| Abstract |
Fulminant hepatitis is a clinical syndrome characterised by sudden and severe impairment of liver function, resulting from massive liver inflammatory infiltration with subsequent death of hepatocytes. Acute liver failure can be devastating and is associated with high mortality. However, the underlying pathophysiological mechanisms are not yet fully understood and therefore an effective therapeutic approach is difficult. With regard to novel therapeutic approaches of fulminant hepatitis, at the present time a significant number of research groups have been focused on the potential of gene silencing techniques for future therapeutic implementation. For this purpose, a promising candidate molecule is Tpl2, a serine/threonine protein kinase that has been classified as a member of the mitogen-activated protein kinase kinase kinase family (MAP3K). Based on its role in inflammation, Tpl2 has been recognized as an important target for the development of anti-inflammatory drugs. In this connection, Tpl2 protein was initially identified as a proto-oncogene that is activated by provirus insertion in retrovirus-induced T cell lymphomas and mammary adenocarcinomas in rodents. Since, Tpl2 has been classified into the mitogen-activated protein kinase kinase kinase (MAP3K) family, is a serine-threonine protein kinase and is known to have a pleiotropic role. Tpl-2 is implicated in the regulation of several cellular kinase pathways and has also been found to induce miscellaneous transcription factors. In addition, Tpl2 also plays an obligatory role in the transduction of Toll-like receptor and regulate the expression of cytokines, chemokines and other molecules involved in inflammation as well as in the regulation of innate and adaptive immunity. The finding that Tpl2 is involved in the Toll-like receptor 4 (TLR4) signalling pathway emerged by using Tpl2 knockout mice, revealed that after binding with TLR4, lipopolysaccharide (LPS) activates extracellular signal-regulated kinase (ERK) and induces the production of tumor necrosis factor-a (TNF-a) in a Tpl2-dependent manner. As a result, Tpl2-deficient mice are resistant to LPS-induced endotoxic shock because they lack ERK activation, resulting in lower TNF-a production. It should be noted that mice deficient to Tpl2 were studied in the context of an established inflammatory bowel disease (IBD) mouse model (TNFΔARE) showing that Tpl-2 kinase regulate the lymphocytic response and its absence caused a delayed onset and progression of IBD. Thus, above and beyond its role as a MAP3K kinase, Tpl2 mediates TNF-a and other cytokine
The role of Tpl2 in Fulminant Hepatitis
production, and is closely linked with the development of many inflammatory diseases, such as rheumatoid arthritis or inflammatory bowel disease. We will try to delineate the precise role of tpl2 protein in the context of inflammation and apoptosis in liver injury. Along these lines, we are going to investigate whether Tpl2 is critically involved in the pathophysiology of fulminant hepatitis and try to determine the molecular mechanism of its kinase action regarding inflammation and apoptosis-related signals. Finally, in course of defining the significant biological role and function of Tpl2 kinase in ConA-induced hepatitis we will investigate the value of Tpl2 inhibitor as potent hepatoprotective drug.
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Ο ρόλος της κινάσης Tpl2 στην παθοφυσιολογία της κεραυνοβόλου ηπατίτιδας
