T cell immunoglobulin‐ and mucin‐domain‐containing molecule‐4 attenuates concanavalin A‐induced hepatitis by regulating macrophage
T cell immunoglobulin‐ and mucin‐domain‐containing molecule‐4 attenuates concanavalin A‐induced hepatitis by regulating macrophage
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DOI：
10.1189/jlb.1209797
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发表时间：
2010-08
影响因子：
5.5
通讯作者：
Liyun Xu;Jianni Qi;Peiqing Zhao;Xiaohong Liang;Y. Ju;Peng Liu;Bing Liu;Chun Guo;Lining Zhang-Lining
中科院分区：
文献类型：
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作者：
Liyun Xu;Jianni Qi;Peiqing Zhao;Xiaohong Liang;Y. Ju;Peng Liu;Bing Liu;Chun Guo;Lining Zhang-Lining
Tim-4主要在APC（包括巨噬细胞）上表达，并已被证明在T细胞调节中发挥关键作用。然而，目前尚不清楚Tim-4是否也在调节巨噬细胞功能中发挥作用。在本研究中，我们研究了Tim-4对Con A诱导的小鼠肝炎中巨噬细胞活性的影响。我们发现Tim-4的高水平表达与Con A诱导的肝炎中血清ALT水平降低相关。此外，T4-RAW细胞的过继转移导致小鼠ALT水平和Con A诱导的肝损伤显著降低。同时，T4-RAW细胞转移显示，肝脏中的细胞凋亡显著减少，血清中的TNF-α分泌减少，支持Tim-4通过负调节巨噬细胞保护Con A诱导的肝炎的假设。与体内研究结果一致，体外研究表明，RAW 264.7细胞中Tim-4过表达与CD 80、CD 86和MHCII分子表达减少以及TNF-α产生相关。此外，Tim-4阻断促进LPS诱导的巨噬细胞活化。总之，这些发现表明Tim-4通过抑制巨噬细胞活性在减轻肝损伤方面起着重要作用。Tim-4通路可能成为治疗急性肝炎的潜在靶点。
Tim‐4 is expressed primarily on APCs, including macrophages, and has been shown to play a critical role in T cell regulation. However, it remains unclear whether Tim‐4 also plays a role in the regulation of macrophage functions. In the present study, we investigated the effects of Tim‐4 on macrophage activity in Con A‐induced hepatitis in mice. We found that high levels of Tim‐4 expression were associated with a diminished serum level of ALT in Con A‐induced hepatitis. In addition, adoptive transfer of T4‐RAW cells resulted in a significant decrease in ALT levels and Con A‐induced liver injuries in mice. Concurrently, T4‐RAW cells transfer displayed, markedly decreased apoptosis in liver and depressed TNF‐α secretion in serum, supporting the hypothesis that Tim‐4 protects Con A‐induced hepatitis by negatively regulating macrophages. Consistent with the in vivo findings, in vitro studies showed that Tim‐4 overexpression in RAW264.7 cells was associated with decreased expression of CD80, CD86, and MHCII molecules and the production of TNF‐α. Moreover, Tim‐4 blockade promoted LPS‐induced macrophage activation. In conclusion, these findings indicate that Tim‐4 plays an important role in alleviating liver damage by inhibition of macrophage activity. Tim‐4 pathway could be a potential target for the treatment of acute hepatitis.