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IL6 — SOCS3
Pathways - manually collected, often from reviews:
-
NCI Pathway Database IL6-mediated signaling events:
IL6/IL6RA/gp130 (dimer)/JAK1/JAK1/LMO4 complex (IL6-IL6R-IL6ST-JAK1-LMO4)
→
IL6/IL6RA/gp130 (dimer)/JAK1/JAK1/LMO4/SOCS3 complex (IL6-IL6R-IL6ST-JAK1-LMO4-SOCS3)
(modification, activates)
Lang et al., Nat Immunol 2003, Schaper et al., Biochem J 1998
Evidence: mutant phenotype, physical interaction, other species
-
NCI Pathway Database IL6-mediated signaling events:
IL6/IL6RA/gp130 (dimer)/JAK1/JAK1/LMO4 complex (IL6-IL6R-IL6ST-JAK1-LMO4)
→
SOCS3 (SOCS3)
(modification, collaborate)
Schmitz et al., J Biol Chem 2000
Evidence: physical interaction
-
NCI Pathway Database IL6-mediated signaling events:
IL6/IL6RA/gp130 (dimer)/JAK1/JAK1/LMO4 complex (IL6-IL6R-IL6ST-JAK1-LMO4)
→
IL6/IL6RA/gp130 (dimer)/JAK1/JAK1/LMO4/SOCS3 complex (IL6-IL6R-IL6ST-JAK1-LMO4-SOCS3)
(modification, collaborate)
Schmitz et al., J Biol Chem 2000
Evidence: physical interaction
-
NCI Pathway Database IL6-mediated signaling events:
SOCS3 (SOCS3)
→
IL6/IL6RA/gp130 (dimer)/JAK1/JAK1/LMO4/SOCS3 complex (IL6-IL6R-IL6ST-JAK1-LMO4-SOCS3)
(modification, collaborate)
Schmitz et al., J Biol Chem 2000
Evidence: physical interaction
-
NCI Pathway Database IL6-mediated signaling events:
IL6/IL6RA/gp130 (dimer)/JAK1/JAK1/LMO4 complex (IL6-IL6R-IL6ST-JAK1-LMO4)
→
IL6/IL6RA/gp130 (dimer)/JAK1/JAK1/LMO4/SOCS3 complex (IL6-IL6R-IL6ST-JAK1-LMO4-SOCS3)
(modification, activates)
Croker et al., Nat Immunol 2003, Lang et al., Nat Immunol 2003, Guschin et al., EMBO J 1995, Wegenka et al., Mol Cell Biol 1994, Lütticken et al., Science 1994, Gerhartz et al., J Biol Chem 1996
Evidence: mutant phenotype, other species
-
NCI Pathway Database IL6-mediated signaling events:
IL6/IL6RA/gp130 (dimer)/JAK1/JAK1/LMO4 complex (IL6-IL6R-IL6ST-JAK1-LMO4)
→
IL6/IL6RA/gp130 (dimer)/JAK1/JAK1/LMO4/SOCS3 complex (IL6-IL6R-IL6ST-JAK1-LMO4-SOCS3)
(modification, activates)
Jain et al., J Biol Chem 1999, Schuringa et al., J Biol Chem 2001, Novotny-Diermayr et al., J Biol Chem 2002, Croker et al., Nat Immunol 2003, Lang et al., Nat Immunol 2003, Yasukawa et al., Nat Immunol 2003, Novotny-Diermayr et al., J Biol Chem 2005, Guschin et al., EMBO J 1995, Wegenka et al., Mol Cell Biol 1993, Zhong et al., Science 1994, Wegenka et al., Mol Cell Biol 1994, Lütticken et al., Science 1994, Kaptein et al., J Biol Chem 1996, Gerhartz et al., J Biol Chem 1996, Haan et al., J Biol Chem 1999
Evidence: mutant phenotype, assay, physical interaction, other species
-
NCI Pathway Database IL6-mediated signaling events:
nPKC-delta (PRKCD)
→
IL6/IL6RA/gp130 (dimer)/JAK1/JAK1/LMO4/SOCS3 complex (IL6-IL6R-IL6ST-JAK1-LMO4-SOCS3)
(modification, activates)
Jain et al., J Biol Chem 1999, Schuringa et al., J Biol Chem 2001, Novotny-Diermayr et al., J Biol Chem 2002, Croker et al., Nat Immunol 2003, Lang et al., Nat Immunol 2003, Yasukawa et al., Nat Immunol 2003, Novotny-Diermayr et al., J Biol Chem 2005, Guschin et al., EMBO J 1995, Wegenka et al., Mol Cell Biol 1993, Zhong et al., Science 1994, Wegenka et al., Mol Cell Biol 1994, Lütticken et al., Science 1994, Kaptein et al., J Biol Chem 1996, Gerhartz et al., J Biol Chem 1996, Haan et al., J Biol Chem 1999
Evidence: mutant phenotype, assay, physical interaction, other species
-
Reactome Reaction:
IL6
→
SOCS3
(reaction)
Schmitz et al., J Biol Chem 2000
-
Reactome Reaction:
IL6
→
SOCS3
(indirect_complex)
Schmitz et al., J Biol Chem 2000
Text-mined interactions from Literome
Lebel et al., Endocrinology 2000
(Endotoxemia) :
The endothelium of the brain capillaries also exhibited up-regulation of both IL-6 receptor and gp130 subunits during systemic inflammation, which allowed
SOCS-3 expression in
response to circulating
IL-6
Bode et al., Biol Chem 2001
(Carcinoma, Hepatocellular) :
Accordingly, overexpression of a constitutively active MKK6 in HepG2 cells enhanced basal activity or IL-6 induced transcriptional activation of a SOCS3 promoter reporter construct, whereas overexpression of a dominant negative mutant of MKK6 downregulated the
IL-6 mediated activation of the
SOCS3 promoter ... These data indicate that p38MAPK-activation is crucial for
IL-6 induced
SOCS3 expression and downregulation of IL-6 mediated gene induction
Berlato et al., J Immunol 2002
(MAP Kinase Signaling System) :
Herein, we show that stable transfection of
SOCS-3 into the mouse macrophage cell line J774 resulted in an
inhibition of NO, TNF-alpha,
IL-6 , and GM-CSF secretion in response to LPS at levels similar to those exerted by IL-10 in LPS stimulated wild-type J774 ... Constitutive
SOCS-3 expression also
down-regulated the mRNA expression of inducible NO synthase and
IL-6 and impaired the production of TNF-alpha, mainly at a post-transcriptional level
Croker et al., Nat Immunol 2003
:
SOCS3 negatively
regulates IL-6 signaling in vivo
Yasukawa et al., Nat Immunol 2003
:
SOCS3 specifically
prevents activation of STAT3 by
IL-6 but not IL-10
Bode et al., J Immunol 2003
:
Recently, it has been demonstrated that TNF-alpha and LPS induce the expression of
suppressor of cytokine signaling 3 ( SOCS3 ) and
inhibit IL-6 induced STAT3 activation in macrophages
Yang et al., J Biol Chem 2004
:
Dual function of interleukin-1beta for the regulation of
interleukin-6 induced
suppressor of cytokine signaling 3 expression ... Herein we analyzed IL-1beta mediated regulation of
IL-6 induced expression of the feedback inhibitor
SOCS3 ... Such a regulatory network allows IL-1beta to counteract IL-6 dependent expression of acute-phase protein genes without inhibiting
IL-6 induced
SOCS3 expression and provides a reasonable mechanism for the IL-1beta dependent inhibition of acute-phase gene induction, because reduced SOCS3 expression would lead to enhanced IL-6 activity
Rieusset et al., Diabetes 2004
(Diabetes Mellitus...) :
IL-6 inhibited insulin signaling and
induced SOCS-3 expression in differentiated myotubes ... In subcutaneous adipose tissue, SOCS-3 mRNA levels were increased in obese individuals and strongly correlated with IL-6 expression, supporting a paracrine
effect of
IL-6 on
SOCS-3 expression in fat
Ehlting et al., Biochem J 2005
:
In the present study, we show that mutation of this GC-rich element abolishes
IL-6 dependent transcriptional activation of the SOCS3 promoter and that Sp3 ( specificity protein 3 ), a ubiquitously expressed transcription factor, but not Sp1 binds to this GC-rich motif, suggesting that Sp3 is
involved in the regulation of
SOCS3 expression ... The results suggest that Sp3 is important for
IL-6 induced transcriptional activation of the
SOCS3 ( gene ) promoter and acts as an enhancer of basal as well as induced transcriptional activity, resulting in enhanced SOCS3 mRNA and protein expression
Sommer et al., J Biol Chem 2005
:
We set out to investigate whether
SOCS3 phosphorylation may
play a role in
IL-6 signaling ... Using Src and Janus kinase inhibitors as well as Src kinase-deficient mouse embryonic fibroblasts, we provide evidence that Src kinases, which we found to be constitutively active in these cells, are involved in the phosphorylation of
IL-6 induced
SOCS3 ... In addition, we found that receptor-tyrosine kinases such as platelet derived growth factor receptor or epidermal growth factor receptor can very potently phosphorylate
IL-6 induced
SOCS3
Yang et al., J Hepatol 2005
(Disease Models, Animal...) :
Interleukin-6 plays a crucial role in the hepatic expression of
SOCS3 during acute inflammatory processes in vivo ... However, several signaling pathways converge on SOCS3 :
SOCS3 can be induced by other mediators in vitro, and it does not exclusively
inhibit IL-6 signaling ... Using IL-6-deficient mice we analyzed the
role of
interleukin-6 for the hepatic
SOCS3 expression in response to turpentine and LPS as models of aseptic and bacterial inflammation, respectively ... Our data strongly argue for a crucial
role of
IL-6 in the hepatic expression of
SOCS3 during acute inflammatory processes in vivo
Spangenburg et al., J Physiol 2006
:
SOCS-3 overexpression
increased IL-6 transcriptional activity by 15-fold, however, when the NF-kappaB site was mutated SOCS-3 failed to increase IL-6 transcriptional activity
Rakshit et al., J Bone Joint Surg Am 2006
(Osteolysis) :
Titanium and polymethylmethacrylate also both induced expression of
SOCS3 , an
inhibitor of
interleukin-6 signaling ... Wear particle inhibition of interleukin-6 specifically involves the activation of p38 mitogen activated protein kinase and is accompanied by substantial induction of
SOCS3 , an
inhibitor of
interleukin-6 signaling
Stumhofer et al., Nat Immunol 2006
(Encephalitis...) :
In vitro, treatment of naive primary T cells with IL-27 suppressed the development T ( H ) -17 cells induced by IL-6 and transforming growth factor-beta, which was dependent on the intracellular signaling molecule STAT1 but was independent of inhibition of
IL-6 signaling
mediated by the suppressor protein
SOCS3
Pietrangelo et al., Gastroenterology 2007
:
IL-6 stimulated phospho STAT3, serum amyloid A (SAA), and
suppressor of cytokine signaling 3 ( SOCS3 ) expression in livers of wild-type and alfpCregp130 ( Y757F/LoxP ) mice, whereas this response was blocked in alfpCre gp130 ( LoxP/LoxP ) and alfpCre gp130 ( DeltaSTAT/LoxP ) mice
Isomoto et al., Gastroenterology 2007
(Bile Duct Neoplasms...) :
Treatment with a demethylating agent, 5-aza-2'-deoxycytidine ( DAC ), restored
IL-6 induction of
SOCS-3 , terminated the phospho-STAT-3 response, and reduced cellular levels of Mcl-1 ... Enforced expression of
SOCS-3 also
reduced IL-6 induction of phospho-STAT-3 and Mcl-1
Boyle et al., J Reprod Immunol 2008
:
The creation of mice with conditional deletion of SOCS3 in different tissues has also uncovered critical
roles for
SOCS3 in the regulation of
IL-6 , G-CSF and leptin signalling
Kim et al., J Biol Chem 2008
(Carcinoma, Hepatocellular...) :
Furthermore, IL-6 induced SOCS3 expression is inhibited by rapamycin, and ectopic expression of
SOCS3 blocks the ability of rapamycin to enhance insulin sensitivity in the presence of
IL-6
Yu et al., Int J Biochem Cell Biol 2008
:
SOCS 3 and PPAR-gamma ligands
inhibit the expression of
IL-6 and TGF-beta1 by regulating JAK2/STAT3 signaling in pancreas
Uno et al., Horm Metab Res 2008
:
These results suggest that the IL-1alpha mediated deterioration of insulin signaling is largely due to the
IL-6 production and
SOCS3 induction in 3T3-L1 adipocytes
Yarwood et al., J Biol Chem 2008
:
Secondly, knockdown of C/EBPbeta and -delta isoforms abolished both
SOCS-3 induction and
inhibition of
IL-6 signaling in response to cAMP
Kiu et al., Growth Factors 2007
:
Analysis of suppressor of cytokine signalling 3 ( SOCS3 ) -deficient macrophages reveal that
SOCS3 is
necessary but surprisingly, not sufficient for the complete crosstalk inhibition of
IL-6 signaling induced by LPS and TNFalpha
Zhang et al., J Immunol 2008
(Multiple Sclerosis) :
Our results demonstrated statin mediated increases in suppressor of cytokine secretion
(SOCS) 3 and suppressor of cytokine secretion 7, which negatively
regulate the STAT/JAK signal transduction pathway and
IL-6 and IL-23 gene expression in monocytes
Zou et al., FEBS Lett 2008
:
The role of microtubule associated protein 1S in
SOCS3 regulation of
IL-6 signaling
Orabona et al., Proc Natl Acad Sci U S A 2008
:
We found that SOCS3-known to interact with phosphotyrosine containing peptides and be selectively
induced by
CD28-Ig/IL-6-would bind IDO and target the
IDO/SOCS3 complex for ubiquitination and subsequent proteasomal degradation
Kageyama et al., J Endocrinol 2009
:
In the present study, we examined whether
SOCS-3 is
regulated by
IL-6 and cAMP in hypothalamic 4B cells ... Therefore,
SOCS-3 ,
induced by a cAMP stimulant and
IL-6 , would be involved in the negative regulation of CRF gene expression in hypothalamic cells
Thompson et al., J Biol Chem 2009
:
Interleukin-6 , but not interleukin-10, stimulated phosphorylation of STAT3, and induction of
SOCS3 mRNA expression were
potentiated in a time- and dose dependent manner in macrophage cell lines derived from AFABP/aP2-EFABP/mal1 double knock-out mice relative to cells from wild type animals
Qin et al., J Immunol 2009
:
TGF-beta inhibits
IL-6 induced
SOCS3 promoter activity in T cells
Henkel et al., Hepatology 2009
(Insulin Resistance) :
IL-6 but not PGE ( 2 )
induced suppressors of cytokine signaling (
SOCS3 )
John et al., J Orthop Res 2010
:
TNFalpha stimulation augmented SOCS1, whereas
SOCS3 expression in tenocytes was also
induced by
IL-6
Ma et al., J Immunol 2010
:
Moreover, we elucidated an important
role for suppressor of cytokine signaling
(SOCS) 3 in IL-17 enhancement of
IL-6 signaling in astrocytes
Fukushima et al., J Endod 2010
:
IL-1beta and
IL-6 simultaneously
induced IL-8 and monocyte chemoattractant protein-1 secretion in PDL cells, whereas
SOCS-3 overexpression suppressed secretion of these chemokines through inhibition of phosphorylation in downstream signaling
Chang et al., J Pharmacol Sci 2011
(Carcinoma, Hepatocellular...) :
Both compounds blocked
suppressor of cytokine signaling 3 ( SOCS-3 ) -mRNA expression
induced by
IL-6
Lesina et al., Cancer Cell 2011
(Adenocarcinoma...) :
Here, we establish that, in addition to oncogenic Kras ( G12D ),
IL-6 transsignaling dependent
activation of
Stat3/Socs3 is required to promote PanIN progression and pancreatic ductal adenocarcinoma ( PDAC )
Funaoka et al., J Virol 2011
:
In conclusion, HCV R70 and L91 core mutants were resistant to interferon in vitro, and the resistance may be induced by
IL-6 induced upregulation of
SOCS3
Serrano-Marco et al., Diabetes 2011
:
In addition, this drug treatment abolished
IL-6 induced
SOCS3 expression in differentiated 3T3-L1 adipocytes
Scheller et al., J Cell Biochem 2011
:
Inhibition of
SOCS3 by ZA
resulted in significant increases in
IL-6 production
Al-Shanti et al., J Cell Biochem 2012
:
Inhibitory effects of
IL-6 on IGF-1 activity in skeletal myoblasts could be
mediated by the activation of
SOCS-3
Kim et al., Diabetologia 2012
(Insulin Resistance) :
IL-6 induced STAT3 transactivation and
SOCS3 production were significantly repressed by metformin, adenoviral constitutively active AMPK ( Ad-CA-AMPK ), and adenoviral SHP ( Ad-SHP ), but not in Shp knockdown, or with the adenoviral dominant negative form of AMPK ( Ad-DN-AMPK )
Yang et al., Curr Drug Metab 2012
:
SOCS-3 , CRP, and LBP were extensively
induced by
IL-6 , with maximal induction observed at 2 ( SOCS-3 ) and 12 hrs ( CRP ; LBP ), demonstrating that the cultured human hepatocytes responded to IL-6 treatment
Lewkowicz et al., Immunobiology 2013
:
We showed that LPS activated Treg cells promote generation of IL-10 and TGF-ß1,
inhibit IL-6 production by PMNs and induce the expression of heme oxygenase-1 (HO-1) and the
suppressor of cytokine signaling 3 molecule ( SOCS3 )
Rossa et al., PloS one 2012
(Carcinoma, Squamous Cell...) :
Immunofluorescence and western blot were used to study the subcellular localization of endogenous
SOCS3 induced by
IL-6
Kleinsteuber et al., Blood 2012
(Tuberculosis) :
SOCS3 promotes
interleukin-17 expression of human T cells
Park et al., PloS one 2012
:
In parallel to STAT3 phosphorylation, OSM and
IL-6/R induce
SOCS3 expression at the mRNA and protein level ... P6 treatment inhibits SOCS3 expression, indicating that STAT3 is required for OSM and
IL-6/R induced
SOCS3 expression
Romain et al., Arterioscler Thromb Vasc Biol 2013
(Aortic Aneurysm, Abdominal...) :
Overexpression of
SOCS3 in T lymphocytes
leads to impaired
interleukin-17 production and severe aortic aneurysm formation in mice -- brief report
Park et al., J Allergy Clin Immunol 2013
(Nasal Polyps...) :
Nasal epithelial cell culture was used to elucidate the
effect of IL-4, IL-5,
IL-6 , IL-10, IL-13, IFN-?, TNF-a, and TGF-ß1 on SOCS1 and
SOCS3 expression in sinus mucosa
Teramo et al., Blood 2013
(Leukemia, Large Granular Lymphocytic) :
By treating neoplastic LGLs with a demethylating agent,
IL-6 mediated
SOCS3 expression was restored with consequent P-STAT3 and myeloid cell leukemia-1 down-modulation
Collins et al., PloS one 2013
:
Furthermore, miR-19a mediated reduction of
SOCS3 enhanced IFN-a and
interleukin (IL)-6 signal transduction through STAT3
Suzuki et al., Oncogene 1998
(Leukemia, Myeloid, Acute) :
In M1 myeloid leukemia cells,
CIS3 was
induced by neither interleukin 6 (IL6) nor interferon gamma (IFNgamma), while JAB was induced strongly by IFNgamma and slightly by
IL6 and leukemia inhibitory factor (ILF)
Nicholson et al., EMBO J 1999
:
SOCS-1 and
SOCS-3 inhibited both
interleukin-6 (IL-6)- and leukemia inhibitory factor (LIF) induced macrophage differentiation of murine monocytic leukemic M1 cells and LIF induction of a Stat3-responsive reporter construct in 293T fibroblasts