_enti_e7
_enti_e8
_enti_e9
_enti_e1
_enti_e10
_enti_e4
_enti_e3
_enti_e2
_enti_e55
_enti_e53
_enti_e59
_enti_e50
_enti_e52
_enti_e54
_enti_e56
_enti_e51
_enti_e61
_enti_e57
_enti_e58
_enti_e62
_enti_e60
g1_fact_g1
g2_fact_g12
g2_fact_g13
g1_fact_g14
p1_propro_p1
PMID: 14620137
The impaired
capacity of MIF-deficient macrophages to respond to LPS
was shown to be due to reduced expression of TLR4, the
signal-transducing molecule of the LPS receptor complex.
c1 cso30:c:InputProcess connector
c2 cso30:c:InputProcess connector
c3 cso30:c:OutputProcess connector
p2_propro_p2
PMID: 14620137, 9006339
Systemic administration of LPS causes a rapid release of
MIF from essentially all tissues, leading to profound
depletion of the cellular pools of MIF, which are quickly
restored by a robust induction of MIF mRNA and de novo
synthesis of the MIF protein
c4 cso30:c:InputAssociation connector
c6 cso30:c:InputAssociation connector
c5 cso30:c:OutputProcess connector
p3_propro_p3
PMID: 14620137, 9006339
Systemic administration of LPS causes a rapid release of
MIF from essentially all tissues, leading to profound
depletion of the cellular pools of MIF, which are quickly
restored by a robust induction of MIF mRNA and de novo
synthesis of the MIF protein
c7 cso30:c:InputAssociation connector
c8 cso30:c:OutputProcess connector
p4_propro_p4
PMID: 14620137, 9006339
Systemic administration of LPS causes a rapid release of
MIF from essentially all tissues, leading to profound
depletion of the cellular pools of MIF, which are quickly
restored by a robust induction of MIF mRNA and de novo
synthesis of the MIF protein
c9 cso30:c:InputAssociation connector
c10 cso30:c:OutputProcess connector
p5_propro_p5
PMID: 14620137
TNF-alpha binds its respective receptor.
c11 cso30:c:InputProcess connector
c12 cso30:c:InputProcess connector
c13 cso30:c:OutputProcess connector
p6_propro_p6
PMID: 14620137
IFN-gamma binds its corresponding receptor.
c14 cso30:c:InputProcess connector
c15 cso30:c:InputProcess connector
c16 cso30:c:OutputProcess connector
p7_propro_p7
PMID: 14620137, 8195715, 9736745, 10722628
Gram-negative and Gram-positive bacteria, bacterial endotoxin
(LPS) and exotoxins [toxic shock syndrome toxin-1
(TSST-1) and streptococcal pyrogenic exotoxin A (SPEA)],
mycobacteria, malaria pigment and proinflammatory cytokines
[tumour necrosis factor-a (TNF-a) and interferon-g
(IFN-g) have been found to induce macrophages to release
MIF (12-14).
c17 cso30:c:InputAssociation connector
c22 cso30:c:InputAssociation connector
c27 cso30:c:OutputProcess connector
p7_propro_p8
PMID: 14620137, 8195715, 9736745, 10722628
Gram-negative and Gram-positive bacteria, bacterial endotoxin
(LPS) and exotoxins [toxic shock syndrome toxin-1
(TSST-1) and streptococcal pyrogenic exotoxin A (SPEA)],
mycobacteria, malaria pigment and proinflammatory cytokines
[tumour necrosis factor-a (TNF-a) and interferon-g
(IFN-g) have been found to induce macrophages to release
MIF (12-14).
c18 cso30:c:InputAssociation connector
c23 cso30:c:InputAssociation connector
c28 cso30:c:OutputProcess connector
p7_propro_p9
PMID: 14620137, 8195715, 9736745, 10722628
Gram-negative and Gram-positive bacteria, bacterial endotoxin
(LPS) and exotoxins [toxic shock syndrome toxin-1
(TSST-1) and streptococcal pyrogenic exotoxin A (SPEA)],
mycobacteria, malaria pigment and proinflammatory cytokines
[tumour necrosis factor-a (TNF-a) and interferon-g
(IFN-g) have been found to induce macrophages to release
MIF (12-14).
c19 cso30:c:InputAssociation connector
c24 cso30:c:InputAssociation connector
c29 cso30:c:OutputProcess connector
p7_propro_p10
PMID: 14620137, 8195715, 9736745, 10722628
Gram-negative and Gram-positive bacteria, bacterial endotoxin
(LPS) and exotoxins [toxic shock syndrome toxin-1
(TSST-1) and streptococcal pyrogenic exotoxin A (SPEA)],
mycobacteria, malaria pigment and proinflammatory cytokines
[tumour necrosis factor-a (TNF-a) and interferon-g
(IFN-g) have been found to induce macrophages to release
MIF (12-14).
c20 cso30:c:InputAssociation connector
c25 cso30:c:InputAssociation connector
c30 cso30:c:OutputProcess connector
p7_propro_p11
PMID: 14620137, 8195715, 9736745, 10722628
Gram-negative and Gram-positive bacteria, bacterial endotoxin
(LPS) and exotoxins [toxic shock syndrome toxin-1
(TSST-1) and streptococcal pyrogenic exotoxin A (SPEA)],
mycobacteria, malaria pigment and proinflammatory cytokines
[tumour necrosis factor-a (TNF-a) and interferon-g
(IFN-g) have been found to induce macrophages to release
MIF (12-14).
c21 cso30:c:InputAssociation connector
c26 cso30:c:InputAssociation connector
c31 cso30:c:OutputProcess connector
p7_propro_p12
PMID: 14620137, 8195715, 9736745, 10722628
Gram-negative and Gram-positive bacteria, bacterial endotoxin
(LPS) and exotoxins [toxic shock syndrome toxin-1
(TSST-1) and streptococcal pyrogenic exotoxin A (SPEA)],
mycobacteria, malaria pigment and proinflammatory cytokines
[tumour necrosis factor-a (TNF-a) and interferon-g
(IFN-g) have been found to induce macrophages to release
MIF (12-14).
c32 cso30:c:InputAssociation connector
c33 cso30:c:InputAssociation connector
c34 cso30:c:OutputProcess connector
p13_propro_p13
PMID: 14620137
MIF has been shown to up-regulate TLR4 expression, to
counter-regulate the immunosuppressive effects of glucocorticoids,
to activate the extracellular signal-regulated kinase-
1/2 (ERK-1/2), to suppress p53 activity and to inhibit Jab-1/
CSN5 activity.
c35 cso30:c:InputAssociation connector
c36 cso30:c:OutputProcess connector
p14_propro_p14
PMID: 14620137
MIF has been shown to up-regulate TLR4 expression, to
counter-regulate the immunosuppressive effects of glucocorticoids,
to activate the extracellular signal-regulated kinase-
1/2 (ERK-1/2), to suppress p53 activity and to inhibit Jab-1/
CSN5 activity.
ERK-1/2 activation
by MIF requires protein kinase A activation and results
in the augmentation of cytoplasmic phospholipase A2
(cPLA2) activity and ensuing production of arachidonic
acid, prostaglandins and leukotrienes.
The
protection afforded by MIF against apoptosis was found to
require the sequential activation of ERK-1/2, cPLA2,
cyclooxygenase-2 and prostaglandin E2.
c37 cso30:c:InputAssociation connector
c38 cso30:c:InputProcess connector
c72 cso30:c:InputAssociation connector
c39 cso30:c:OutputProcess connector
p14_propro_p15
PMID: 14620137
MIF has been shown to up-regulate TLR4 expression, to
counter-regulate the immunosuppressive effects of glucocorticoids,
to activate the extracellular signal-regulated kinase-
1/2 (ERK-1/2), to suppress p53 activity and to inhibit Jab-1/
CSN5 activity.
ERK-1/2 activation
by MIF requires protein kinase A activation and results
in the augmentation of cytoplasmic phospholipase A2
(cPLA2) activity and ensuing production of arachidonic
acid, prostaglandins and leukotrienes.
The
protection afforded by MIF against apoptosis was found to
require the sequential activation of ERK-1/2, cPLA2,
cyclooxygenase-2 and prostaglandin E2.
c40 cso30:c:InputAssociation connector
c41 cso30:c:InputProcess connector
c71 cso30:c:InputAssociation connector
c42 cso30:c:OutputProcess connector
p16_propro_p16
PMID: 14620137, 10734131
Transcription of the human
Tlr4 gene was shown to be dependent on the activity of
PU.1, a member of the Ets family of transcription factors
(16).
c43 cso30:c:InputAssociation connector
c44 cso30:c:OutputProcess connector
p17_propro_p17
PMID: 14620137
By contrast, expression of TLR2, a member of the TLR
family of pattern-recognition receptors involved in the
recognition of Gram-positive bacteria, was unchanged in
MIF-deficient macrophages, as one might have predicted
given the normal responses of these cells to Gram-positive
bacteria and yeast particles.
c45 cso30:c:InputProcess connector
c46 cso30:c:InputProcess connector
c47 cso30:c:OutputProcess connector
p18_propro_p18
PMID: 14620137
Glucocorticoids bind the corresponding receptors.
Classically, glucocorticoids suppress cytokine production by
immune cells.
c48 cso30:c:InputProcess connector
c49 cso30:c:InputProcess connector
c50 cso30:c:OutputProcess connector
p19_propro_p19
PMID: 14620137
Classically, glucocorticoids suppress cytokine production by
immune cells.
c51 cso30:c:InputAssociation connector
c53 cso30:c:InputInhibitor connector
c52 cso30:c:OutputProcess connector
p20_propro_p20
PMID: 14620137, 7659164, 8755565, 10446857
By contrast, MIF production was induced
when cells were exposed to low concentrations of glucocorticoids
(17-19)
c54 cso30:c:InputAssociation connector
c62 cso30:c:InputAssociation connector
c55 cso30:c:OutputProcess connector
p21_propro_p21
c56 cso30:c:InputProcess connector
c57 cso30:c:InputProcess connector
c58 cso30:c:OutputProcess connector
p22_propro_p22
PMID: 14620137
As observed with many stimuli, MIF release
in response to dexamethasone or cortisol was bell-shaped
c59 cso30:c:InputAssociation connector
c61 cso30:c:InputAssociation connector
c60 cso30:c:OutputProcess connector
p23_propro_p23
c63 cso30:c:InputProcess connector
c64 cso30:c:InputProcess connector
c65 cso30:c:OutputProcess connector
p24_propro_p24
PMID: 14620137
As observed with many stimuli, MIF release
in response to dexamethasone or cortisol was bell-shaped
c66 cso30:c:InputAssociation connector
c67 cso30:c:InputAssociation connector
c68 cso30:c:OutputProcess connector
p25_propro_p25
PMID: 14620137
ERK-1/2 activation
by MIF requires protein kinase A activation and results
in the augmentation of cytoplasmic phospholipase A2
(cPLA2) activity and ensuing production of arachidonic
acid, prostaglandins and leukotrienes.
c69 cso30:c:InputProcess connector
c70 cso30:c:OutputProcess connector
p26_propro_p26
PMID: 14620137, 10364264
MIF was found to induce rapid and sustained activation of
the ERK-1/2 mitogen-activated protein kinase pathway and
proliferation of quiescent fibroblasts (21)
c73 cso30:c:InputAssociation connector
c74 cso30:c:OutputProcess connector
p27_propro_p27
PMID: 14620137, 10364264
ERK-1/2 activation
by MIF requires protein kinase A activation and results
in the augmentation of cytoplasmic phospholipase A2
(cPLA2) activity and ensuing production of arachidonic
acid, prostaglandins and leukotrienes.
ERK-1/2-mediated induction of cPLA2 is one mechanism
whereby MIF could override the inhibitory effects of
steroids on synthesis of arachidonic acid induced by proinflammatory
stimuli (21).
The
protection afforded by MIF against apoptosis was found to
require the sequential activation of ERK-1/2, cPLA2,
cyclooxygenase-2 and prostaglandin E2.
c75 cso30:c:InputProcess connector
c77 cso30:c:InputAssociation connector
c76 cso30:c:OutputProcess connector
p27_propro_p28
PMID: 14620137, 10364264
ERK-1/2 activation
by MIF requires protein kinase A activation and results
in the augmentation of cytoplasmic phospholipase A2
(cPLA2) activity and ensuing production of arachidonic
acid, prostaglandins and leukotrienes.
ERK-1/2-mediated induction of cPLA2 is one mechanism
whereby MIF could override the inhibitory effects of
steroids on synthesis of arachidonic acid induced by proinflammatory
stimuli (21).
The
protection afforded by MIF against apoptosis was found to
require the sequential activation of ERK-1/2, cPLA2,
cyclooxygenase-2 and prostaglandin E2.
c78 cso30:c:InputAssociation connector
c79 cso30:c:InputProcess connector
c80 cso30:c:OutputProcess connector
p29_propro_p29
PMID: 14620137, 10364264
ERK-1/2 activation
by MIF requires protein kinase A activation and results
in the augmentation of cytoplasmic phospholipase A2
(cPLA2) activity and ensuing production of arachidonic
acid, prostaglandins and leukotrienes.
c81 cso30:c:InputAssociation connector
c82 cso30:c:OutputProcess connector
p30_propro_p30
PMID: 14620137, 10364264
ERK-1/2 activation
by MIF requires protein kinase A activation and results
in the augmentation of cytoplasmic phospholipase A2
(cPLA2) activity and ensuing production of arachidonic
acid, prostaglandins and leukotrienes.
c83 cso30:c:InputAssociation connector
c85 cso30:c:OutputProcess connector
p30_propro_p31
PMID: 14620137, 10364264
ERK-1/2 activation
by MIF requires protein kinase A activation and results
in the augmentation of cytoplasmic phospholipase A2
(cPLA2) activity and ensuing production of arachidonic
acid, prostaglandins and leukotrienes.
c84 cso30:c:InputAssociation connector
c86 cso30:c:OutputProcess connector
p32_propro_p32
PMID: 14620137
The
protection afforded by MIF against apoptosis was found to
require the sequential activation of ERK-1/2, cPLA2,
cyclooxygenase-2 and prostaglandin E2.
c87 cso30:c:InputAssociation connector
c88 cso30:c:InputProcess connector
c89 cso30:c:OutputProcess connector
p34_propro_p34
PMID: 14620137
It revealed that MIF
binds to Jab-1/CSN5 (for Jun activation domain-binding
protein-1 and subunit 5 of the COP9 signalosome).
c93 cso30:c:InputProcess connector
c94 cso30:c:InputProcess connector
c95 cso30:c:OutputProcess connector
p35_propro_p35
PMID: 14620137, 11089976
Jab1/
CSN5 is a co-activator of the transcription factor activator
protein-1 (AP-1), which is implicated in cell growth,
transformation and death.
Therefore, MIF inhibits the
positive regulatory effects of Jab1/CSN5 on AP-1 and
JNK activities (24).
c96 cso30:c:InputAssociation connector
c97 cso30:c:InputProcess connector
c99 cso30:c:InputInhibitor connector
c98 cso30:c:OutputProcess connector
p33_propro_p33
PMID: 14620137
The
protection afforded by MIF against apoptosis was found to
require the sequential activation of ERK-1/2, cPLA2,
cyclooxygenase-2 and prostaglandin E2.
c90 cso30:c:InputAssociation connector
c91 cso30:c:OutputProcess connector
LPS_enti_e5
LPS
TLR4_enti_e6
TLR4
MIF mRNA_enti_e11
MIF mRNA
LPS:TLR4_enti_e12
LPS:TLR4
MIF_enti_e13
MIF
Gram negative_enti_e14
Gram negative
Gram positive_enti_e15
Gram positive
TSST-1_enti_e16
TSST-1
SPEA_enti_e17
SPEA
Mycobacteria_enti_e18
Mycobacteria
Malaria pigment_enti_e19
Malaria pigment
TNF-alpha receptor_enti_e20
TNF-alpha receptor
TNF-alpha_enti_e21
TNF-alpha
TNF-alpha:receptor_enti_e22
TNF-alpha:receptor
IFN-gamma_enti_e23
IFN-gamma
IFN-gamma receptor_enti_e24
IFN-gamma receptor
IFN-gamma:receptor_enti_e26
IFN-gamma:receptor
tlr4_enti_e27
tlr4
ERK-1_enti_e28
ERK-1
ERK-1{active}_enti_e29
ERK-1{active}
ERK-2_enti_e30
ERK-2
ERK-2{active}_enti_e31
ERK-2{active}
PU.1_enti_e32
PU.1
TLR2_enti_e33
TLR2
Gram positive:TLR2_enti_e34
Gram positive:TLR2
Glucocorticoid_enti_e35
Glucocorticoid
receptor_enti_e36
receptor
glucocorticoid:receptor_enti_e37
glucocorticoid:receptor
cytokines_enti_e38
cytokines
cytokines_enti_e39
cytokines
Dexamethasone_enti_e25
Dexamethasone
cortisol_enti_e40
cortisol
receptor_enti_e41
receptor
dexamethasone:receptor_enti_e42
dexamethasone:receptor
receptor_enti_e43
receptor
cortisol:receptor_enti_e44
cortisol:receptor
PKA{active}_enti_e45
PKA{active}
PKA_enti_e46
PKA
fibroblasts_enti_e47
fibroblasts
CPLA2_enti_e48
CPLA2
CPLA2{active}_enti_e49
CPLA2{active}
arachidonic acid_enti_e63
arachidonic acid
prostaglandins_enti_e64
prostaglandins
Leukotrines_enti_e65
Leukotrines
cyclooxygenase-2_enti_e66
cyclooxygenase-2
cyclooxygenase-2{active}_enti_e67
cyclooxygenase-2{active}
PGE2_enti_e68
PGE2
MIF_enti_e70
MIF
Jab-1/CSN5_enti_e71
Jab-1/CSN5
MIF:Jab-1/CSN5_enti_e72
MIF:Jab-1/CSN5
AP-1_enti_e73
AP-1
AP-1{active}_enti_e74
AP-1{active}