Role of interleukin-1beta and tumour necrosis factor-alpha in lipopolysaccharide-induced sickness behaviour: a study with interleukin-1 type I receptor-deficient mice

Eur J Neurosci. 2000 Dec;12(12):4447-56.


Interleukin-1 (IL-1) mediates symptoms of sickness during the host response to infection. IL-1 exerts its effects via several subtypes of receptors. To assess the role of IL-1 receptor type I (IL-1RI) in the sickness-inducing effects of IL-1, IL-1beta and the cytokine inducer lipopolysaccharide were administered to IL-1RI-deficient mice (IL-1RI-/-). Sickness was assessed by depression of social exploration, anorexia, immobility and body weight loss. IL-1RI-/- mice were resistant to the sickness-inducing effects of IL-1beta administered intraperitoneally (2 microg/mouse) and intracerebroventricularly (2 ng/mouse), but still fully responsive to lipopolysaccharide administered intraperitoneally (2.5 microg/mouse) and intracerebroventricularly (3 ng/mouse). The sensitivity of IL-1RI-/- mice to lipopolysaccharide was not due to a higher brain expression of proinflammatory cytokines other than IL-1, since lipopolysaccharide-induced expression of brain IL-1 beta, tumour necrosis factor-alpha (TNF-alpha) and IL-6 transcripts were identical in IL-1RI-/- and control mice when measured by semiquantitative reverse-transcriptase polymerase chain reaction 1 h after treatment. Blockade of TNF-alpha action in the brain by intracerebroventricular administration of a fragment of the soluble TNF receptor, TNF binding protein (3.6 microg/mouse), attenuated the depressive effects of intraperitoneal injection of lipopolysaccharide (1 microg/mouse) on behaviour in IL-1RI-/- but not in control mice. Since IL-1RI-/- mice were not more sensitive to intracerebroventricularly TNF-alpha (50 ng) than control mice, these results indicate that IL-1RI mediates the sickness effect of IL-1 and that TNF-alpha simply replaces IL-1 when this last cytokine is deficient.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Brain / drug effects
  • Brain / physiology*
  • Brain / physiopathology
  • Exploratory Behavior*
  • Gene Expression Regulation / drug effects
  • Injections, Intraperitoneal
  • Injections, Intraventricular
  • Interleukin-1 / genetics
  • Interleukin-1 / pharmacology
  • Interleukin-1 / physiology*
  • Interleukin-6 / genetics
  • Interleukin-6 / physiology
  • Lipopolysaccharides / administration & dosage
  • Lipopolysaccharides / toxicity*
  • Mice
  • Mice, Inbred C57BL
  • Mice, Inbred Strains
  • Mice, Knockout
  • Receptors, Interleukin-1 / deficiency
  • Receptors, Interleukin-1 / genetics
  • Receptors, Interleukin-1 / physiology*
  • Receptors, Interleukin-1 Type I
  • Reverse Transcriptase Polymerase Chain Reaction
  • Social Behavior*
  • Tumor Necrosis Factor-alpha / genetics
  • Tumor Necrosis Factor-alpha / physiology*


  • Interleukin-1
  • Interleukin-6
  • Lipopolysaccharides
  • Receptors, Interleukin-1
  • Receptors, Interleukin-1 Type I
  • Tumor Necrosis Factor-alpha