Recent evidence suggests important functions for the Toll-like and IL-1 receptor (TIR) signaling system in liver disease. A variety of TIR receptors are expressed on Kupffer cells (KC - hepatic macrophages) and hepatic stellate cells (HSC the major hepatic fibrogenic cell). Inflammatory and fibrogenic gene expression is induced in KC and HSC in response to LPS (classic activator of the TIR system) and TIR-activating alarmins (e.g. IL-1 ) released by injured hepatocytes. As hepatocyte damage a nd bacterial exposure are mechanistically important in most forms of liver disease the TIR system is clinically of great relevance. We aim to discover extracellular hepatocyte-derived alarmins and intracellular MAP3Ks that operate as critical and selective regulators of the fibrogenic activities of KC and HSC. These fibrogenic TIR signaling molecules can then be targeted to attenuate fibrosis while retaining other essential functions of the TIR system. Key Aims: (i) Discovery and functiona l characterisation of hepatocyte-derived alarmins that activate fibrogensis and examine the profibrogenic function of IL-1alpha. (ii) Discovery of MAP3K signaling molecules that promote pro- or anti-fibrogenic activities of TIRs and that can be exploited to selectively attenuate fibrosis. (iii) Discovery of the antifibrogenic functions of the TIR effector JNK2.