Mechanistic Insights in TNF Signaling and Drug-Induced Liver Injury: Towards a Predictive Preclinical Toolbox

Abstract

There is an increasing body of evidence that various drugs can sensitize hepatocytes to TNF-mediated killing. This interaction is likely due to perturbations of the normal hepatocyte physiology that triggers a pro-apoptotic TNFR pathway when TNF is present in the system. We have focussed on the effects of DILI compounds on endoplasmic reticulum (ER) stress as well as the Nrf2-mediated oxidative stress adaptive toxicity pathways and how these two pathways converge with adverse TNFR signaling. Moreover, we have deepened our understanding on effects of DILI compounds on the TNFR-mediated NF-kappa B regulation. We have integrated primary human hepatocyte transcriptomics data with live cell imaging adaptive stress response GFP-reporter data to unravel in detail the interaction between different adaptive stress pathways and TNF/drug cytotoxic synergy. Moreover we have applied RNA interference screening to identify key modulators of these signaling pathways that define this synergistic toxic interaction. Our data provide suggestions on the toolbox components that can be used in a preclinical drug safety testing phase to assess safety liabilities for a drug/cytokine interplay in the development of DILI. This work is part of the MIP-DILI project supported by the Innovative Medicines Initiative (grant agreement n° 115336), and the FP7 SEURAT-1 DETECTIVE project (grant agreement 266838).