The long-term objective of this proposal is to elucidate the mechanisms whereby alcohol consumption produces immunosuppressive and deleterious metabolic effects. It has recently become evident that alcohol interferes with the """"""""cytokine world"""""""" inducing alterations in cytokine production by various cells. The cytokine network, controlling all immunocompetent cell types as well as a number of nonimmunocompetent cell types, operates through two arms: cytokine production and cytokine interaction with cytokine-responding cells. While the first has been scarcely investigated with respect to possible effects of alcohol, the second has been only tangentially approached from this point of view. We hypothesize that some of the alcohol immunosuppressive and deleterious metabolic effects are mediated not only by changes in cytokine production, but also by alterations in the state and dynamics of cytokine receptors (Rs) on cytokine-responding cells. Three questions are asked and will be answered by this proposal: 1) Can some of the immunosuppressive and deleterious metabolic effects of alcohol be explained through alcohol-induced alterations in cytokine Rs? 2) What are the mechanisms underlying alcohol-induced alterations in the state and dynamics of cytokine Rs? and 3) To what extent is the control exerted by cytokines on immuno- and nonimmunocompetent cells' functions affected by alcohol-induced alterations in cytokine Rs? The hypothesis will be tested in acute and chronic alcoholic rats, subjected to an immune insult (Escherichia coli lipopolysaccharide administration) by measuring the amount (Bmax), of cell-surface and total R pool and affinity (KD) of cytokine Rs, as well as R internalization and externalization, rate of R synthesis (as judged on the basis of fluctuations in the corresponding mRNA) and shedding (including measurements of soluble Rs) in several immunocompetent (Kupffer, blood polymorphonuclear and endothelial) and nonimmunocompetent (hepatic parenchymal and adipose) cells. Two cytokines will be considered: tumor necrosis factor (TNF) alpha and interleukin (IL) 6, for they cover a wide spectrum of nonimmune and immune functions. Among the first, induction of acute phase protein synthesis in liver parenchymal cells (controlled by both cytokines) and regulation of lipoprotein lipase activity of the adipocyte (controlled by TNF-alpha) are most important. Among the second, cytotoxic and cytocidal activity (controlled by TNF-alpha) and antibody formation (controlled by IL-6) are most prominent. Possible alterations by alcohol of cell's ability to handle protein kinases C (Ca2+- and phospholipid- dependent) and A (cyclic AMP-dependent) - which are known to play a pivotal role as cellular instruments in cytokine R regulation - will also be investigated in an attempt to understand the biochemical basis of alcohol-induced alterations in cytokine Rs. Functional tests specific for each cell type and each cytokine will be performed to answer question 3. Overall, the proposal will explore a new, very promising and fecund avenue in research on alcoholism, which will significantly advance our understanding of immunosuppressive and metabolic deleterious effects of alcohol, paving the way to possible future pharmacological interventions to restore the compromised immunodefense capacity of the body.
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