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.