title: Tissue-Specific Regulation of p38α-Mediated Inflammation in Con A-Induced Acute Liver Damage.
abstract: 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.
authors.affiliation: Department of Immunology and Microbial Science, The Scripps Research Institute, La Jolla, CA 92037; ykang@scripps.edu.
authors.forename: Young Jun
authors.initials: YJ
authors.lastname: Kang
authors.affiliation: Department of Immunology and Microbial Science, The Scripps Research Institute, La Jolla, CA 92037;
authors.forename: Bo-Ram
authors.initials: BR
authors.lastname: Bang
authors.affiliation: Department of Gastroenterology, Graduate School of Medicine, University of Tokyo, Tokyo 113-8655, Japan;
authors.forename: Motoyuki
authors.initials: M
authors.lastname: Otsuka
authors.affiliation: Department of Cardiovascular Medicine, Osaka University Graduate School of Medicine, Osaka 565-0871, Japan; and Cardiovascular Division, King's College London, London SE5 9NU, United Kingdom.
authors.forename: Kinya
authors.initials: K
authors.lastname: Otsu
mesh_terms: D000818:Animals; D003208:Concanavalin A / Q000633:toxicity; D004195:Disease Models, Animal; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D055786:Gene Knockout Techniques; D015151:Immunoblotting; D007150:Immunohistochemistry; D007249:Inflammation / Q000276:immunology / Q000378:metabolism; D018836:Inflammation Mediators / Q000378:metabolism; D008099:Liver / Q000276:immunology / Q000378:metabolism*; D008107:Liver Diseases / Q000276:immunology / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D048308:Mitogen-Activated Protein Kinase 14 / Q000276:immunology / Q000378:metabolism*; D055611:Natural Killer T-Cells / Q000276:immunology / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013601:T-Lymphocytes / Q000276:immunology / Q000378:metabolism
chemical_list: D018836:Inflammation Mediators; D003208:Concanavalin A; D048308:Mitogen-Activated Protein Kinase 14