title: NF-κB1 deficiency stimulates the progression of non-alcoholic steatohepatitis (NASH) in mice by promoting NKT-cell-mediated responses.
abstract: 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.
authors.affiliation: Department of Health Sciences and Interdisciplinary Research Centre for Autoimmune Diseases, University 'Amedeo Avogadro' of East Piedmont, Novara, Italy.
authors.forename: Irene
authors.initials: I
authors.lastname: Locatelli
authors.forename: Salvatore
authors.initials: S
authors.lastname: Sutti
authors.forename: Marco
authors.initials: M
authors.lastname: Vacchiano
authors.forename: Cristina
authors.initials: C
authors.lastname: Bozzola
authors.forename: Emanuele
authors.initials: E
authors.lastname: Albano
mesh_terms: D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D004032:Diet; D005234:Fatty Liver / Q000209:etiology* / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D005434:Flow Cytometry; D008103:Liver Cirrhosis / Q000209:etiology / Q000276:immunology / Q000378:metabolism; D008264:Macrophages / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D052002:NF-kappa B p50 Subunit / Q000172:deficiency*; D055611:Natural Killer T-Cells / Q000378:metabolism*; D065626:Non-alcoholic Fatty Liver Disease; D060888:Real-Time Polymerase Chain Reaction
chemical_list: D015415:Biomarkers; D052002:NF-kappa B p50 Subunit