Physiological responses to cachectin

Abstract

Mammals infected with parasitic, bacterial or viral organisms or bearing tumours characteristically display a catabolic state and weight loss which can advance to cachexia (or wasting), shock and death. Although the phenomenon is commonly observed in many parasitic diseases its mechanism is not understood. We have identified and isolated a macrophage protein, cachectin, as the molecule that may be responsible for cachexia and shock. Cachectin is produced by macrophages in response to endotoxin or a number of other bacterial or protozoal products. The released cachectin acts as a hormone, binding to specific high affinity receptors and eliciting biological responses. In the adipocyte anabolic enzymes such as lipoprotein lipase are suppressed through the selective inhibition of mRNA production. An intriguing aspect of cachectin is its pivotal role in the pathogenesis of endotoxin-induced shock. Cachectin causes fever and anorexia and can induce lethal shock and tissue injury in experimental animals. During its chemical characterization cachectin was shown to be identical to tumour necrosis factor (TNF), a macrophage protein that kills tumour cells. This finding emphasizes the extensive range of effects associated with this protein. Cachectin has many properties in common with interleukin 1 but binds to a different receptor and lacks structural homology. Presumably, low levels of cachectin help the host in its battle to remove invasive pathogens, but extensive production of cachectin can lead to shock and catabolic stress hormone responses. These findings have added a new dimension to the biological properties of cachectin, its production, and its role in cachexia and shock.