title: Comparative gene and protein expression analyses of a panel of cytokines in acute and chronic drug-induced liver injury in rats.
abstract: Drug-induced liver injury (DILI) is a significant safety issue associated with medication use, and is the major cause of failures in drug development and withdrawal in post marketing. Cytokines are signaling molecules produced and secreted by immune cells and play crucial roles in the progression of DILI. Although there are numerous reports of cytokine changes in several DILI models, a comprehensive analysis of cytokine expression changes in rat liver injury induced by various compounds has, to the best of our knowledge, not been performed. In the past several years, we have built a public, free, large-scale toxicogenomics database, called Open TG-GATEs, containing microarray data and toxicity data of the liver of rats treated with various hepatotoxic compounds. In this study, we measured the protein expression levels of a panel of 24 cytokines in frozen liver of rats treated with a total of 20 compounds, obtained in the original study that formed the basis of the Open TG-GATEs database and analyzed protein expression profiles combined with mRNA expression profiles to investigate the correlation between mRNA and protein expression levels. As a result, we demonstrated significant correlations between mRNA and protein expression changes for interleukin (IL)-1β, IL-1α, monocyte chemo-attractant protein (MCP)-1/CC-chemokine ligand (Ccl)2, vascular endothelial growth factor A (VEGF-A), and regulated upon activation normal T cell expressed and secreted (RANTES)/Ccl5 in several different types of DILI. We also demonstrated that IL-1β protein and MCP-1/Ccl2 mRNA were commonly up-regulated in the liver of rats treated with different classes of hepatotoxicants and exhibited the highest accuracy in the detection of hepatotoxicity. The results also demonstrate that hepatic mRNA changes do not always correlate with protein changes of cytokines in the liver. This is the first study to provide a comprehensive analysis of mRNA-protein correlations of factors involved in various types of DILI, as well as additional insights into the importance of understanding complex cytokine expression changes in assessing DILI.
authors: Developmental Research Laboratories, Shionogi & Co., Ltd., Futaba-cho, Toyonaka, Osaka, Japan.
authors: Hiroyuki
authors: H
authors: Hanafusa
authors: Developmental Research Laboratories, Shionogi & Co., Ltd., Futaba-cho, Toyonaka, Osaka, Japan; Toxicogenomics Informatics Project, National Institute of Biomedical Innovation, Asagi, Ibaraki, Osaka, Japan.
authors: Yuji
authors: Y
authors: Morikawa
authors: Developmental Research Laboratories, Shionogi & Co., Ltd., Futaba-cho, Toyonaka, Osaka, Japan; Toxicogenomics Informatics Project, National Institute of Biomedical Innovation, Asagi, Ibaraki, Osaka, Japan,. Electronic address: takeki.uehara@shionogi.co.jp.
authors: Takeki
authors: T
authors: Uehara
authors: Developmental Research Laboratories, Shionogi & Co., Ltd., Futaba-cho, Toyonaka, Osaka, Japan.
authors: Masako
authors: M
authors: Kaneto
authors: Toxicogenomics Informatics Project, National Institute of Biomedical Innovation, Asagi, Ibaraki, Osaka, Japan,; National Institute of Health Sciences, Kamiyoga, Setagaya-ku, Tokyo, Japan.
authors: Atsushi
authors: A
authors: Ono
authors: Toxicogenomics Informatics Project, National Institute of Biomedical Innovation, Asagi, Ibaraki, Osaka, Japan.
authors: Hiroshi
authors: H
authors: Yamada
authors: National Institute of Health Sciences, Kamiyoga, Setagaya-ku, Tokyo, Japan.
authors: Yasuo
authors: Y
authors: Ohno
authors: Toxicogenomics Informatics Project, National Institute of Biomedical Innovation, Asagi, Ibaraki, Osaka, Japan,; Department of Pathophysiology, Faculty of Pharmaceutical Sciences, Doshisha Women's College of Liberal Arts, Kodo, Kyotanabe, Kyoto, Japan.
authors: Tetsuro
authors: T
authors: Urushidani
mesh_terms: D000208:Acute Disease; D000818:Animals; D019540:Area Under Curve; D056486:Chemical and Drug Induced Liver Injury / Q000209:etiology / Q000235:genetics* / Q000276:immunology / Q000378:metabolism*; D056487:Chemical and Drug Induced Liver Injury, Chronic / Q000209:etiology / Q000235:genetics* / Q000276:immunology / Q000378:metabolism*; D016000:Cluster Analysis; D016207:Cytokines / Q000235:genetics* / Q000378:metabolism*; D030541:Databases, Genetic; D004195:Disease Models, Animal; D020869:Gene Expression Profiling / Q000379:methods; D005786:Gene Expression Regulation; D007118:Immunoassay; D008297:Male; D020411:Oligonucleotide Array Sequence Analysis; D012333:RNA, Messenger / Q000378:metabolism; D012372:ROC Curve; D051381:Rats; D017207:Rats, Sprague-Dawley; D043922:Toxicogenetics
chemical_list: D016207:Cytokines; D012333:RNA, Messenger
keywords: Biomarkers; Cytokines; Hepatotoxicity; Protein; Toxicogenomics; mRNA