Activation of Hepatic Metabolism Byimmune Aggregate

Buxton, Denis

Abstract

The objective of this study will be to investigate the metabolic consequences of stimulation of the reticuloendothelial system in the liver, the molecular events taking place in the main cell types during such stimulation, and the cell-cell communication taking place. My recent studies have demonstrated that the interaction of heat-aggregated immunoglobulin G with the liver is accompanied by a stimulation of hepatic glycogenolysis. The metabolic changes associated with IgG aggregate infusion are calcium-dependent and indomethacine-sensitive, and may be partially mimicked by the infusion of prostaglandin E2. Production of a platelet activating activity with physio-chemical properties resembling those of synthetic acetyl glyceryl ether phosphocholine (AGEPC) is also observed in the effluent perfusate of livers in response to infusion of immune aggregate. The experimental approach which will be taken in this study can be summarized with the following specific aims. 1. Investigation of the roles of prostanoid mediators and AGEPC in the metabolic and hemodynamic responses to immune aggregate. 2. Characterization of hepatic cell types responding to IgG aggregate. 3. Determination of the molecular mechanisms by which hepatic glycogenolysis is enhanced by immune aggregate. 4. Effects of other phagocytosed particles on hepatic metabolism. This project should lead to a more precise understanding of the molecular events occurring in the hepatic Kupffer cells during interaction with immune complexes and particulate material, and the relationship(s) between events at the Kupffer cell and the stimulation of hepatic metabolism observed under such conditions. The experimental evidence obtained in this study should expand our understanding of autoimmune diseases in which defective immune complex clearance is observed, or others in which inhibition of immune complex clearance might be desirable.