EXCEEDTHE SPACE PROVIDED. Alcoholic liver disease (ALD) is a major cause of liver disease and liver related morbidity/mortality in the United States. One major difficulty in devising specific therapies for ALD has been our limited understanding of the mechanism(s) for the development andprogression of this liver injury. Cytokines are low molecular weight mediators of cellular communication that are produced and released by numerouscell types such as monocytes, macrophages, and of particular relevance to liver disease, Kupffer cells. Pro-inflammatory cytokines, such as tumor necrosis factor a (TNF), and chemokines, such as interleukin-8, have been postulated to play a role in modulating many of the systemic manifestations of ALD and certain aspects of the liver injury in ALD. Many factors stimulate cytokine production, including endotoxin (lipopolysaccharide orLPS) and reactive oxygen intermediates (ROIs), both ofwhich are of direct relevance to this proposal. Endotoxin stimulates cytokine production via interaction with LPS binding protein (LBP), membranebound CD14, and ultimately the recently described LPS receptor, Toll-like receptor TLR4. TLR4then causes activation ofthe redox sensitive transcription factor, NFicB, with subsequent production of cytokines such as TNF. NFicB also has been identified as a survival factor against TNF induced apoptosis in multiple cell types Thus, NFicB not only serves as a transcription factor for several inflammatory cytokines such as TNF andTL-8, but also for several potentially protective factors such as inhibitors of apoptosis (lAPs). Inhibition of NFicB can initiate fulminant liver injury and hepatocyte apoptosis, at least in part, by allowing unregulated signaling via the TNF 'death domain'. We postulate that in ALD there is: 1)increased NFicB activation and TNF production in the major cytokine producing cell in the liver (Kupffer cell); and 2) decreased NFicBactivation and decreased 'protective signaling' in conjunction with increased TNF death signaling in the target cell (hepatocyte). In this proposal, we will use in vitro systems, in vivo animal models of ALD and ultimately will perform translational human studies to further define mechanisms of liver injury in ALD and potential pathways for intervention.
The specific aims of this proposal are to: 1) Evaluate mechanisms for increased NFicB activation and TNF production by monocyte/Kupffer cells in ALD (priming), 2) Evaluate mechanisms of increased susceptibility to TNF/cytokinehepatotoxicity in ALD (sensitization). PERFORMANCE SITE ========================================Section End===========================================
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