Department of Health Sciences and Interdisciplinary Research Centre for Autoimmune Diseases, University 'Amedeo Avogadro' of East Piedmont, Novara, Italy.
Clin Sci (Lond). 2013 Feb;124(4):279-87. doi: 10.1042/CS20120289.
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.
越来越多的证据表明，NF-κB（核因子κB）的激活有助于 NASH（非酒精性脂肪性肝炎）的发病机制。在 NF-κB 亚基中，p50/NF-κB1 具有下调 NF-κB 介导的反应的调节活性。在本研究中，我们研究了 NF-κB1 缺乏对 MCD（蛋氨酸/胆碱缺乏）饮食喂养小鼠诱导的 NASH 进展的影响。在用 MCD 饮食喂养 4 周后，NF-κB1（-/-）（NF-κB1 敲除）小鼠的脂肪变性、ALT（丙氨酸氨基转移酶）释放、肝细胞凋亡、小叶炎症和 TNFα（肿瘤坏死因子α）产生均高于 WT（野生型）小鼠。NF-κB1（-/-）小鼠还表现出明显的中央区胶原沉积、活化的肝星状细胞数量增加以及Ⅰ型前胶原-α和 TIMP-1（金属蛋白酶组织抑制剂-1）mRNA 表达增加。尽管 NF-κB p50 同源二聚体调节巨噬细胞活化，但两种品系的肝巨噬细胞数量和肝脏 iNOS（诱导型一氧化氮合酶）、IL（白细胞介素）-12p40、CCL2（CC 趋化因子配体 2）和 CXCL10（CXC 趋化因子配体 10）的 mRNAs 相似。NASH 与肝浸润 T 细胞的增加有关，在 MCD 喂养的 NF-κB1（-/-）小鼠中比在类似处理的 WT 小鼠中更为明显。流式细胞术显示，T 细胞募集涉及效应 CD8+T 细胞，而辅助性 CD4+T 细胞亚群没有变化。此外，尽管 NASH 降低了 WT 小鼠肝脏中的 NKT 细胞[自然杀伤（NK）T 细胞]，但 MCD 喂养的 NF-κB1（-/-）小鼠肝脏中的 NKT 细胞库选择性增加。这种 NKT 细胞募集与 IL-15 的早期过表达有关，IL-15 是一种控制 NKT 细胞存活和成熟的细胞因子。在 MCD 喂养的 NF-κB1（-/-）小鼠的肝脏中，但在 WT 同窝仔鼠的肝脏中，我们还观察到 NKT 相关细胞因子 IFN（干扰素）-γ和骨桥蛋白的产生上调。综上所述，这些结果表明，NF-κB1 的下调通过促进 NKT 细胞募集增强了 NASH 向纤维化的进展，强调了 NKT 细胞在 NASH 发病机制中的作用。
