Kang Young Jun, Bang Bo-Ram, Otsuka Motoyuki, Otsu Kinya
Department of Immunology and Microbial Science, The Scripps Research Institute, La Jolla, CA 92037;
Department of Gastroenterology, Graduate School of Medicine, University of Tokyo, Tokyo 113-8655, Japan;
J Immunol. 2015 May 15;194(10):4759-66. doi: 10.4049/jimmunol.1402954. Epub 2015 Apr 17.
Because p38α plays a critical role in inflammation, it has been an attractive target for the development of anti-inflammation therapeutics. However, p38α inhibitors showed side effects, including severe liver toxicity, that often prevailed over the benefits in clinical studies, and the mechanism of toxicity is not clear. In this study, we demonstrate that p38α regulates the inflammatory responses in acute liver inflammation in a tissue-specific manner, and liver toxicity by p38α inhibitors may be a result of the inhibition of protective activity of p38α in the liver. Genetic ablation of p38α in T and NKT cells protected mice from liver injury in Con A-induced liver inflammation, whereas liver-specific deletion of p38α aggravated liver pathology. We found that p38α deficiency in the liver increased the expression of chemokines to recruit more inflammatory cells, indicating that p38α in the liver plays a protective anti-inflammatory role during acute liver inflammation. Therefore, our results suggest that p38α regulates the inflammatory responses in a tissue-specific manner, and that the tissue-specific p38α targeting strategies can be used for the development of an effective anti-inflammation treatment with an improved side-effect profile.
由于p38α在炎症中起关键作用，它一直是抗炎治疗药物开发的一个有吸引力的靶点。然而，p38α抑制剂显示出副作用，包括严重的肝毒性，在临床研究中这些副作用往往超过了疗效，而且毒性机制尚不清楚。在本研究中，我们证明p38α以组织特异性方式调节急性肝炎症中的炎症反应，p38α抑制剂导致的肝毒性可能是由于抑制了p38α在肝脏中的保护活性。T细胞和NKT细胞中p38α的基因敲除使小鼠在刀豆蛋白A诱导的肝炎症中免受肝损伤，而肝脏特异性缺失p38α则加重了肝脏病理变化。我们发现肝脏中p38α的缺乏增加了趋化因子的表达以募集更多炎症细胞，这表明肝脏中的p38α在急性肝炎症期间发挥保护性抗炎作用作用。因此，我们的结果表明p38α以组织特异性方式调节炎症反应，并且组织特异性p38α靶向策略可用于开发具有改善副作用的有效抗炎治疗方法。
