Much interest has recently been directed to the pleiotropic effects of the monokine tumor necrosis factor (TNF) a product of activated macrophages as well as another cytokine interleukin-1 (IL-1). TNF was originally described as the agent responsible for hemorrhagic necrosis in transplanted murine sarcomas after endotoxin administration. Subsequently, TNF was shown to be identical to cachectin, the peptide which induces hypertriglyceridemia in mice. TNF/cachectin was suggested to be responsible for the syndrome of body wasting or cachexia which accompanies malignancy. It has recently been shown that TNF injection simulates many of the metabolic and physiologic effects seen in the acute phase response to tissue injury or infection. Interleukin-1 (IL-1) also has been suggested to be important in mediating metabolic aspects of the acute phase response to tissue injury. This proposal is addressed at the further definition of the metabolic roles of TNF and IL-1 both acutely in the response to tissue injury and more chronically in the cachexia of cancer. We will study the effects of TNF and IL-1 administration upon amino acid, protein, and glucose metabolism. In preliminary experiments, we have shown that TNf injection results in increased hepatic amino acid uptake concomitant with hormonal and serum zinc alterations: identical changes are seen in the acute phase response to tissue injury. Amino acid distribution, protein synthesis, and gluconeogenesis will be examined in the liver and in skeletal muscle in a rat model of cancer cachexia at varying stages of tumor development. The presence of TNF and IL-1 in this cancer cachexia model will be assessed by immunocytochemical examination and by measurement of mRNA levels. Parallel metabolic studies will be performed in normal rats administered TNF and/or IL-1 and these findings compared with the metabolic abnormalities associated with the tumor-bearing state. An investigation of the mechanisms of action of TNf and IL-1 further study of the permissive effect of TNF upon the peptide hormone glucagon will be conducted in isolated rat hepatocytes. This work should help elucidate the metabolic roles played by TNf and IL-1 in the acute phase response and in the cachexia and body wasting of malignancy.
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