Greater than 60% of the body's reticuloendothelial capacity resides in the Kupffer cells of the liver. The Kupffer cells function protectively as immune cells and also as scavenger cells removing potentially toxic material from the portal vein. Malfunction of these cells can therefore have important consequences in the development of disease. Kupffer cells have not been as well studied as other macrophages due to their inaccessibility and the assumption that in general the biochemistry that applies to other macrophages will also apply to the Kupffer cell. Kupffer cells are now known to have unique properties including the way they catabolize and respond to endotoxin. Many Kupffer cell functions are brought about by their production of cytokines including IL-1, IL-6 and TNF. These proteins are induced by external stimuli, the most important of which is endotoxin. The low level endotoxemia of the portal vein may be needed to keep the cells primed while higher levels switch on the genes for cytokine production. This study examines the control of cytokine production by the Kupffer cell. Studies of cytokine mRNA levels will be measured in stimulated and unstimulated cells. Experiments will be carried out to determine the relative importance of transcription rate, message stability and the role of repressor or activator proteins in regulation. The role of protein kinases in the transcriptional activation of these genes will be studied. Changes in total Kupffer cell protein expression on acute and chronic endotoxin stimulation will be examined by 2D PAGE. Specific endotoxin responsive genes other than cytokines will also be studied and new genes identified using both differential and subtractive hybridization of cDNA libraries. These studies should provide new insights into Kupffer cell function and their role in the etiology of liver disease and sepsis.
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