NF-κB1 deficiency stimulates the progression of non-alcoholic steatohepatitis (NASH) in mice by promoting NKT-cell-mediated responses
| Autor: | Cristina Bozzola, Salvatore Sutti, Marco Vacchiano, Emanuele Albano, Irene Locatelli |
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| Rok vydání: | 2012 |
| Předmět: |
Liver Cirrhosis
medicine.medical_specialty medicine.medical_treatment Biology Real-Time Polymerase Chain Reaction Mice Non-alcoholic Fatty Liver Disease Interferon Internal medicine medicine Animals CXCL10 Mice Knockout Macrophages NF-kappa B p50 Subunit Interleukin General Medicine Flow Cytometry medicine.disease Natural killer T cell Diet Fatty Liver Mice Inbred C57BL Endocrinology Cytokine Immunology Hepatic stellate cell Natural Killer T-Cells Tumor necrosis factor alpha Steatohepatitis Biomarkers medicine.drug |
| Zdroj: | Clinical Science. 124:279-287 |
| ISSN: | 1470-8736 0143-5221 |
| DOI: | 10.1042/cs20120289 |
| Popis: | Growing evidence indicates that NF-κB (nuclear factor κB) activation contributes to the pathogenesis of NASH (non-alcoholic steatohepatisis). Among the NF-κB subunits, p50/NF-κB1 has regulatory activities down-modulating NF-κB-mediated responses. In the present study, we investigated the effects of NF-κB1 deficiency on the progression of NASH induced by feeding mice on an MCD (methionine/choline-deficient) diet. Following 4 weeks on the MCD diet, steatosis, ALT (alanine aminotransferase) release, hepatocyte apoptosis, lobular inflammation and TNFα (tumour necrosis factor α) production were higher in NF-κB1−/− (NF-κB1-knockout) mice than in WT (wild-type) mice. NF-κB1−/− mice also showed appreciable centrilobular collagen deposition, an increased number of activated hepatic stellate cells and higher type-I procollagen-α and TIMP-1 (tissue inhibitor of metalloproteases-1) mRNA expression. Although NF-κB p50 homodimers regulate macrophage activation, the number of hepatic macrophages and liver mRNAs for iNOS (inducible NO synthase), IL (interleukin)-12p40, CCL2 (CC chemokine ligand 2) and CXCL10 (CXC chemokine ligand 10) were comparable in the two strains. NASH was associated with an increase in liver infiltrating T-cells that was more evident in MCD-fed NF-κB1−/− than in similarly treated WT mice. Flow cytorimetry showed that T-cell recruitment involved effector CD8+ T-cells without changes in the helper CD4+ T-cell fraction. Furthermore, although NASH lowered hepatic NKT cells [NK (natural killer) T-cells] in WT mice, the NKT cell pool was selectively increased in the livers of MCD-fed NF-κB1−/− mice. Such NKT cell recruitment was associated with an early overexpression of IL-15, a cytokine controlling NKT cell survival and maturation. In the livers of MCD-fed NF-κB1−/− mice, but not in those of WT littermates, we also observed an up-regulation in the production of NKT-related cytokines IFN (interferon)-γ and osteopontin. Taken together, these results indicate that NF-κB1 down-modulation enhanced NASH progression to fibrosis by favouring NKT cell recruitment, stressing the contribution of NKT cells in the pathogenesis of NASH. |
| Databáze: | OpenAIRE |
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