Metabolic effects of proinflammatory cytokines

Abstract

The metabolic responses to trauma are well characterized and there is growing evidence supporting an important role for cytokines in its pathogenesis. Interleukin-1 (IL-1), Interleukin-6 (IL-6), and Tumour necrosis factor (TNF) are synthesized in the brain, and other tissues, in trauma. In order to test the hypothesis that these cytokines play an important role in the metabolic responses associated with trauma, the effects of chronic cerebroventricular and peripheral infusions of IL-1, IL-6, and TNF on protein metabolism, weight loss, anorexia, and pyrexia in Sprague-Dawley rats were examined. Specifically the aims of these investigations were: 1. To examine the effect of chronic central nervous system exposure to the proinflammatory cytokines IL-1, IL-6, and TNF. 2. To investigate the role of anorexia in the catabolic responses to centrally infused IL-1. 3. To investigate the effects of IL-1 on the hypothalamic-pituitary-adrenal axis. 4. To investigate the role of glucocorticoids in the metabolic effects produced by chronic central infusion of IL-1. 5. To examine the metabolic effects of increasing doses of chronic peripherally infused IL-1 and to distinguish between those responses mediated centrally and those mediated outside the blood-brain-barrier. The major findings of these studies were: 1. IL-1, but not IL-6 in the same dose, nor TNF in a lower dose, produced net protein catabolism, weight loss, and pyrexia in excess of that produced by anorexia alone. 2. Furthermore the loss of weight and nitrogen did not require sustained elevations of glucocorticoids, as IL-1 infusion in corticosterone-replaced, adrenalectomized rats resulted in similar losses of weight and nitrogen as observed in sham-adrenalectomized animals infused with IL-1. 3. Peripheral infusion of increasing doses of IL-1 mimicked the effects of increasing injury with low doses causing a mild acute phase response (as assessed by a fall in serum iron and albumin and a leucocytosis) and larger doses causing net protein catabolism and weight loss. An attempt was made to distinguish between the central and peripherally mediated metabolic effects of IL-1 using a novel model utilizing peripheral infusions of IL-1 and central infusions of IL-1 receptor antagonist. Using this model the data were consistent with the hypotheses that pyrexia is mediated inside and outside the blood-brain barrier and that leucocytosis is mediated by a direct peripheral effect, probably on the bone-marrow. In conclusion, centrally produced IL-1 may play an important role in the metabolic responses associated with trauma and this is in excess of the anorexia and adrenocortical activation produced by centrally acting IL-1. Peripherally produced IL-1 may play a role in various organs such as the bone-marrow and the liver to produce other features of the metabolic responses associated with injury.