Involvement of interleukin-1 type 1 receptors in lipopolysaccharide-induced sickness responses

Brain Behav Immun. 2017 Nov:66:165-176. doi: 10.1016/j.bbi.2017.06.013. Epub 2017 Jun 24.


Sickness responses to lipopolysaccharide (LPS) were examined in mice with deletion of the interleukin (IL)-1 type 1 receptor (IL-1R1). IL-1R1 knockout (KO) mice displayed intact anorexia and HPA-axis activation to intraperitoneally injected LPS (anorexia: 10 or 120µg/kg; HPA-axis: 120µg/kg), but showed attenuated but not extinguished fever (120µg/kg). Brain PGE2 synthesis was attenuated, but Cox-2 induction remained intact. Neither the tumor necrosis factor-α (TNFα) inhibitor etanercept nor the IL-6 receptor antibody tocilizumab abolished the LPS induced fever in IL-1R1 KO mice. Deletion of IL-1R1 specifically in brain endothelial cells attenuated the LPS induced fever, but only during the late, 3rd phase of fever, whereas deletion of IL-1R1 on neural cells or on peripheral nerves had little or no effect on the febrile response. We conclude that while IL-1 signaling is not critical for LPS induced anorexia or stress hormone release, IL-1R1, expressed on brain endothelial cells, contributes to the febrile response to LPS. However, also in the absence of IL-1R1, LPS evokes a febrile response, although this is attenuated. This remaining fever seems not to be mediated by IL-6 receptors or TNFα, but by some yet unidentified pyrogenic factor.

Keywords: ACTH; Anorexia; Corticosterone; Endothelial cells; Fever; Interleukin-1 type 1 receptor; Interleukin-6; Lipopolysaccharide; PGE(2); TNFα.

MeSH terms

  • Adrenocorticotropic Hormone / blood
  • Animals
  • Anorexia / chemically induced
  • Anorexia / metabolism*
  • Brain / metabolism
  • Corticosterone / blood
  • Eating
  • Endothelial Cells / metabolism
  • Female
  • Fever / chemically induced
  • Fever / metabolism*
  • Hypothalamus / metabolism
  • Illness Behavior*
  • Inflammation / blood
  • Inflammation / complications
  • Inflammation Mediators / blood
  • Lipopolysaccharides / administration & dosage
  • Male
  • Mice, Knockout
  • Receptors, Interleukin-1 Type I / genetics
  • Receptors, Interleukin-1 Type I / metabolism*


  • Inflammation Mediators
  • Lipopolysaccharides
  • Receptors, Interleukin-1 Type I
  • Adrenocorticotropic Hormone
  • Corticosterone