Tissue-Specific Regulation of p38?-Mediated Inflammation in Con A-Induced Acute Liver Damage.

ABSTRACT: Because p38? plays a critical role in inflammation, it has been an attractive target for the development of anti-inflammation therapeutics. However, p38? 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 p38? regulates the inflammatory responses in acute liver inflammation in a tissue-specific manner, and liver toxicity by p38? inhibitors may be a result of the inhibition of protective activity of p38? in the liver. Genetic ablation of p38? in T and NKT cells protected mice from liver injury in Con A-induced liver inflammation, whereas liver-specific deletion of p38? aggravated liver pathology. We found that p38? deficiency in the liver increased the expression of chemokines to recruit more inflammatory cells, indicating that p38? in the liver plays a protective anti-inflammatory role during acute liver inflammation. Therefore, our results suggest that p38? regulates the inflammatory responses in a tissue-specific manner, and that the tissue-specific p38? targeting strategies can be used for the development of an effective anti-inflammation treatment with an improved side-effect profile.

SUBMITTER: Kang YJ 

PROVIDER: S-EPMC4417423 | biostudies-literature | 2015 May

REPOSITORIES: biostudies-literature