Tissue-Specific Regulation of p38α-Mediated Inflammation in Con A-Induced Acute Liver Damage.
Tissue-Specific Regulation of p38α-Mediated Inflammation in Con A-Induced Acute Liver Damage.
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DOI：
10.4049/jimmunol.1402954
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发表时间：
2015-05-15
期刊：
影响因子：
--
通讯作者：
Otsu K
中科院分区：
文献类型：
--
作者：
Kang YJ;Bang BR;Otsuka M;Otsu K
由于p38α在炎症中起着关键作用，因此成为抗炎治疗药物开发的一个有吸引力的靶点。然而，p38α抑制剂表现出副作用，包括严重的肝脏毒性，在临床研究中往往优于益处，毒性机制尚不清楚。在这里，我们证明了p38α以组织特异性的方式调节急性肝脏炎症中的炎症反应，p38α抑制剂对肝脏的毒性可能是由于抑制了p38α在肝脏中的保护活性所致。基因消融T细胞和NKT细胞中的p38α可保护小鼠免受ConA诱导的肝脏炎症所致的肝损伤，而肝脏特异性缺失的p38α则加重肝脏病理。我们发现肝脏中p38α缺乏增加了趋化因子的表达以募集更多的炎性细胞，表明肝脏中的p38α在急性肝脏炎症过程中起到保护性抗炎作用。因此，我们的结果表明，p38α以组织特异性的方式调节炎症反应，并且组织特异性的p38α靶向策略可以用于开发具有改善副作用的有效抗炎治疗。
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. Here, we demonstrate that p38α regulates the inflammatory responses in the acute liver inflammation in a tissue-specific manner, and liver toxicity by p38α inhibitors may be resulted from the inhibition of protective activity of p38α in the liver. Genetic ablation of p38α in T and NKT cells protected mice from the liver injury in ConA-induced liver inflammation, while liver-specific deletion of p38α aggravated the 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.
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影响因子：
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作者：
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期刊：
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DOI：
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发表时间：
2010-01-01
期刊：
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影响因子：
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作者：
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