector
p8_propro_p15
PMID: 16723122,9657155,9346241
Whereas all these NF-kB inducers signal through different
receptors and adaptor proteins, they all converge to the
activation of the so called IkB-kinase (IKK) complex, which
includes the scaffold protein NF-kB essential modulator
(NEMO, also called IKKg, IKKa and IKKb kinases.
c38 cso30:c:InputAssociation connector
c39 cso30:c:InputProcess connector
c40 cso30:c:OutputProcess connector
p8_propro_p16
PMID: 16723122,9657155,9346241
Whereas all these NF-kB inducers signal through different
receptors and adaptor proteins, they all converge to the
activation of the so called IkB-kinase (IKK) complex, which
includes the scaffold protein NF-kB essential modulator
(NEMO, also called IKKg, IKKa and IKKb kinases.
c41 cso30:c:InputAssociation connector
c42 cso30:c:InputProcess connector
c43 cso30:c:OutputProcess connector
p17_propro_p17
PMID: 16723122
Once activated by phosphorylation, the IKK complex phosphorylates
IkBa on Ser32 and Ser36, which is subsequently
ubiquitinated and degraded via the proteasome pathway
c44 cso30:c:InputAssociation connector
c45 cso30:c:InputProcess connector
c46 cso30:c:OutputProcess connector
p18_propro_p18
PMID: 16723122
Once activated by phosphorylation, the IKK complex phosphorylates
IkBa on Ser32 and Ser36, which is subsequently
ubiquitinated and degraded via the proteasome pathway
PMID: 16723122
They showed that, whereas NAC and PDTC efficiently
blocked TNF-induced IkBa degradation and NF-kB activation,the more potent antioxidants epigallocatechin-gallate (EGCG)
and Vitamin E analog Trolox failed to inhibit TNF-stimulated
NF-kB activation, suggesting that the effect of NAC and PDTC
on NF-kB signalling does not rely on their antioxidant
capacities, but rather acts by inhibiting a crucial step in TNF
signalling.
PMID: 16723122
PDTC is likely to inhibit IkB-ubiquitin ligase
activity.
c47 cso30:c:InputProcess connector
c223 cso30:c:InputInhibitor connector
c48 cso30:c:OutputProcess connector
p19_propro_p19
PMID: 16723122
Once activated by phosphorylation, the IKK complex phosphorylates
IkBa on Ser32 and Ser36, which is subsequently
ubiquitinated and degraded via the proteasome pathway
PMID: 16723122
They showed that, whereas NAC and PDTC efficiently
blocked TNF-induced IkBa degradation and NF-kB activation,the more potent antioxidants epigallocatechin-gallate (EGCG)
and Vitamin E analog Trolox failed to inhibit TNF-stimulated
NF-kB activation, suggesting that the effect of NAC and PDTC
on NF-kB signalling does not rely on their antioxidant
capacities, but rather acts by inhibiting a crucial step in TNF
signalling.
c49 cso30:c:InputProcess connector
c222 cso30:c:InputInhibitor connector
c50 cso30:c:OutputProcess connector
c51 cso30:c:OutputProcess connector
p20_propro_p20
PMID: 16723122
The
freed NF-kB then translocates into the nucleus where it
activates the transcription of target genes such as cytokines,
chemokines, adhesion molecules and inhibitors of apoptosis
c52 cso30:c:InputProcess connector
c53 cso30:c:OutputProcess connector
p21_propro_p21
PMID: 16723122
The
freed NF-kB then translocates into the nucleus where it
activates the transcription of target genes such as cytokines,
chemokines, adhesion molecules and inhibitors of apoptosis
c54 cso30:c:InputAssociation connector
c55 cso30:c:OutputProcess connector
p21_propro_p22
PMID: 16723122
The
freed NF-kB then translocates into the nucleus where it
activates the transcription of target genes such as cytokines,
chemokines, adhesion molecules and inhibitors of apoptosis
c56 cso30:c:InputAssociation connector
c57 cso30:c:OutputProcess connector
p21_propro_p23
PMID: 16723122
The
freed NF-kB then translocates into the nucleus where it
activates the transcription of target genes such as cytokines,
chemokines, adhesion molecules and inhibitors of apoptosis
c58 cso30:c:InputAssociation connector
c59 cso30:c:OutputProcess connector
p21_propro_p24
PMID: 16723122
The
freed NF-kB then translocates into the nucleus where it
activates the transcription of target genes such as cytokines,
chemokines, adhesion molecules and inhibitors of apoptosis
c60 cso30:c:InputAssociation connector
c61 cso30:c:OutputProcess connector
p25_propro_p25
PMID: 16723122,12352969
It is induced by B-cell activating factor (BAFF)
, lymphotoxin b (LTb), CD40 ligand and human T
cell leukemia (HTLV) and Epstein-Barr (EBV) virus. It
enhances NF-kB inducing kinase (NIK)- and IKKa-dependent
processing of p100 into p52, which binds DNA in association
with its partners, like RelB.
c66 cso30:c:InputProcess connector
c68 cso30:c:InputAssociation connector
c69 cso30:c:InputAssociation connector
c70 cso30:c:InputAssociation connector
c67 cso30:c:OutputProcess connector
p26_propro_p26
PMID: 16723122,9657155,9346241
Whereas all these NF-kB inducers signal through different
receptors and adaptor proteins, they all converge to the
activation of the so called IkB-kinase (IKK) complex, which
includes the scaffold protein NF-kB essential modulator
(NEMO, also called IKKg, IKKa and IKKb kinases.
c62 cso30:c:InputProcess connector
c63 cso30:c:InputProcess connector
c65 cso30:c:InputProcess connector
c64 cso30:c:OutputProcess connector
p25_propro_p27
PMID: 16723122,12387745
It is induced by B-cell activating factor (BAFF)
, lymphotoxin b (LTb), CD40 ligand and human T
cell leukemia (HTLV) and Epstein-Barr (EBV) virus. It
enhances NF-kB inducing kinase (NIK)- and IKKa-dependent
processing of p100 into p52, which binds DNA in association
with its partners, like RelB.
c71 cso30:c:InputProcess connector
c75 cso30:c:InputAssociation connector
c77 cso30:c:InputAssociation connector
c79 cso30:c:InputAssociation connector
c72 cso30:c:OutputProcess connector
p25_propro_p28
PMID: 16723122,12374738
It is induced by B-cell activating factor (BAFF)
, lymphotoxin b (LTb), CD40 ligand and human T
cell leukemia (HTLV) and Epstein-Barr (EBV) virus. It
enhances NF-kB inducing kinase (NIK)- and IKKa-dependent
processing of p100 into p52, which binds DNA in association
with its partners, like RelB.
c73 cso30:c:InputProcess connector
c76 cso30:c:InputAssociation connector
c78 cso30:c:InputAssociation connector
c80 cso30:c:InputAssociation connector
c74 cso30:c:OutputProcess connector
p29_propro_p29
PMID: 16723122
It
enhances NF-kB inducing kinase (NIK)- and IKKa-dependent
processing of p100 into p52, which binds DNA in association
with its partners, like RelB.
c81 cso30:c:InputProcess connector
c82 cso30:c:InputProcess connector
c83 cso30:c:OutputProcess connector
p30_propro_p30
PMID: 16723122
It
enhances NF-kB inducing kinase (NIK)- and IKKa-dependent
processing of p100 into p52, which binds DNA in association
with its partners, like RelB.
c84 cso30:c:InputProcess connector
c85 cso30:c:OutputProcess connector
p31_propro_p31
PMID: 16723122
It
enhances NF-kB inducing kinase (NIK)- and IKKa-dependent
processing of p100 into p52, which binds DNA in association
with its partners, like RelB.
c86 cso30:c:InputProcess connector
c87 cso30:c:InputProcess connector
c88 cso30:c:OutputProcess connector
p32_propro_p32
PMID: 16723122,15592513
a recent study in Jurkat leukemic cells has shown
that NF-kB activation by H2O2 induces Bfl-1, which, in turn,
attenuates Fas-mediated apoptosis
c89 cso30:c:InputAssociation connector
c90 cso30:c:InputProcess connector
c91 cso30:c:OutputProcess connector
p33_propro_p33
PMID: 16723122,15592513
a recent study in Jurkat leukemic cells has shown
that NF-kB activation by H2O2 induces Bfl-1, which, in turn,
attenuates Fas-mediated apoptosis
c92 cso30:c:InputAssociation connector
c93 cso30:c:OutputProcess connector
p34_propro_p34
PMID: 16723122,10754328
Furthermore, the IkBa degradation mechanism
appears to be proteasome-independent, but instead relies
on a calpain-mediated digestion after phophorylation on S/T
in the so-called PEST sequence of the inhibitor
c94 cso30:c:InputAssociation connector
c95 cso30:c:InputProcess connector
c96 cso30:c:OutputProcess connector
c97 cso30:c:OutputProcess connector
p35_propro_p35
PMID: 16723122,11231305,8797825
NF-kB
activation induced by tyrosine phosphorylation of IkBa was
also observed after pervanadate (a potent tyrosine phosphatase
inhibitor) and hypoxia/reoxygenation treatment
PMID: 16723122,11231305
TCR-associated tyrosine kinases
p56Lck and ZAP-70 were required for pervanadate-induced
IkBa tyrosine phosphorylation, without showing that these
kinases indeed phosphorylate IkBa directly
PMID: 16723122,12429743
In that case, the
tyrosine kinase c-Src has been reported to be responsible for
IkBa tyrosine phosphorylation
c98 cso30:c:InputAssociation connector
c99 cso30:c:InputProcess connector
c132 cso30:c:InputAssociation connector
c133 cso30:c:InputAssociation connector
c134 cso30:c:InputAssociation connector
c276 cso30:c:InputInhibitor connector
c277 cso30:c:InputInhibitor connector
c288 cso30:c:InputInhibitor connector
c100 cso30:c:OutputProcess connector
p36_propro_p36
PMID: 16723122,12711606
Recently,Takada et al. reported that Syk tyrosine kinase was required
for H2O2-induced IkBa tyrosine phosphorylation and NF-kB
activation, and was capable of phosphorylating IkBa in vitro,
suggesting that Syk may be the terminal tyrosine kinase
responsible for IkBa tyrosine phosphorylation
c101 cso30:c:InputAssociation connector
c102 cso30:c:InputProcess connector
c103 cso30:c:OutputProcess connector
p37_propro_p37
PMID: 16723122,16619039
Unexpectedly, micromolar amounts of
H2O2 were shown indeed capable of inducing IKK activation in
these cell lines, leading to a classical IkBa phosphorylation on
Ser32 and 36
c104 cso30:c:InputAssociation connector
c105 cso30:c:InputProcess connector
c106 cso30:c:OutputProcess connector
p38_propro_p38
PMID: 16723122,16619039
Unexpectedly, micromolar amounts of
H2O2 were shown indeed capable of inducing IKK activation in
these cell lines, leading to a classical IkBa phosphorylation on
Ser32 and 36
c107 cso30:c:InputAssociation connector
c108 cso30:c:InputProcess connector
c109 cso30:c:OutputProcess connector
p39_propro_p39
PMID: 16723122,10995586
SHIP-1, a lipid
phosphatase, acts by dephosphorylating the membranebound
PtdIns(3,4,5)P3, generated by PI3Kinase, and has thus
been described as a negative regulator of immune receptor,
cytokine and growth factor receptor signalling
c110 cso30:c:InputAssociation connector
c111 cso30:c:InputProcess connector
c112 cso30:c:OutputProcess connector
c113 cso30:c:OutputProcess connector
p40_propro_p40
PMID: 16723122,10995586
SHIP-1, a lipid
phosphatase, acts by dephosphorylating the membranebound
PtdIns(3,4,5)P3, generated by PI3Kinase, and has thus
been described as a negative regulator of immune receptor,
cytokine and growth factor receptor signalling
c114 cso30:c:InputAssociation connector
c115 cso30:c:OutputProcess connector
p42_propro_p42
PMID: 16723122
First, activated Src
induces Abl-mediated phophorylation of PKD at Y463 in the PH
domain.
c119 cso30:c:InputAssociation connector
c120 cso30:c:InputProcess connector
c121 cso30:c:OutputProcess connector
p43_propro_p43
PMID: 16723122
First, activated Src
induces Abl-mediated phophorylation of PKD at Y463 in the PH
domain.This facilitates release of the PH domain, which
exposes the catalytic domain and activation loop residues to a
second phosphorylation by PKCd on S738/S742. This induces a
fully activated PKD which, in turn, activates the IKK complex
c122 cso30:c:InputAssociation connector
c123 cso30:c:InputAssociation connector
c124 cso30:c:InputProcess connector
c125 cso30:c:OutputProcess connector
p43_propro_p44
PMID: 16723122
First, activated Src
induces Abl-mediated phophorylation of PKD at Y463 in the PH
domain.This facilitates release of the PH domain, which
exposes the catalytic domain and activation loop residues to a
second phosphorylation by PKCd on S738/S742. This induces a
fully activated PKD which, in turn, activates the IKK complex
c126 cso30:c:InputProcess connector
c128 cso30:c:InputAssociation connector
c127 cso30:c:OutputProcess connector
p45_propro_p45
PMID: 16723122
First, activated Src
induces Abl-mediated phophorylation of PKD at Y463 in the PH
domain.This facilitates release of the PH domain, which
exposes the catalytic domain and activation loop residues to a
second phosphorylation by PKCd on S738/S742. This induces a
fully activated PKD which, in turn, activates the IKK complex
c129 cso30:c:InputAssociation connector
c130 cso30:c:InputProcess connector
c131 cso30:c:OutputProcess connector
p46_propro_p46
PMID: 16723122,11479295
Korn
et al. reported that, in this case, H2O2 is capable of inhibiting
TNF-induced NF-kB activation in lung epithelial cells by
reducing IKKb activity through oxidation of cysteine residues
in the IKK complex
PMID: 16723122,16344117
Other
works demonstrated that ammonia monochloramine (NH2Cl)
and glycine chloramine (GlyCl), two others neutrophils-derived
oxidants, but not TauCl, were capable of inhibiting TNFinduced
NF-kB activation via the same molecular mechanism
c136 cso30:c:InputAssociation connector
c137 cso30:c:InputProcess connector
c142 cso30:c:InputInhibitor connector
c174 cso30:c:InputInhibitor connector
c175 cso30:c:InputInhibitor connector
c138 cso30:c:OutputProcess connector
p47_propro_p47
PMID: 16723122,11479295
Korn
et al. reported that, in this case, H2O2 is capable of inhibiting
TNF-induced NF-kB activation in lung epithelial cells by
reducing IKKb activity through oxidation of cysteine residues
in the IKK complex
c139 cso30:c:InputAssociation connector
c140 cso30:c:InputProcess connector
c141 cso30:c:OutputProcess connector
p49_propro_p49
PMID: 16723122,10333500
HOCl is a strong oxidant that kills
phagocytosed bacteria, but can also react with amines to
produce chloramines and N-chlorinated derivatives which
have long lifetimes
PMID: 16723122
Among these chloramines, taurine
chloramine (TauCl) is generated in great amount in HOClproducing
neutrophils because these cells contain high
concentrations of taurine, a free amino acid not incorporated
in proteins.
c147 cso30:c:InputProcess connector
c148 cso30:c:InputProcess connector
c149 cso30:c:OutputProcess connector
c150 cso30:c:OutputProcess connector
c157 cso30:c:OutputProcess connector
p48_propro_p48
PMID: 16723122,9787133
HOCl is formed from H2O2 and Cl ion by
myeloperoxidase
c143 cso30:c:InputProcess connector
c144 cso30:c:InputProcess connector
c146 cso30:c:InputAssociation connector
c145 cso30:c:OutputProcess connector
p51_propro_p51
PMID: 16723122,11490015
For example, TauCl was shown to decrease LPSinduced
NF-kB activation and IKK activity in alveolar macrophages,
resulting in inhibition of iNOS and TNFa gene
expression
c154 cso30:c:InputAssociation connector
c155 cso30:c:InputProcess connector
c158 cso30:c:InputInhibitor connector
c156 cso30:c:OutputProcess connector
c159 cso30:c:OutputProcess connector
p51_propro_p52
PMID: 16723122,11490015
For example, TauCl was shown to decrease LPSinduced
NF-kB activation and IKK activity in alveolar macrophages,
resulting in inhibition of iNOS and TNFa gene
expression
c160 cso30:c:InputAssociation connector
c161 cso30:c:InputProcess connector
c163 cso30:c:InputInhibitor connector
c162 cso30:c:OutputProcess connector
p53_propro_p53
PMID: 16723122,11490015
For example, TauCl was shown to decrease LPSinduced
NF-kB activation and IKK activity in alveolar macrophages,
resulting in inhibition of iNOS and TNFa gene
expression
c165 cso30:c:InputAssociation connector
c164 cso30:c:OutputProcess connector
p53_propro_p54
PMID: 16723122,11490015
For example, TauCl was shown to decrease LPSinduced
NF-kB activation and IKK activity in alveolar macrophages,
resulting in inhibition of iNOS and TNFa gene
expression
c166 cso30:c:InputAssociation connector
c167 cso30:c:OutputProcess connector
p55_propro_p55
PMID: 16723122,11983684
The molecular mechanism of this inhibition
relied on oxidation of IkBa methionine 45, which renders the
inhibitor resistant to TNF-induced degradation
c168 cso30:c:InputProcess connector
c169 cso30:c:OutputProcess connector
p56_propro_p56
PMID: 16723122,11983684
The molecular mechanism of this inhibition
relied on oxidation of IkBa methionine 45, which renders the
inhibitor resistant to TNF-induced degradation
c170 cso30:c:InputAssociation connector
c171 cso30:c:InputProcess connector
c173 cso30:c:InputInhibitor connector
c172 cso30:c:OutputProcess connector
p57_propro_p57
PMID: 16723122,2154753
Peroxinitrite is formed by the reaction of nitric
oxide (NO) with superoxide
c176 cso30:c:InputProcess connector
c177 cso30:c:InputProcess connector
c178 cso30:c:OutputProcess connector
p59_propro_p59
PMID: 16723122,9374458,9371760,10854325
IL-1b is a potent pro-inflammatory cytokine that exerts its
effects by binding to its receptor (IL1-R1) on the plasma membrane. This binding induces the recruitment to the
receptor cytoplasmic tail of adaptator and effector proteins,
including IL-1RacP, MyD88 and Tollip
c182 cso30:c:InputProcess connector
c183 cso30:c:InputProcess connector
c184 cso30:c:OutputProcess connector
p59_propro_p60
PMID: 16723122,9374458,9371760,10854325
IL-1b is a potent pro-inflammatory cytokine that exerts its
effects by binding to its receptor (IL1-R1) on the plasma membrane. This binding induces the recruitment to the
receptor cytoplasmic tail of adaptator and effector proteins,
including IL-1RacP, MyD88 and Tollip
c185 cso30:c:InputProcess connector
c186 cso30:c:InputProcess connector
c187 cso30:c:OutputProcess connector
p59_propro_p61
PMID: 16723122,9374458,9371760,10854325
IL-1b is a potent pro-inflammatory cytokine that exerts its
effects by binding to its receptor (IL1-R1) on the plasma membrane. This binding induces the recruitment to the
receptor cytoplasmic tail of adaptator and effector proteins,
including IL-1RacP, MyD88 and Tollip
c188 cso30:c:InputProcess connector
c189 cso30:c:InputProcess connector
c190 cso30:c:OutputProcess connector
p62_propro_p62
PMID: 16723122,9430229,11518704
MyD88 then
mediates the recruitment of the interleukin-1 receptorassociated
kinase (IRAK) family members to the IL-1R,
which, in turn, recruit TRAF6
c191 cso30:c:InputProcess connector
c192 cso30:c:InputProcess connector
c193 cso30:c:OutputProcess connector
p62_propro_p63
PMID: 16723122,9430229,11518704
MyD88 then
mediates the recruitment of the interleukin-1 receptorassociated
kinase (IRAK) family members to the IL-1R,
which, in turn, recruit TRAF6
c194 cso30:c:InputProcess connector
c195 cso30:c:InputProcess connector
c196 cso30:c:OutputProcess connector
p64_propro_p64
PMID: 16723122,11460167
Then, TRAF6 recruits TAK1
that mediates phosphorylation of the IKK complex, a crucial
step in NF-kB activation
c197 cso30:c:InputProcess connector
c198 cso30:c:InputProcess connector
c199 cso30:c:OutputProcess connector
p65_propro_p65
PMID: 16723122,11460167
Then, TRAF6 recruits TAK1
that mediates phosphorylation of the IKK complex, a crucial
step in NF-kB activation
c200 cso30:c:InputAssociation connector
c201 cso30:c:InputProcess connector
c202 cso30:c:OutputProcess connector
p66_propro_p66
PMID: 16723122
It binds to its cellular TNFR1 receptor, which triggers
signalling cascades that activate NF-kB and AP-1 transcription
factors.
c203 cso30:c:InputAssociation connector
c204 cso30:c:InputProcess connector
c205 cso30:c:OutputProcess connector
p67_propro_p67
PMID: 16723122,9915703
The ligation of TNFR1 by
trimeric TNFa leads to the aggregation of the receptor and
dissociation of silencer of death domain (SODD), an inhibitor
of TNFR1 activity, which allows binding of TNFR-associated
death domain protein (TRADD protein)
c206 cso30:c:InputProcess connector
c207 cso30:c:InputProcess connector
c208 cso30:c:OutputProcess connector
p67_propro_p68
PMID: 16723122,9915703
The ligation of TNFR1 by
trimeric TNFa leads to the aggregation of the receptor and
dissociation of silencer of death domain (SODD), an inhibitor
of TNFR1 activity, which allows binding of TNFR-associated
death domain protein (TRADD protein)
c210 cso30:c:InputProcess connector
c211 cso30:c:InputProcess connector
c212 cso30:c:OutputProcess connector
p69_propro_p69
PMID: 16723122,12787559
Although many
members of the TRAF family have been implicated in TNF
signalling, it appears that both TRAF2 and TRAF5 have a role in
NF-kB activation by TNFa
c213 cso30:c:InputProcess connector
c214 cso30:c:InputProcess connector
c215 cso30:c:OutputProcess connector
p70_propro_p70
PMID: 16723122,10755617
RIP1 functions as a scaffold protein notably through its
direct binding to NEMO, which allows the recruitment of the
IKK complex in TNF signalling
c216 cso30:c:InputProcess connector
c217 cso30:c:InputProcess connector
c218 cso30:c:OutputProcess connector
p70_propro_p71
PMID: 16723122,10755617
RIP1 functions as a scaffold protein notably through its
direct binding to NEMO, which allows the recruitment of the
IKK complex in TNF signalling
c219 cso30:c:InputProcess connector
c220 cso30:c:InputProcess connector
c221 cso30:c:OutputProcess connector
p72_propro_p72
PMID: 16723122
These results are reinforced by the observation that,
whereas NAC does not inhibit IL-1 or TPA-induced IkBa
degradation, PDTC does
c224 cso30:c:InputProcess connector
c226 cso30:c:InputAssociation connector
c227 cso30:c:InputInhibitor connector
c225 cso30:c:OutputProcess connector
p73_propro_p73
PMID: 16723122
These results are reinforced by the observation that,
whereas NAC does not inhibit IL-1 or TPA-induced IkBa
degradation, PDTC does
c228 cso30:c:InputProcess connector
c229 cso30:c:InputProcess connector
c230 cso30:c:OutputProcess connector
p72_propro_p74
PMID: 16723122
These results are reinforced by the observation that,
whereas NAC does not inhibit IL-1 or TPA-induced IkBa
degradation, PDTC does
c231 cso30:c:InputProcess connector
c232 cso30:c:InputAssociation connector
c233 cso30:c:InputInhibitor connector
c300 cso30:c:OutputProcess connector
p75_propro_p75
PMID:16723122
They showed that ROS (induced by
cigarette smoke or H2O2 treatment) reduce HDAC2 expression
c234 cso30:c:InputInhibitor connector
c235 cso30:c:OutputProcess connector
p76_propro_p76
PMID: 16723122,12368228
Finally, it should also
be noted that NAC was shown to inhibit p65 ser536 phosphorylation,
suggesting that post-translationalmodifications affecting
p65 are also redox-sensitive
c236 cso30:c:InputInhibitor connector
c179 cso30:c:InputProcess connector
c238 cso30:c:OutputProcess connector
p77_propro_p79
PMID: 16723122,14743220
In that respect, they identified growth
arrest and DNA damage-inducing protein 45b (GADD45b) and
X chromosome-linked IAP (XIAP) as capable of inhibiting JNK
signalling by inactivating MEKK7
c245 cso30:c:InputProcess connector
c247 cso30:c:InputAssociation connector
c116 cso30:c:InputInhibitor connector
c117 cso30:c:InputInhibitor connector
c118 cso30:c:InputInhibitor connector
c246 cso30:c:OutputProcess connector
p78_propro_p78
PMID: 16723122
They showed that TNFinduced
ROS production is responsible for sustained JNK
activation in NF-kB-activation deficient cells,whereas wildtype
cells exhibited neither ROS production nor sustained JNK
activation upon TNF challenge.
c243 cso30:c:InputAssociation connector
c9 cso30:c:OutputProcess connector
p5_propro_p5
PMID: 16723122
In fact, several laboratories have independently
reported that NF-kB down-regulates JNK activation by
suppressing TNF-induced ROS accumulation
PMID: 16723122
Moreover, prolonged JNK
activation is inhibited by pre-treatment of NF-kB-defective
cells with the antioxidants BHA or NAC, suggesting that ROS
are key messengers of prolonged JNK activation after TNF
induction.
c10 cso30:c:InputAssociation connector
c244 cso30:c:InputProcess connector
c249 cso30:c:InputInhibitor connector
c250 cso30:c:InputInhibitor connector
c251 cso30:c:InputInhibitor connector
c248 cso30:c:OutputProcess connector
p80_propro_p80
PMID: 16723122,14751757,: 1475175
Upon binding of TLR4 to LPS, the
cytoplasmic region of TLR4 recruits MyD88, which links TLR4
to IRAK and TRAF6 that mediates NF-kB activation
c252 cso30:c:InputProcess connector
c253 cso30:c:InputProcess connector
c254 cso30:c:OutputProcess connector
p80_propro_p81
PMID: 16723122
Upon binding of TLR4 to LPS, the
cytoplasmic region of TLR4 recruits MyD88, which links TLR4
to IRAK and TRAF6 that mediates NF-kB activation
c255 cso30:c:InputProcess connector
c256 cso30:c:InputProcess connector
c257 cso30:c:OutputProcess connector
p80_propro_p82
PMID: 16723122
Upon binding of TLR4 to LPS, the
cytoplasmic region of TLR4 recruits MyD88, which links TLR4
to IRAK and TRAF6 that mediates NF-kB activation
c258 cso30:c:InputProcess connector
c259 cso30:c:InputProcess connector
c260 cso30:c:OutputProcess connector
p83_propro_p83
PMID: 16723122
Upon binding of TLR4 to LPS, the
cytoplasmic region of TLR4 recruits MyD88, which links TLR4
to IRAK and TRAF6 that mediates NF-kB activation
PMID: 16723122,14764725,15039334
Pre-treatment of neutrophils with NAC or atocopherol
prevented LPS-induced NF-kB activation and the
production of pro-inflammatory cytokines, and NAC and
DMSO were reported to block NF-kB activation and IL-8
secretion in monocyte-like THP-1 cells challenged with LPS
c262 cso30:c:InputProcess connector
c261 cso30:c:InputAssociation connector
c278 cso30:c:InputInhibitor connector
c279 cso30:c:InputInhibitor connector
c280 cso30:c:InputInhibitor connector
c135 cso30:c:InputAssociation connector
c263 cso30:c:OutputProcess connector
c264 cso30:c:OutputProcess connector
p84_propro_p84
PMID:16723122,1698311,7681082,2402637
CD14, which is expressed on the surface and in the cytoplasm
(sCD14) of monocytes/macrophages and neutrophils, has also
been reported to play a key role in the recognition of LPS and in
downstream cytokine release, notably through its interaction
with LPS-binding protein (LBP), which binds the lipid A region
of LPS and aids LPS to dock at the TLR4
c265 cso30:c:InputProcess connector
c266 cso30:c:InputProcess connector
c267 cso30:c:OutputProcess connector
p84_propro_p50
PMID:16723122,1698311,7681082,2402637
CD14, which is expressed on the surface and in the cytoplasm
(sCD14) of monocytes/macrophages and neutrophils, has also
been reported to play a key role in the recognition of LPS and in
downstream cytokine release, notably through its interaction
with LPS-binding protein (LBP), which binds the lipid A region
of LPS and aids LPS to dock at the TLR4
c151 cso30:c:InputProcess connector
c152 cso30:c:InputProcess connector
c153 cso30:c:OutputProcess connector
p84_propro_p85
PMID:16723122,1698311,7681082,2402637
CD14, which is expressed on the surface and in the cytoplasm
(sCD14) of monocytes/macrophages and neutrophils, has also
been reported to play a key role in the recognition of LPS and in
downstream cytokine release, notably through its interaction
with LPS-binding protein (LBP), which binds the lipid A region
of LPS and aids LPS to dock at the TLR4
c268 cso30:c:InputProcess connector
c269 cso30:c:InputProcess connector
c270 cso30:c:OutputProcess connector
c271 cso30:c:OutputProcess connector
c272 cso30:c:OutputProcess connector
p86_propro_p86
PMID: 16723122
They showed that, in HEK293T cells, LPS-induced ROS
generation and NF-kB activation are mediated by direct
interaction of TLR4 with NADPH oxidase 4 (Nox4
c273 cso30:c:InputProcess connector
c274 cso30:c:InputProcess connector
c275 cso30:c:OutputProcess connector
p77_propro_p77
PMID: 16723122,14743220
In that respect, they identified growth
arrest and DNA damage-inducing protein 45b (GADD45b) and
X chromosome-linked IAP (XIAP) as capable of inhibiting JNK
signalling by inactivating MEKK7
c239 cso30:c:InputProcess connector
c180 cso30:c:InputAssociation connector
c181 cso30:c:InputAssociation connector
c240 cso30:c:OutputProcess connector
p89_propro_p89
PMID: 16723122
Indeed, ROS inactivate
MAP kinase phosphatases (MKPs, which are known to
suppress JNK activation) by oxidizing critical residues in their
phosphatase domain, which leads to prolonged JNK activation
(Fig. 5). Moreover, oxidized MKPs are rapidly degraded by the
ubiquitin-proteasome pathway
c281 cso30:c:InputAssociation connector
c282 cso30:c:InputProcess connector
c283 cso30:c:OutputProcess connector
p88_propro_p88
PMID: 16723122
Indeed, ROS inactivate
MAP kinase phosphatases (MKPs, which are known to
suppress JNK activation) by oxidizing critical residues in their
phosphatase domain, which leads to prolonged JNK activation
(Fig. 5). Moreover, oxidized MKPs are rapidly degraded by the
ubiquitin-proteasome pathway
c284 cso30:c:InputProcess connector
c285 cso30:c:OutputProcess connector
p90_propro_p90
PMID: 16723122
Indeed, ROS inactivate
MAP kinase phosphatases (MKPs, which are known to
suppress JNK activation) by oxidizing critical residues in their
phosphatase domain, which leads to prolonged JNK activation
(Fig. 5). Moreover, oxidized MKPs are rapidly degraded by the
ubiquitin-proteasome pathway
c286 cso30:c:InputProcess connector
c287 cso30:c:OutputProcess connector
p93_propro_p93
PMID: 16723122,15864310
It should, however, be noted that ROS production
after LPS challenge has been showed to mediate the formation
of a complex between TRAF6 and the redox-sensitive ASK1,
which, in turn, triggers p38 activation, another downstream
target of LPS signalling
c293 cso30:c:InputAssociation connector
c294 cso30:c:InputProcess connector
c295 cso30:c:InputProcess connector
c296 cso30:c:OutputProcess connector
p94_propro_p94
PMID: 16723122,15864310
It should, however, be noted that ROS production
after LPS challenge has been showed to mediate the formation
of a complex between TRAF6 and the redox-sensitive ASK1,
which, in turn, triggers p38 activation, another downstream
target of LPS signalling
c297 cso30:c:InputAssociation connector
c298 cso30:c:InputProcess connector
c299 cso30:c:OutputProcess connector
p95_propro_p95
PMID: 16723122,15864310
It should, however, be noted that ROS production
after LPS challenge has been showed to mediate the formation
of a complex between TRAF6 and the redox-sensitive ASK1,
which, in turn, triggers p38 activation, another downstream
target of LPS signalling
c301 cso30:c:InputAssociation connector
c302 cso30:c:OutputProcess connector
p58_propro_p58
PMID: 16723122
Using blocking antibodies, they also reported that the ROS-dependent Rac1 activation is independent of the CD14
receptor, suggesting that alternative pathways contribute to
NF-kB activation by LPS
c237 cso30:c:InputAssociation connector
c241 cso30:c:InputProcess connector
c242 cso30:c:OutputProcess connector
lipoxygenases_enti_e5
lipoxygenases
superoxide anion_enti_e6
superoxide anion
cycloxygenases_enti_e9
cycloxygenases
phagocytic NADPH oxidases_enti_e11
phagocytic NADPH oxidases
Non-phagocytic oxidases_enti_e12
Non-phagocytic oxidases
Myeloperoxidase_enti_e13
Myeloperoxidase
NF-KappaB_enti_e15
NF-KappaB
NF-KappaB:IKappaB_enti_e16
NF-KappaB:IKappaB
IKappaB_enti_e17
IKappaB
TNF-alpha_enti_MO000000289
TNF-alpha
TNF-alphaR_enti_e18
TNF-alphaR
TNF-alpha:TNF-alphaR_enti_e19
TNF-alpha:TNF-alphaR
IL-1beta_enti_MO000016597
IL-1beta
IL-1betaR_enti_e20
IL-1betaR
IL-1beta:IL-1betaR_enti_e21
IL-1beta:IL-1betaR
TLRs_enti_e22
TLRs
PAMPs_enti_e23
PAMPs
TLRs:PAMPs_enti_e24
TLRs:PAMPs
T-cell antigen_enti_e25
T-cell antigen
B-cell antigen_enti_e26
B-cell antigen
TCR_enti_MO000017777
TCR
BCR_enti_MO000017690
BCR
T-cell antigen:TCR_enti_e27
T-cell antigen:TCR
B-cell antigen:BCR_enti_e28
B-cell antigen:BCR
IKK_enti_MO000000248
IKK
IKK{p}_enti_e29
IKK{p}
NF-KappaB:IKappaB{p}_enti_e30
NF-KappaB:IKappaB{p}
NF-KappaB:IKappaB{p}{ub}_enti_e31
NF-KappaB:IKappaB{p}{ub}
degradants_enti_e32
NF-KappaB_enti_e33
NF-KappaB
cytokines_enti_e34
cytokines
chemokines_enti_e35
chemokines
adhesion molecules_enti_e36
adhesion molecules
inhibitors of apoptosis_enti_e37
inhibitors of apoptosis
BAFF_enti_e38
BAFF
Lymphotoxin beta_enti_e39
Lymphotoxin beta
CD40_enti_e40
CD40
NIK_enti_MO000000203
NIK
IKK-alpha_enti_MO000000210
IKK-alpha
IKK-beta_enti_MO000000211
IKK-beta
IKK-gamma_enti_MO000016599
IKK-gamma
p100_enti_MO000000202
p100
p52_enti_MO000000196
p52
RelB_enti_MO000000194
RelB
RelB:p52_enti_e41
RelB:p52
RelB:p52_enti_e42
RelB:p52
DNA_enti_e43
DNA
RelB:p52:DNA_enti_e44
RelB:p52:DNA
H2O2_enti_e45
H2O2
Bfl-1_enti_e46
Bfl-1
calpain_enti_e47
calpain
pervanadate_enti_e48
pervanadate
Syk_enti_MO000008301
Syk
IKK{active}_enti_e49
IKK{active}
PtdIns{p}_enti_MO000017583
PtdIns{p}
SHIP-1_enti_e63
SHIP-1
PtdIns_enti_e64
PtdIns
Inorganic phosphate_enti_e65
Inorganic phosphate
PI3K_enti_MO000000030
PI3K
Src_enti_e66
Src
Src{active}_enti_e67
Src{active}
Ab1_enti_e68
Ab1
PKD_enti_MO000078383
PKD
PKD{pY463}_enti_e69
PKD{pY463}
PKD{pS738/S742}_enti_e70
PKD{pS738/S742}
PKCdelta_enti_MO000017065
PKCdelta
ZAP-70_enti_MO000017772
ZAP-70
p56Lck_enti_e7
p56Lck
IKK{oxidized}_enti_e71
IKK{oxidized}
Chloride ion_enti_e72
Chloride ion
HOCl_enti_e74
HOCl
amines_enti_e75
amines
chloramines_enti_e76
chloramines
N-chlorinated derivatives_enti_e77
N-chlorinated derivatives
LPS_enti_MO000016882
LPS
TLR4_enti_MO000019394
TLR4
LPS:TLR4_enti_e78
LPS:TLR4
Taurine chloramine_enti_e79
Taurine chloramine
iNOS_enti_G010514
iNOS
TNF-alpha_enti_G010329
TNF-alpha
IKappaB{oxidized}_enti_e80
IKappaB{oxidized}
degradants_enti_e81
NH2Cl_enti_e73
NH2Cl
GlyCl_enti_e82
GlyCl
peroxinitrite_enti_e83
peroxinitrite
NO_enti_e84
NO
superoxide_enti_e85
superoxide
IL-1RacP_enti_e87
IL-1RacP
Il-1beta:IL-1R1:IL-1RacP_enti_e88
Il-1beta:IL-1R1:IL-1RacP
MyD88_enti_MO000016573
MyD88
IL-1beta:IL-1R1:IL-1RcaP:MyD88_enti_e89
IL-1beta:IL-1R1:IL-1RcaP:MyD88
Tollip_enti_MO000019406
Tollip
IL-1beta:IL-1R1:IL-1RcaP:MyD88:Tollip_enti_e90
IL-1beta:IL-1R1:IL-1RcaP:MyD88:Tollip
IRAK_enti_MO000000213
IRAK
IL-1beta:IL-1R1:IL-1RcaP:MyD88:Tollip:IRAK_enti_e91
IL-1beta:IL-1R1:IL-1RcaP:MyD88:Tollip:IRAK
TRAF6_enti_MO000000212
TRAF6
IL-1beta:IL-1R1:IL-1RcaP:MyD88:Tollip:IRAK:TRAF6_enti_e92
IL-1beta:IL-1R1:IL-1RcaP:MyD88:Tollip:IRAK:TRAF6
TAK1_enti_MO000016574
TAK1
IL-1beta:IL-1R1:IL-1RcaP:MyD88:Tollip:IRAK:TRAF6:TAK1_enti_e93
IL-1beta:IL-1R1:IL-1RcaP:MyD88:Tollip:IRAK:TRAF6:TAK1
AP-1_enti_MO000000276
AP-1
AP-1{active}_enti_e94
AP-1{active}
SODD_enti_MO000018873
SODD
TNFR:SODD_enti_e95
TNFR:SODD
TRADD_enti_MO000000207
TRADD
TNFR:TNF:alpha:TRADD_enti_e96
TNFR:TNF:alpha:TRADD
TRAF_enti_e97
TRAF
TNFR:TNF-alpha:TRADD:TRAF_enti_e98
TNFR:TNF-alpha:TRADD:TRAF
RIP1_enti_e99
RIP1
TNFR:TNF-alpha:TRADD:TRAF:RIP1_enti_e100
TNFR:TNF-alpha:TRADD:TRAF:RIP1
TNFR:TNF-alpha:TRADD:TRAF:RIP1:nemo_enti_e101
TNFR:TNF-alpha:TRADD:TRAF:RIP1:nemo
NAC_enti_e102
NAC
PTDC_enti_e103
PTDC
tPA_enti_MO000062257
tPA
IL-1_enti_MO000000214
IL-1
IL-1R_enti_e104
IL-1R
Il-1:Il-1R_enti_e105
Il-1:Il-1R
HDAC2_enti_G011488
HDAC2
RelA-p65{p}_enti_e106
RelA-p65{p}
MEKK7_enti_e107
MEKK7
MEKK7{inactive}_enti_e108
MEKK7{inactive}
GADD45beta_enti_e109
GADD45beta
XIAP_enti_MO000017876
XIAP
JNK_enti_MO000000023
JNK
JNK{active}_enti_e110
JNK{active}
ROS_enti_e111
ROS
BHA_enti_e14
BHA
LPS:TLR4:MyD88_enti_e112
LPS:TLR4:MyD88
LPS:TLR4:MyD88:IRAK_enti_e113
LPS:TLR4:MyD88:IRAK
LPS:TLR4:MyD88:IRAK:TRAF6_enti_e114
LPS:TLR4:MyD88:IRAK:TRAF6
LBP_enti_MO000019420
LBP
LPS:LBP_enti_MO000021928
LPS:LBP
LPS:LBP:CD14_enti_MO000021929
LPS:LBP:CD14
CD14_enti_MO000018132
CD14
NOX4_enti_MO000068593
NOX4
LPS:TLR4:MyD88:IRAK:TRAF6:Nox4_enti_e115
LPS:TLR4:MyD88:IRAK:TRAF6:Nox4
alpha-octopherol_enti_e116
alpha-octopherol
DMSO_enti_e117
DMSO
MAPK phosphatases_enti_e118
MAPK phosphatases
MAPK phosphatases{oxidized}_enti_e119
MAPK phosphatases{oxidized}
MAPK phosphatases{oxidized}{ub}_enti_e120
MAPK phosphatases{oxidized}{ub}
ASK1_enti_MO000000079
ASK1
ASK1:TRAF6_enti_e126
ASK1:TRAF6
p38{active}_enti_MO000000022
p38{active}
p38_enti_e127
p38
RelA-p65_enti_e10
RelA-p65
Rac1_enti_MO000000166
Rac1
Rac1{active}_enti_e86
Rac1{active}