Glucocorticoids (GCs) are steroids that bind to the glucocorticoid receptor (GR) and are potent inhibitors of inflammation. Treatment with GCs is often constrained by the occurrence of GC resistance (GCR). In this project we aim to investigate the molecular basis of TNF-induced GCR. Using different technologies (MAPPIT, iMixPro and Mass spectrometry) in hepatocytes, we investigate the effects of TNF on the physiological activities of GR, focusing on its interaction profile and posttranslational modifications of GR. Next, molecules contributing to GCR will be evaluated in TNF-mediated disease mouse models. It is expected that insights into the mechanisms of GCR will result in the identification of new drug targets potentially useful in innovative therapeutic strategies for the treatment of inflammatory diseases.