Tumour necrosis factor alpha (TNF)-TNF receptor 1-inducible cytoprotective proteins in the mouse liver: relevance of suppressors of cytokine signalling.
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Tumour necrosis factor alpha (TNF)-TNF receptor 1-inducible cytoprotective proteins in the mouse liver: relevance of suppressors of cytokine signalling. / Sass, Gabriele; Shembade, Noula D; Tiegs, Gisa.
In: BIOCHEM J, Vol. 385, No. Pt 2, Pt 2, 2005, p. 537-544.Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review
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TY - JOUR
T1 - Tumour necrosis factor alpha (TNF)-TNF receptor 1-inducible cytoprotective proteins in the mouse liver: relevance of suppressors of cytokine signalling.
AU - Sass, Gabriele
AU - Shembade, Noula D
AU - Tiegs, Gisa
PY - 2005
Y1 - 2005
N2 - TNF (tumour necrosis factor alpha) induces tolerance towards itself in experimental liver injury. Tolerance induction has been shown to be dependent on TNFR1 (TNF receptor 1) signalling, but mechanisms and mediators of TNF-induced hepatic tolerance are unknown. We investigated the TNF-inducible gene-expression profile in livers of TNFR2-/- mice, using cDNA array technology. We found that, out of 793 investigated genes involved in inflammation, cell cycle and signal transduction, 282 were expressed in the mouse liver in response to TNF via TNFR1. Among those, expression of 78 genes was induced, while expression of 60 genes was reduced. We investigated further the cellular expression of the 27 most prominently induced genes, and found that 20 of these genes were up-regulated directly in parenchymal liver cells, representing potentially protective proteins and possible mediators of TNF tolerance. In vitro experiments revealed that overexpression of SOCS1 (silencer of cytokine signalling 1), a member of the SOCS family of proteins, as well as of HO-1 (haem oxygenase-1), but not of SOCS2 or SOCS3, protected isolated primary mouse hepatocytes from TNF-induced apoptosis. The identification of protective genes in hepatocytes is the prerequisite for future development of gene therapies for immune-mediated liver diseases.
AB - TNF (tumour necrosis factor alpha) induces tolerance towards itself in experimental liver injury. Tolerance induction has been shown to be dependent on TNFR1 (TNF receptor 1) signalling, but mechanisms and mediators of TNF-induced hepatic tolerance are unknown. We investigated the TNF-inducible gene-expression profile in livers of TNFR2-/- mice, using cDNA array technology. We found that, out of 793 investigated genes involved in inflammation, cell cycle and signal transduction, 282 were expressed in the mouse liver in response to TNF via TNFR1. Among those, expression of 78 genes was induced, while expression of 60 genes was reduced. We investigated further the cellular expression of the 27 most prominently induced genes, and found that 20 of these genes were up-regulated directly in parenchymal liver cells, representing potentially protective proteins and possible mediators of TNF tolerance. In vitro experiments revealed that overexpression of SOCS1 (silencer of cytokine signalling 1), a member of the SOCS family of proteins, as well as of HO-1 (haem oxygenase-1), but not of SOCS2 or SOCS3, protected isolated primary mouse hepatocytes from TNF-induced apoptosis. The identification of protective genes in hepatocytes is the prerequisite for future development of gene therapies for immune-mediated liver diseases.
KW - Animals
KW - Cells, Cultured
KW - Mice
KW - Mice, Inbred C57BL
KW - Gene Expression Profiling/methods
KW - Gene Expression Regulation/physiology
KW - DNA-Binding Proteins/genetics
KW - Carrier Proteins/genetics
KW - Membrane Proteins
KW - Receptors, Tumor Necrosis Factor, Type I/metabolism
KW - Apoptosis/physiology
KW - Cytokines/antagonists & inhibitors/physiology
KW - Galactosamine/pharmacology
KW - Genes/physiology
KW - Heme Oxygenase (Decyclizing)/genetics
KW - Heme Oxygenase-1
KW - Hepatocytes/chemistry/metabolism
KW - Liver/chemistry/drug effects/metabolism
KW - Microarray Analysis/methods
KW - Receptors, Tumor Necrosis Factor, Type II/deficiency/physiology
KW - Repressor Proteins/genetics
KW - Signal Transduction/physiology
KW - Suppressor of Cytokine Signaling Proteins
KW - Trans-Activators/genetics
KW - Transcription Factors/genetics
KW - Tumor Necrosis Factor-alpha/metabolism/pharmacology
KW - Animals
KW - Cells, Cultured
KW - Mice
KW - Mice, Inbred C57BL
KW - Gene Expression Profiling/methods
KW - Gene Expression Regulation/physiology
KW - DNA-Binding Proteins/genetics
KW - Carrier Proteins/genetics
KW - Membrane Proteins
KW - Receptors, Tumor Necrosis Factor, Type I/metabolism
KW - Apoptosis/physiology
KW - Cytokines/antagonists & inhibitors/physiology
KW - Galactosamine/pharmacology
KW - Genes/physiology
KW - Heme Oxygenase (Decyclizing)/genetics
KW - Heme Oxygenase-1
KW - Hepatocytes/chemistry/metabolism
KW - Liver/chemistry/drug effects/metabolism
KW - Microarray Analysis/methods
KW - Receptors, Tumor Necrosis Factor, Type II/deficiency/physiology
KW - Repressor Proteins/genetics
KW - Signal Transduction/physiology
KW - Suppressor of Cytokine Signaling Proteins
KW - Trans-Activators/genetics
KW - Transcription Factors/genetics
KW - Tumor Necrosis Factor-alpha/metabolism/pharmacology
M3 - SCORING: Journal article
VL - 385
SP - 537
EP - 544
JO - BIOCHEM J
JF - BIOCHEM J
SN - 0264-6021
IS - Pt 2
M1 - Pt 2
ER -