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- Title
NF<sub>-?</sub>B1 deficiency stimulates the progression of non-alcoholic steatohepatitis (NASH) in mice by promoting NKT-cell-mediated responses.
- Authors
LOCATELLI, Irene; SUTTI, Salvatore; VACCHIANO, Marco; BOZZOLA, Cristina; ALBANO, Emanuele
- Abstract
Growing evidence indicates that NF-KB (nuclear factor ?B) activation contributes to the pathogenesis of NASH (non-alcoholic steatohepatisis). Among the NF-KB subunits, p50/NF-KB1 has regulatory activities down-modulating NF-KB-mediated responses. In the present study, we investigated the effects of NF-KB1 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 TNFa (tumour necrosis factor a) production were higher in NF-KB1-/- (NF-KB1-knockout) mice than in WT (wild-type) mice. NF-KB1-/- mice also showed appreciable centrilobular collagen deposition, an increased number of activated hepatic stellate cells and higher type-I procollagen-a and TIMP-1 (tissue inhibitor of metalloproteases-1) mRNA expression. Although NF-KB 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-KB1-/- 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-KB1-/- 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-KB1-/- mice, but not in those of WT littermates, we also observed an up-regulation in the production of NKT-related cytokines IFN (interferon)-? and osteopontin. Taken together, these results indicate that NF-KB1 down-modulation enhanced NASH progression to fibrosis by favouring NKT cell recruitment, stressing the contribution of NKT cells in the pathogenesis of NASH.
- Subjects
NF-kappa B; FATTY liver; DISEASE progression; LABORATORY mice; ALANINE aminotransferase; APOPTOSIS; TUMOR necrosis factors
- Publication
Clinical Science, 2013, Vol 124, Issue 4, p279
- ISSN
0143-5221
- Publication type
Article
- DOI
10.1042/CS20120289