Metabolic responses to cachectin/TNF. A brief review

Ann N Y Acad Sci. 1990;587:325-31. doi: 10.1111/j.1749-6632.1990.tb00173.x.

Abstract

Cachectin/tumor necrosis factor (TNF-alpha) is a macrophage-secreted cytokine initially found to be a lipoprotein lipase-suppressing serum factor in cachectic, parasite-infected animals. Cloning of the cDNA encoding the gene for cachectin enabled biosynthesis of recombinant human cachectin and proof that the protein is identical to TNF-alpha. Numerous biological activities have subsequently been attributed to this pluripotent cytokine. In addition to suppressing LPL, cachectin/TNF mediates decreased lipogenic enzyme synthesis in adipocytes, causing a state of "cellular cachexia" in vitro. Similarly, catabolic cellular energy responses are induced by cachectin/TNF in cultured skeletal muscle cells which exhibit accelerated glycogenolysis, enhanced lactate production, and increased expression of hexose transporters. Persistent cachectin/TNF production occurs in chronic infection and malignancy, and chronic exposure induces a cachexia syndrome characterized by anorexia, weight loss, and anemia. Acute systemic appearance of cachectin/TNF is capable of inducing a state of lethal shock, disseminated hemorrhagic necrosis, catabolic hormone release, and multiple organ injury. Inhibiting the toxic effects of cachectin/TNF with monoclonal anti-cachectin antibodies during overwhelming Gram-negative bacteremia confers protection against septic shock. In these studies, the unprotected controls succumbed within hours, but baboons immunized against cachectin/TNF did not develop the characteristic increases of IL-1, IL-6, or catabolic stress hormones and did not die, suggesting that cachectin/TNF is a pivotal, proximal factor in the humoral cascade mediating septic shock syndrome. Recent evidence indicates that when produced in lesser quantities, cachectin/TNF may participate in the degradative and reparative mechanisms of physiological tissue remodelling and homeostasis. Future studies of the immunological and metabolic effects of cachectin/TNF should lead to a better understanding of the pathogenesis of infection and inflammation.

Publication types

  • Review

MeSH terms

  • Animals
  • Cachexia / metabolism
  • Humans
  • Sepsis / metabolism
  • Tumor Necrosis Factor-alpha / isolation & purification
  • Tumor Necrosis Factor-alpha / metabolism*
  • Tumor Necrosis Factor-alpha / physiology

Substances

  • Tumor Necrosis Factor-alpha