Synergy between tumor necrosis factor alpha and interleukin-1 in the induction of sickness behavior in mice

Psychoneuroendocrinology. 1994;19(2):197-207. doi: 10.1016/0306-4530(94)90009-4.


Like interleukin-1, recombinant human tumor necrosis factor alpha (TNF alpha) has been found to decrease social exploration and induce weight loss in mice in a dose and time-dependent manner. The present study was carried out to study the interaction between these two cytokines. Mice were injected IP with subthreshold doses of TNF alpha (2.5 micrograms/mouse) and IL-1 beta (50 ng/mouse). Social exploration was decreased 2 and 4 h after injection of TNF and IL-1, but body weight was not affected. Subthreshold doses of TNF alpha (90 ng/mouse) and IL-1 beta (100 pg/mouse) were also injected intracerebroventricularly (ICV). Social exploration was decreased 1.5 and 3 h after injections of the two cytokines and body weight was decreased for 6 h. To test the possibility of central induction of IL-1 by TNF alpha, mice pretreated with IL-1 receptor antagonist (IL-1ra, 1.8 micrograms/mouse, ICV) were injected with 90 ng TNF alpha. Pretreatment with IL-1ra antagonized the depressive effect of TNF alpha on behavior, but had no effect on weight loss induced by this cytokine. These results suggest that TNF alpha-induced behavioral alterations are mediated by endogenously released IL-1, whereas metabolic changes are dependent on the release of other cytokines.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Arousal / drug effects*
  • Body Weight
  • Dose-Response Relationship, Drug
  • Drug Synergism
  • Exploratory Behavior / drug effects*
  • Interleukin 1 Receptor Antagonist Protein
  • Interleukin-1 / pharmacology*
  • Male
  • Mice
  • Motor Activity / drug effects*
  • Recombinant Proteins / pharmacology
  • Sialoglycoproteins / pharmacology
  • Social Behavior
  • Tumor Necrosis Factor-alpha / pharmacology*


  • IL1RN protein, human
  • Il1rn protein, mouse
  • Interleukin 1 Receptor Antagonist Protein
  • Interleukin-1
  • Recombinant Proteins
  • Sialoglycoproteins
  • Tumor Necrosis Factor-alpha