Metabolic effects of cachectin/tumor necrosis factor are modified by site of production. Cachectin/tumor necrosis factor-secreting tumor in skeletal muscle induces chronic cachexia, while implantation in brain induces predominantly acute anorexia.
We have developed a murine model of wasting by injecting intracerebrally cells which continuously secrete h-cachectin/TNF (CHO-TNF) to: (a) determine the effects of cachectin/TNF produced continuously in the central nervous system (CNS), and (b) compare the metabolic effects of cachectin/TNF-secreting tumor in the brain to the cachexia caused by CHO-TNF tumor in peripheral tissue (IM). Intracerebral CHO-TNF tumors produced increased serum h-cachectin/TNF levels with lethal hypophagia and weight loss (mean survival time of 11 d); these changes were not observed in association with nonsecretory control brain tumors. The metabolic consequences of intracerebral cachectin/TNF production were indistinguishable from acute, lethal starvation: whole-body lipid content was decreased significantly but protein was conserved. Although intramuscular cachectin/TNF-secreting tumors caused similar increases of serum h-cachectin/TNF levels, profound anorexia did not develop; wasting developed after a longer period of tumor burden (50 d) with classical signs of cachexia (i.e., anemia and depletion of both protein and lipid). These studies provide a reproducible animal model of site-specific cytokine production and suggest that, regardless of serum levels, cachectin/TNF produced locally in brain influences both the rate of development of wasting and its net metabolic effects.
Tracey
K J
KJ
Laboratory of Medical Biochemistry, Rockefeller University, New York, New York.
Morgello
S
S
Koplin
B
B
Fahey
T J
TJ
Fox
J
J
Aledo
A
A
Manogue
K R
KR
Cerami
A
A
D000818:Animals; D000855:Anorexia / Q000503:physiopathology*; D000911:Antibodies, Monoclonal; D001823:Body Composition; D001835:Body Weight; D001921:Brain / Q000503:physiopathology*; D002100:Cachexia / Q000503:physiopathology*; D002460:Cell Line; D005247:Feeding Behavior / Q000502:physiology; D051379:Mice; D008819:Mice, Nude; D009132:Muscles / Q000503:physiopathology*; D009368:Neoplasm Transplantation; D009374:Neoplasms, Experimental / Q000503:physiopathology; D014409:Tumor Necrosis Factor-alpha / Q000502:physiology*
D000911:Antibodies, Monoclonal; D014409:Tumor Necrosis Factor-alpha