Tumour necrosis factor alpha (TNF)-TNF receptor 1-inducible cytoprotective proteins in the mouse liver: relevance of suppressors of cytokine signalling.
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.
Sass
Gabriele
G
Institute of Experimental and Clinical Pharmacology and Toxicology, University of Erlangen-Nuremberg, D-91054 Erlangen, Germany.
Shembade
Noula D
ND
Tiegs
Gisa
G
D000818:Animals; D017209:Apoptosis / Q000502:physiology; D002352:Carrier Proteins / Q000235:genetics; D002478:Cells, Cultured; D016207:Cytokines / Q000037:antagonists & inhibitors* / Q000502:physiology; D004268:DNA-Binding Proteins / Q000235:genetics; D005688:Galactosamine / Q000494:pharmacology; D020869:Gene Expression Profiling / Q000379:methods; D005786:Gene Expression Regulation / Q000502:physiology; D005796:Genes / Q000502:physiology; D006419:Heme Oxygenase (Decyclizing) / Q000235:genetics; D051547:Heme Oxygenase-1; D022781:Hepatocytes / Q000737:chemistry / Q000378:metabolism; D008099:Liver / Q000737:chemistry / Q000187:drug effects / Q000378:metabolism; D008565:Membrane Proteins; D051379:Mice; D008810:Mice, Inbred C57BL; D046228:Microarray Analysis / Q000379:methods; D047888:Receptors, Tumor Necrosis Factor, Type I / Q000378:metabolism*; D047889:Receptors, Tumor Necrosis Factor, Type II / Q000172:deficiency / Q000502:physiology; D012097:Repressor Proteins / Q000235:genetics; D015398:Signal Transduction / Q000502:physiology*; D000071222:Suppressor of Cytokine Signaling 1 Protein; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D015534:Trans-Activators / Q000235:genetics; D014157:Transcription Factors / Q000235:genetics; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism* / Q000494:pharmacology
D002352:Carrier Proteins; D016207:Cytokines; D004268:DNA-Binding Proteins; D008565:Membrane Proteins; D047888:Receptors, Tumor Necrosis Factor, Type I; D047889:Receptors, Tumor Necrosis Factor, Type II; D012097:Repressor Proteins; C491590:Socs1 protein, mouse; C491409:Socs2 protein, mouse; C491411:Socs3 protein, mouse; D000071222:Suppressor of Cytokine Signaling 1 Protein; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D015534:Trans-Activators; D014157:Transcription Factors; D014409:Tumor Necrosis Factor-alpha; D005688:Galactosamine; D006419:Heme Oxygenase (Decyclizing); D051547:Heme Oxygenase-1; C496542:Hmox1 protein, mouse