Tumor necrosis factor-α inhibits peroxisome proliferator-activated receptor γ activity at a posttranslational level in hepatic stellate cells
| Autor: | Hidekazu Tsukamoto, Hongyun She, Chin K. Sung, Shigang Xiong |
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| Rok vydání: | 2004 |
| Předmět: |
Male
Transcriptional Activation medicine.medical_specialty Transcription Genetic Physiology medicine.medical_treatment Receptors Cytoplasmic and Nuclear Peroxisome proliferator-activated receptor Biology Response Elements Cell Line Benzophenones Physiology (medical) Internal medicine medicine Animals RNA Messenger Phosphorylation Rats Wistar Receptor chemistry.chemical_classification Mitogen-Activated Protein Kinase 3 Hepatology Tumor Necrosis Factor-alpha JNK Mitogen-Activated Protein Kinases NF-kappa B Gastroenterology DNA Peroxisome NFKB1 Rats Enzyme Activation Cytokine Endocrinology Liver chemistry Cell culture Mutation Cancer research Hepatic stellate cell Tyrosine Tumor necrosis factor alpha Mitogen-Activated Protein Kinases Protein Processing Post-Translational Transcription Factors |
| Zdroj: | American Journal of Physiology-Gastrointestinal and Liver Physiology. 286:G722-G729 |
| ISSN: | 1522-1547 0193-1857 |
| DOI: | 10.1152/ajpgi.00411.2003 |
| Popis: | Diminished activity of peroxisome proliferator-activated receptor γ (PPARγ) is implicated in activation of hepatic stellate cells (HSC), a critical event in the development of liver fibrosis. In the present study, we investigated PPARγ regulation by TNF-α in an HSC line designated as BSC. In BSC, TNF-α decreased both basal and ligand (GW1929)-induced PPARγ mRNA levels without changing its protein expression. Nuclear extracts from BSC treated with TNF-α showed decreased binding of PPARγ to PPAR-responsive element (PPRE) as determined by electrophoretic mobility shift assay. In BSC transiently transfected with a PPARγ1 expression vector and a PPRE-luciferase reporter gene, TNF-α decreased both basal and GW1929-induced transactivation of the PPRE promoter. TNF-α increased activation of ERK1/2 and JNK, previously implicated in phosphorylation of Ser82 of PPARγ1 and resultant negative regulation of PPARγ transactivity. In fact, TNF-α failed to inhibit transactivity of a Ser82Ala PPARγ1 mutant in BSC. TNF-α-mediated inhibition of PPARγ transactivity was not blocked with a Ser32Ala/Ser36Ala mutant of inhibitory NF-κBα (IκBα). These results suggest that TNF-α inhibits PPARγ transactivity in cultured HSC, at least in part, by diminished PPARγ-PPRE (DNA) binding and ERK1/2-mediated phosphorylation of Ser82 of PPARγ1, but not via the NF-κB pathway. |
| Databáze: | OpenAIRE |
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