Role of Vα 14 NKT cells in the development of impaired liver regeneration in vivo
Role of Vα 14 NKT cells in the development of impaired liver regeneration in vivo
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DOI：
10.1053/jhep.2003.50471
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发表时间：
2003-11-01
期刊：
影响因子：
13.5
通讯作者：
Moriwaki, H
中科院分区：
文献类型：
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作者：
Ito, H;Ando, K;Moriwaki, H
尽管我们之前已经证明 IL-12 刺激会增加肝脏自然杀伤 (NK) T (NKT) 细胞的数量，并在肝脏再生的早期阶段增强肝损伤，但 NKT 细胞的作用仍然未知。因此，我们使用 Valpha 14 NKT 敲除小鼠 (Jalpha 281(-/-)) 评估了 11-12 或 α-半乳糖神经酰胺 (α-GalCer) 激活的 NKT 细胞对小鼠肝脏再生的影响。部分肝切除术后 24 小时，Jalpha 281(+/+) 小鼠的血清丙氨酸氨基转移酶 (sALT) 水平有所提高，但 Jalpha 281(-/-) 小鼠的血清丙氨酸氨基转移酶 (sALT) 水平在这两种手术中均没有提高。在 Jalpha 281(+/+) 小鼠中用这两种因子刺激后，肝 NKT 细胞表达显着更多的干扰素 (IFN) γ 和肿瘤坏死因子 α (TNF-α) 信使 RNA (mRNA)。抗IFN-γ或TNF-α抗体均可抑制肝损伤的加重。此外，重组TNF-α注射同样对Jalpha 281(+/+)和Jalpha 281(-/-)小鼠的肝切除肝脏造成损伤；事实上，过继转移的TNF-α(+/+) NKT细胞增强了TNF-α敲除小鼠肝切除术后的肝损伤。肝细胞上的 TNF 受体表达增加，并在部分肝切除后 24 小时达到峰值。总之，肝细胞上同时合成 TNF-α 和高水平 TNF 受体表达会在肝再生过程中激活 NKT 细胞，从而导致严重的肝损伤。
Although we have previously demonstrated that IL-12 stimulation increases the number of hepatic natural killer (NK) T (NKT) cells and enhances liver injury during the early phase of liver regeneration, the role of NKT cells has remained unknown. We therefore evaluated the influence of NKT cells activated by 11-12 or by alpha-galactosylceramide (alpha-GalCer) on murine liver regeneration using Valpha 14 NKT knockout (Jalpha 281(-/-)) mice. Levels of serum alanine aminotransferase (sALT) 24 hours after partial hepatectomy were enhanced in Jalpha 281(+/+) but not in Jalpha 281(-/-) mice by both procedures. Hepatic NKT cells expressed considerably more interferon (IFN) gamma and tumor necrosis factor alpha (TNF-alpha) messenger RNA (mRNA) after stimulation with both factors in Jalpha 281(+/+) mice. Either anti-IFN-gamma or TNF-alpha antibody inhibited the enhancement of liver injury. Furthermore, recombinant TNF-alpha injection similarly caused injury in hepatectomized livers of both Jalpha 281(+/+) and Jalpha 281(-/-) mice; indeed, adoptively transferred TNF-alpha(+/+) NKT cells enhanced liver injury after hepatectomy in TNF-alpha knockout mice. TNF receptor expressions on hepatocytes increased and peaked 24 hours after partial hepatectomy. In conclusion, simultaneous TNF-alpha synthesis and high levels of TNF receptor expression on hepatocytes cause severe liver damage by activated NKT cells during liver regeneration.