_enti_e7
_enti_e8
_enti_e9
_enti_e1
_enti_e10
_enti_e2
_enti_e3
_enti_e4
_enti_e55
_enti_e59
_enti_e53
_enti_e51
_enti_e56
_enti_e52
_enti_e54
_enti_e50
_enti_e58
_enti_e61
_enti_e57
_enti_e62
_enti_e60
g2_fact_g2
g2_fact_g12
g2_fact_g13
g1_fact_g14
g1_fact_g1
p1_propro_p1
PMID: 18336664
Endotoxin/lipopolysaccharide (LPS), a component of the cell wall of Gram-negative bacteria, is an important activator of Kupffer cells, stimulating the production of inflammatory and fibrogeniccytokines, as well as reactive oxygen species (ROS).
PMID: 18336664, 9756487
One working model for the progression of alcoholic liver disease proposes that increased exposure of Kupffer cells to LPS during chronic ethanol consumption contributes to increased production of inflammatory mediators, in particular tumor necrosis factor TNF-alpha and ROS, leading to the progression of fatty liver, inflammation and fibrosis.
c1 cso30:c:InputAssociation connector
c4 cso30:c:InputAssociation connector
c45 cso30:c:InputAssociation connector
c3 cso30:c:OutputProcess connector
p2_propro_p2
PMID: 18336664
Endotoxin/lipopolysaccharide (LPS), a component of the cell wall of Gram-negative bacteria, is an important activator of Kupffer cells, stimulating the production of inflammatory and fibrogeniccytokines, as well as reactive oxygen species (ROS).
PMID: 18336664, 16410364, 10961870, 15033490
Adiponectin suppresses phagocytic activity, as well as lipopolysaccharide (LPS)- stimulated cytokine production in macrophages.
c2 cso30:c:InputAssociation connector
c5 cso30:c:InputAssociation connector
c15 cso30:c:InputInhibitor connector
c6 cso30:c:OutputProcess connector
p3_propro_p3
PMID: 18336664, 9756487
One working model for the progression of alcoholic liver disease proposes that increased exposure of Kupffer cells to LPS during chronic ethanol consumption contributes to increased production of inflammatory mediators, in particular tumor necrosis factor TNF-alpha and ROS, leading to the progression of fatty liver, inflammation and fibrosis.
PMID: 18336664, 1940369, 1940799, 8386517
IL-10 then acts to limit excessive production of pro-inflammatory cytokines, including TNF-alpha and IL-1b by decreasing cytokine gene transcription, as well as regulating the stability and/or translation of target mRNAs.
PMID: 18336664
Increased IL-10 expression was ultimately required for the suppression of TLR4-mediated signaling by gAcrp.
c7 cso30:c:InputAssociation connector
c9 cso30:c:InputAssociation connector
c34 cso30:c:InputInhibitor connector
c46 cso30:c:InputAssociation connector
c8 cso30:c:OutputProcess connector
p4_propro_p4
PMID: 18336664, 12840063
Importantly, treatment of mice with adiponectin during chronic ethanol exposure prevents the development of ethanol-induced liver injury,26 in part by increasing fatty acid oxidation in the liver, thus preventing ethanol-induced steatosis, as well as decreasing TNF-alpha expression.
c10 cso30:c:InputProcess connector
c12 cso30:c:InputAssociation connector
c11 cso30:c:OutputProcess connector
p5_propro_p5
PMID: 18336664, 12840063
Importantly, treatment of mice with adiponectin during chronic ethanol exposure prevents the development of ethanol-induced liver injury,26 in part by increasing fatty acid oxidation in the liver, thus preventing ethanol-induced steatosis, as well as decreasing TNF-alpha expression.
PMID: 18336664, 16410364
Importantly, overnight treatment of Kupffer cells with adiponectin can normalize the chronic ethanol-induced sensitization of LPS-stimulated TNF-alpha expression, normalizing the increased production of ROS, as well as ERK1/2 and p38 phosphorylation.
c14 cso30:c:InputInhibitor connector
c41 cso30:c:InputAssociation connector
c13 cso30:c:OutputProcess connector
p6_propro_p6
PMID: 18336664, 16410364, 15033490, 16325814
In particular, LPS-stimulated NK-kappaB and ERK1/2 activation are sensitive to the inhibitory effects of adiponectin.
c16 cso30:c:InputProcess connector
c18 cso30:c:InputAssociation connector
c23 cso30:c:InputInhibitor connector
c49 cso30:c:InputAssociation connector
c17 cso30:c:OutputProcess connector
p8_propro_p8
PMID: 18336664, 16410364
Importantly, overnight treatment of Kupffer cells with adiponectin can normalize the chronic ethanol-induced sensitization of LPS-stimulated TNF-alpha expression, normalizing the increased production of ROS, as well as ERK1/2 and p38 phosphorylation.
c25 cso30:c:InputAssociation connector
c26 cso30:c:InputProcess connector
c27 cso30:c:InputInhibitor connector
c48 cso30:c:InputAssociation connector
c24 cso30:c:OutputProcess connector
p7_propro_p7
PMID: 18336664, 16410364, 15033490, 16325814
In particular, LPS-stimulated NK-kappaB and ERK1/2 activation are sensitive to the inhibitory effects of adiponectin.
PMID: 18336664, 16410364
Importantly, overnight treatment of Kupffer cells with adiponectin can normalize the chronic ethanol-induced sensitization of LPS-stimulated TNF-alpha expression, normalizing the increased production of ROS, as well as ERK1/2 and p38 phosphorylation.
c19 cso30:c:InputProcess connector
c22 cso30:c:InputInhibitor connector
c47 cso30:c:InputAssociation connector
c21 cso30:c:InputAssociation connector
c20 cso30:c:OutputProcess connector
p9_propro_p9
PMID: 18336664
IL-10 expression is induced by various inflammatory mediators, such as LPS and TNF-alpha.
c28 cso30:c:InputAssociation connector
c30 cso30:c:OutputProcess connector
p10_propro_p10
PMID: 18336664
IL-10 expression is induced by various inflammatory mediators, such as LPS and TNF-alpha.
PMID: 18336664, 17537727
Interestingly, we found that initially adiponectin increases the production of TNF-alpha by RAW 264.7 macrophages; this TNF-alpha, in the continued presence of adiponectin, then increases production of IL-10.
c29 cso30:c:InputAssociation connector
c31 cso30:c:OutputProcess connector
p11_propro_p11
PMID: 18336664, 1940369, 1940799, 8386517
IL-10 then acts to limit excessive production of pro-inflammatory cytokines, including TNF-alpha and IL-1b by decreasing cytokine gene transcription, as well as regulating the stability and/or translation of target mRNAs.
PMID: 18336664, 17537727
Treatment of RAW 264.7 macrophages with adiponectin increases the expression of IL-10 mRNA and peptide.
PMID: 18336664, 17537727
Interestingly, we found that initially adiponectin increases the production of TNF-alpha by RAW 264.7 macrophages; this TNF-alpha, in the continued presence of adiponectin, then increases production of IL-10.
c32 cso30:c:InputAssociation connector
c40 cso30:c:InputAssociation connector
c33 cso30:c:OutputProcess connector
p12_propro_p12
PMID: 18336664, 1940369, 1940799, 8386517
IL-10 then acts to limit excessive production of pro-inflammatory cytokines, including TNF-alpha and IL-1b by decreasing cytokine gene transcription, as well as regulating the stability and/or translation of target mRNAs.
c36 cso30:c:InputAssociation connector
c37 cso30:c:InputInhibitor connector
c35 cso30:c:OutputProcess connector
p13_propro_p13
PMID: 18336664, 15369797, 17537727
While the mechanisms for the long-term anti-inflammatory effects of adiponectin are not well understood, recent data suggest that adiponectin acts, at least in part, to increase the expression of anti-inflammatory mediators, such as interleukin (IL)-10.
PMID: 18336664, 17537727
Treatment of RAW 264.7 macrophages with adiponectin increases the expression of IL-10 mRNA and peptide.
c39 cso30:c:InputAssociation connector
c38 cso30:c:OutputProcess connector
p14_propro_p14
PMID: 18336664, 17537727
Interestingly, we found that initially adiponectin increases the production of TNF-alpha by RAW 264.7 macrophages; this TNF-alpha, in the continued presence of adiponectin, then increases production of IL-10.
PMID: 18336664
This initial gAcrp-mediated increase in TNF-alpha production by macrophages was mediated via activation of ERK1/2→Egr-1 and nuclear factor (NF)-kappaB-dependent mechanisms.
c43 cso30:c:InputAssociation connector
c44 cso30:c:InputAssociation connector
c42 cso30:c:OutputProcess connector
p15_propro_p15
PMID: 18336664
We next identified two parallel signaling pathways required for adiponectin-stimulated IL-10 transcription: (i) an ERK1/2- and protein kinase A (PKA)-dependent increase in cAMP response element-binding protein (CREB) phosphorylation which acted via the CRE in the IL-10 promoter.
c50 cso30:c:InputAssociation connector
c51 cso30:c:InputProcess connector
c52 cso30:c:OutputProcess connector
p16_propro_p16
PMID: 18336664
We next identified two parallel signaling pathways required for adiponectin-stimulated IL-10 transcription: (i) an ERK1/2- and protein kinase A (PKA)-dependent increase in cAMP response element-binding protein (CREB) phosphorylation which acted via the CRE in the IL-10 promoter.
c53 cso30:c:InputAssociation connector
c54 cso30:c:InputProcess connector
c55 cso30:c:OutputProcess connector
p17_propro_p17
PMID: 18336664
We next identified two parallel signaling pathways required for adiponectin-stimulated IL-10 transcription: (i) an ERK1/2- and protein kinase A (PKA)-dependent increase in cAMP response element-binding protein (CREB) phosphorylation which acted via the CRE in the IL-10 promoter.
c56 cso30:c:InputProcess connector
c58 cso30:c:InputProcess connector
c59 cso30:c:InputProcess connector
c57 cso30:c:OutputProcess connector
p18_propro_p18
PMID: 18336664
We next identified two parallel signaling pathways required for adiponectin-stimulated IL-10 transcription: (i) an ERK1/2- and protein kinase A (PKA)-dependent increase in cAMP response element-binding protein (CREB) phosphorylation which acted via the CRE in the IL-10 promoter.
c60 cso30:c:InputProcess connector
c61 cso30:c:OutputProcess connector
p19_propro_p19
PMID: 18336664
We next identified two parallel signaling pathways required for adiponectin-stimulated IL-10 transcription: (i) an ERK1/2- and protein kinase A (PKA)-dependent increase in cAMP response element-binding protein (CREB) phosphorylation which acted via the CRE in the IL-10 promoter.
c63 cso30:c:InputProcess connector
c65 cso30:c:InputProcess connector
c64 cso30:c:OutputProcess connector
p20_propro_p20
PMID: 18336664
We next identified two parallel signaling pathways required for adiponectin-stimulated IL-10 transcription: (i) an ERK1/2- and protein kinase A (PKA)-dependent increase in cAMP response element-binding protein (CREB) phosphorylation which acted via the CRE in the IL-10 promoter.
PMID: 18336664
gAcrp-stimulated IL-10 expression was also dependent on the phosphorylation of cAMP response element-binding protein and the cAMP response element in the IL-10 promoter.
c66 cso30:c:InputAssociation connector
c62 cso30:c:OutputProcess connector
p21_propro_p21
PMID: 18336664
We next identified two parallel signaling pathways required for adiponectin-stimulated IL-10 transcription: (i) an ERK1/2- and protein kinase A (PKA)-dependent increase in cAMP response element-binding protein (CREB) phosphorylation which acted via the CRE in the IL-10 promoter (Park, et al., unpubl. obs, 2007); and (ii) an NF-kappaB and Egr-1 pathway, leading to increased production of TNF-alpha.
c67 cso30:c:InputProcess connector
c69 cso30:c:InputAssociation connector
c68 cso30:c:OutputProcess connector
p22_propro_p22
PMID: 18336664
We next identified two parallel signaling pathways required for adiponectin-stimulated IL-10 transcription: (i) an ERK1/2- and protein kinase A (PKA)-dependent increase in cAMP response element-binding protein (CREB) phosphorylation which acted via the CRE in the IL-10 promoter (Park, et al., unpubl. obs, 2007); and (ii) an NF-kappaB and Egr-1 pathway, leading to increased production of TNF-alpha.
c70 cso30:c:InputProcess connector
c72 cso30:c:InputAssociation connector
c71 cso30:c:OutputProcess connector
p23_propro_p23
PMID: 18336664
We next identified two parallel signaling pathways required for adiponectin-stimulated IL-10 transcription: (i) an ERK1/2- and protein kinase A (PKA)-dependent increase in cAMP response element-binding protein (CREB) phosphorylation which acted via the CRE in the IL-10 promoter (Park, et al., unpubl. obs, 2007); and (ii) an NF-kappaB and Egr-1 pathway, leading to increased production of TNF-alpha.
PMID: 18336664
This initial gAcrp-mediated increase in TNF-alpha production by macrophages was mediated via activation of ERK1/2→Egr-1 and nuclear factor (NF)-kappaB-dependent mechanisms.
c76 cso30:c:InputAssociation connector
c73 cso30:c:OutputProcess connector
p24_propro_p24
PMID: 18336664
We next identified two parallel signaling pathways required for adiponectin-stimulated IL-10 transcription: (i) an ERK1/2- and protein kinase A (PKA)-dependent increase in cAMP response element-binding protein (CREB) phosphorylation which acted via the CRE in the IL-10 promoter (Park, et al., unpubl. obs, 2007); and (ii) an NF-kappaB and Egr-1 pathway, leading to increased production of TNF-alpha.
PMID: 18336664
This initial gAcrp-mediated increase in TNF-alpha production by macrophages was mediated via activation of ERK1/2→Egr-1 and nuclear factor (NF)-kappaB-dependent mechanisms.
c75 cso30:c:InputAssociation connector
c74 cso30:c:OutputProcess connector
LPS_enti_MO000016882
LPS
ROS_enti_MO000008272
ROS
ROS_enti_e5
ROS
cytokines_enti_e6
cytokines
cytokines_enti_MO000019387
cytokines
TNF-alpha_enti_G010329
TNF-alpha
TNF-alpha_enti_MO000000289
TNF-alpha
adiponectin_enti_MO000022523
adiponectin
fatty acids_enti_MO000033598
fatty acids
fatty acids{oxidated}_enti_e11
fatty acids{oxidated}
NF-kappaB_enti_MO000000058
NF-kappaB
NF-kappaB{activated}_enti_e12
NF-kappaB{activated}
ERK_enti_MO000000011
ERK
ERK{p}_enti_MO000038306
ERK{p}
p38_enti_MO000000022
p38
p38{p}_enti_e13
p38{p}
IL-10_enti_MO000017247
IL-10
IL10_enti_G011345
IL10
IL-1beta_enti_G010389
IL-1beta
IL-1beta_enti_MO000016597
IL-1beta
ethanol_enti_e14
ethanol
PKAc_enti_MO000000001
PKAc
PKAc{activated}_enti_e15
PKAc{activated}
CREB_enti_MO000017189
CREB
CREB{p}_enti_e16
CREB{p}
CREB{p}_enti_e17
CREB{p}
IL-10: CREB{p}_enti_e18
IL-10: CREB{p}
IL-10_enti_e19
IL-10
Egr-1_enti_MO000017190
Egr-1
Egr-1{activated}_enti_e20
Egr-1{activated}