Tumor necrosis factor and regulation of metabolism in infection: role of systemic versus tissue levels.
Tumor necrosis factor (TNF), a pleiotropic cytokine, is produced by macrophages and other cells in a variety of infectious and noninfectious diseases. Ultimately, the net biological effects of TNF may be either beneficial or injurious to the host. For instance, during overwhelming bacterial infection, the acute overproduction of TNF causes septic shock syndrome characterized by hypotension, organ failure, and death. Antibodies against TNF prevent and reverse these sequelae in animal models of septic shock, and their use in humans is currently under investigation in clinical trials. In another instance, TNF has been implicated as an injurious mediator in the state of malnutrition that complicates the course of chronic infection and cancer. Termed cachexia, this chronic syndrome inevitably causes the afflicted host to succumb from weight loss, anorexia, and catabolism of protein and lipid. Experimental studies of animals exposed to TNF for protracted periods indicate that this cytokine is capable of causing cachexia, and the biochemical basis for these catabolic changes has been identified. More recent data indicate that the detrimental metabolic effects of TNF are not dependent upon its circulating levels in the bloodstream, but rather are dependent upon its actions locally in vital organs (e.g., brain). Thus, the metabolic basis for cachexia in infection may be largely dependent upon the amount of cytokine produced in metabolically important tissues. As a result, circulating TNF levels in cachectic patients may not accurately reflect the metabolic state of the host, and do not correlate to weight loss.(ABSTRACT TRUNCATED AT 250 WORDS)
Tracey
K J
KJ
Division of Neurosurgery, New York Hospital-Cornell Medical Center, New York 10021.
Cerami
A
A
D000818:Animals; D002100:Cachexia / Q000378:metabolism; D003141:Communicable Diseases / Q000503:physiopathology*; D006801:Humans; D008660:Metabolism / Q000187:drug effects; D012772:Shock, Septic / Q000503:physiopathology*; D014018:Tissue Distribution; D014409:Tumor Necrosis Factor-alpha / Q000502:physiology*
D014409:Tumor Necrosis Factor-alpha