Are the catabolic effects of tumor necrosis factor mediated by glucocorticoids?
K. Mealy, J. J. van Lanschot, B. G. Robinson, J. Rounds and D. W. Wilmore
Department of Surgery, Brigham and Woman's Hospital, Harvard Medical School, Boston, Mass. 02115.
The effect of tumor necrosis factor (TNF) on the hypothalamic-adrenal
stress response was determined by infusion of TNF, 0, 2 x 10(5), and 4 x
10(5) U/kg per 24 hours, in parenterally fed male Wistar rats. Following
infusions over 1 to 6 days, adrenal weight was increased with increasing
dosage of TNF. Tumor necrosis factor at a dosage of 4 x 10(5) U/kg per 24
hours increased the plasma corticotropin level over the same period. In a
further series of experiments the metabolic effects of TNF were compared
with the effects of corticosterone, the predominant glucocorticoid in the
rat. In comparison with controls, rats given corticosterone (75 mg
subcutaneously) or TNF (2 x 10(5) U/kg per 24 hours) demonstrated decreased
nitrogen balance and diminished carcass nitrogen content over a 6-day
period. Tumor necrosis factor alone, however, induced a significant
increase in liver nitrogen content and diminished jejunal mucosa DNA and
protein levels in comparison with the control and corticosterone groups.
Finally, adrenalectomized animals receiving basal corticosterone
replacement were infused with TNF. Urinary nitrogen loss was significantly
diminished in these animals compared with sham adrenalectomized controls,
indicating that an intact adrenal stress response is necessary for the
increased nitrogen loss following TNF infusion. Tumor necrosis factor may
exert an important regulatory influence on the interorgan substrate flux
that occurs during critical illness. The effects of TNF on skeletal muscle
proteolysis can be simulated by adrenal glucocorticoid administration. The
effects of this cytokine on visceral organs appear to be unique to TNF and
cannot be reproduced by the administration of glucocorticoids alone.
