共刺激分子B7-H3的表达调控机制及其在Con A所致肝损伤中的作用

自身免疫性肝炎是自身免疫反应介导的肝脏慢性炎症性疾病，严重损害机体健康。我们前期发现肝脏固有抗原递呈细胞的共刺激分子B7-H3的表达升高与其相关;通过小鼠Con A所致肝损伤模型等研究，进一步发现促炎性因子TNF-α可引起B7-H3蛋白表达升高、mRNA表达降低，同时靶向B7-H3 mRNA的miR-29表达下降。结合文献报道我们推测肝脏固有抗原递呈细胞中可能存在：TNF-α通过激活NF-kB的转录活性，抑制miR-29转录，进而解除miR-29对B7-H3的转录后抑制作用；B7-H3表达增强后参与自身免疫性肝炎中T淋巴细胞免疫活性调节。本研究将通过体外和体内实验证明TNF-α/NF-kB/miR-29/B7-H3通路，并探索TNF-α对抗原递呈细胞B7-H3分子的诱导在自身免疫性肝炎中的作用及意义，为自身免疫性肝炎的机制研究及临床防治提供理论依据。

Autoimmune hepatitis is a disease of liver parenchymal cells attacked by its own immune system. Infiltration of activated T cells and secretion of inflammatory factors lead to the damage of hepatocytes and liver tissue. We found the upregulation of B7-H3 in liver antigen presenting cells was correlated with progression of liver damage in human autoimmune hepatitis and Concanavalin A-induced mouse liver injury. We also found the induction of B7-H3 protein by TNF-α and the decrease of miR-29, a post-transcriptional inhibitor of B7-H3, in Concanavalin A-induced mouse liver injury. Our findings, together with other reports, have suggested that the induction of B7-H3 by TNF-α in liver antigen presenting cells might take part in T lymphocytes responses in Concanavalin A-induced liver injury. Two other regulators, miR-29 and its transcriptional inhibitor NF-kB, might be engaged in the signal transduction from TNF-α to B7-H3. The activation of NF-kB by TNF-α could inhibit miR-29 transcription, leading to the increase of B7-H3 protein expression. Here, we will investigate the induction of B7-H3 via TNF-α/NF-kB/miR-29 both in vitro and in vivo. The immune function of B7-H3 in T lymphocyte regulation and liver injury will be further specified. This research will illustrate the induction of B7-H3 by TNF-α in immune-mediated liver injury, and provide new evidence for clinical application as well.