The transcription factor nuclear factor interleukin 6 mediates pro- and anti-inflammatory responses during LPS-induced systemic inflammation in mice

Brain Behav Immun. 2015 Aug;48:147-64. doi: 10.1016/j.bbi.2015.03.008. Epub 2015 Mar 23.

Abstract

The transcription factor nuclear factor interleukin 6 (NF-IL6) plays a pivotal role in neuroinflammation and, as we previously suggested, hypothalamus-pituitary-adrenal-axis-activation. Here, we investigated its contribution to immune-to-brain communication and brain controlled sickness symptoms during lipopolysaccharide (LPS)-induced (50 or 2500 μg/kg i.p.) systemic inflammation in NF-IL6-deficient (KO) or wildtype mice (WT). In WT LPS induced a dose-dependent febrile response and reduction of locomotor activity. While KO developed a normal fever after low-dose LPS-injection the febrile response was almost abolished 3-7 h after a high LPS-dose. High-dose LPS-stimulation was accompanied by decreased (8 h) followed by enhanced (24 h) inflammation in KO compared to WT e.g. hypothalamic mRNA-expression including microsomal prostaglandin E synthase, inducible nitric oxide synthase and further inflammatory mediators, neutrophil recruitment to the brain as well as plasma levels of inflammatory markers such as IL-6 and IL-10. Interestingly, KO showed reduced locomotor activity even under basal conditions, but enhanced locomotor activity to novel environment stress. Hypothalamic-pituitary-adrenal-axis-activity of KO was intact, but tryptophan-metabolizing enzymes were shifted to enhanced serotonin production and reuptake. Overall, we showed for the first time that NF-IL6 plays a dual role for sickness response and immune-to-brain communication: acting pro-inflammatory at 8h but anti-inflammatory at 24 h after onset of the inflammatory response reflecting active natural programming of inflammation. Moreover, reduced locomotor activity observed in KO might be due to altered tryptophan metabolism and serotonin reuptake suggesting some role for NF-IL6 as therapeutic target for depressive disorders.

Keywords: Cytokines; Fever; Hypothalamic–pituitary–adrenal-axis; Immune-to-brain signaling; Lipopolysaccharide; NF-IL6; Neuroinflammation; Neutrophil granulocytes; Serotonin; Tryptophan metabolism.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Brain / drug effects
  • Brain / metabolism*
  • CCAAT-Enhancer-Binding Protein-delta / genetics
  • CCAAT-Enhancer-Binding Protein-delta / metabolism*
  • Dose-Response Relationship, Drug
  • Female
  • Hypothalamo-Hypophyseal System / metabolism
  • Illness Behavior / drug effects*
  • Inflammation / chemically induced
  • Inflammation / metabolism*
  • Lipopolysaccharides / pharmacology
  • Male
  • Mice
  • Mice, Knockout
  • Motor Activity / drug effects
  • Neutrophil Infiltration / drug effects
  • Pituitary-Adrenal System / metabolism

Substances

  • Lipopolysaccharides
  • CCAAT-Enhancer-Binding Protein-delta