Parasitic and bacterial invasion of mammals is associated with a number of common metabolic derangements of the host. One of these is the induction of a catabolic state, which when prolonged, can lead to cachexia, shock and death. A macrophage product, cachextia, which is made in response to T. brucei. P. berghei. and endotoxin, that inhibits the synthesis of the enzyme lipoprotein lipase of adipocytes in vivo and 3T3-Ll pre-adipocytes in vitro. has been recently isolated. Microsequencing and subsequent cloning of mouse cachectin revealed that cachectin was identical to tumor necrosis factor (TNF). During the past few years, a number of biological activities associated with cachectin have been identified. These have included the ability to selectively turn off transcription of specific anabolic genes, promote anorexia, weight loss and anemia, induce fever, hemorrhagic necrosis, tubular necrosis and lethal shock. Antibodies to cachectin/TNF can prevent the lethality of mice to endotoxin and baboons to lethal septicemia. It thus appears that host overreacts to invasion and produces toxic amounts of cachectin/TNF. In addition, a new monokine has been recently identified, isolated and cloned which has been named macrophage inflammatory protein (MIP). This protein can elicit neutrophil migration in vitro and in vivo. In the next grant period, studies of cachectin/TNF production, mechanism of action in vitro and in vivo with special analysis on its role in promoting cachexia and shock, will be continued. These studies will include detailed analysis of control points for transcription and translation of lipoprotein lipase and the glucose transporter in 3T3-Ll cells. The possible interaction of cachectin/TNF with other cytokines (IL1 and Interferon gamma) of inducing cachexia in vivo will be assessed. Animal models of cachexia will also be examined for possible role of cachectin/TNF by administering anti-cachectin antibodies. Further work is also planned with MIP to determine other biological functions and its relationship to other monokines. In addition, a search will continue, for other monokines produced by macrophages in response to invasion. These studies should give new insight into therapeutics of the cachexia associated with chronic infections.
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