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.