The role of interleukin-1 and tumor necrosis factor α in the neurochemical and neuroendocrine responses to endotoxin

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Abstract

Both interleukin-1 (IL-1) and endotoxin (lipopolysaccharide, LPS) are potent activators of the hypothalamo-pituitary-adrenal (HPA) axis, and they also increase cerebral norepinephrine metabolism and tryptophan. Injections of cause macrophages to synthesize and release various cytokines, including IL-1 and tumor necrosis factor α (TNFα). The hypothesis that macrophage production of IL-1 mediates the HPA-activating effect of LPS was tested in mice using the IL-1-receptor antagonist protein (IRAP). Administration of IRAP largely prevented the effects of IL-1α or IL- 1β on the elevation of plasma corticosterone and the concomitant increase in hypothalamic norepinephrine metabolism, but failed to alter the responses to LPS. IRAP did not prevent the increases in brain tryptophan that occurred after treatment with IL-1 or LPS. Recombinant human TNFa, TNFβ, IL-6, and interferon-a injected intraperitoneally failed to activate the HPA axis, but mouse TNFa was effective by this route, and human TNFα, TNFβ, and IL-6 were effective intravenously. None of these cytokines was as potent as IL-1. Pretreatment with an antibody specific for mouse TNFα, either alone or in combination with IRAP, also failed to prevent the elevation of plasma corticosterone by LPS. Thus, either IL-1 and TNFα are not involved in the HPA and noradrenergic responses to LPS, or there are alternative (redundant) pathways by which LPS can activate the HPA axis. © 1992.

Author-supplied keywords

  • Corticosterone
  • Endotoxin
  • Hypothalamus
  • Interleukin-1
  • Interleukin-1-receptor antagonist protein (IRAP)
  • Lipopolysaccharide
  • MHPG
  • Tryptophan
  • Tumor necrosis factor

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Authors

  • Adrian J. Dunn

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