Selective increase of cerebrospinal fluid IL-6 during experimental systemic inflammation in humans: association with depressive symptoms

Abstract

Systemic inflammation is accompanied by profound behavioral and mood changes that resemble symptoms of depression. Findings in animals suggest that pro-inflammatory cytokines released by activated immune cells in the periphery evoke these behavioral symptoms by driving inflammatory changes in the brain. However, experimental data in humans are lacking. Here we demonstrate in healthy male volunteers (10 endotoxin treated, 8 placebo treated) that intravenous administration of low-dose endotoxin (0.8 ng/kg body weight), a prototypical pathogen-associated molecular pattern that activates the innate immune system, not only induces a significant increase in peripheral blood cytokine concentrations (that is, tumor necrosis factor-α, interleukin (IL)-6, IL-10) but also results, with some latency, in a robust and selective increase of IL-6 in the cerebrospinal fluid (CSF). Moreover, we found a strong association between the endotoxin-induced increase of IL-6 in the CSF and the severity of mood impairment, with larger increases in CSF IL-6 concentration followed by a greater deterioration in mood. Taken together, these findings suggest that the appearance of depressive symptoms in inflammatory conditions might be primarily linked to an increase in central IL-6 concentration, identifying IL-6 as a potential therapeutic target in mood disorders.

Effects of inflammation on social processes and implications for health

“…Furthermore, another study reported increases in the proinflammatory cytokine IL-6 in human cerebrospinal fluid following endotoxin administration. 11 Together, these findings suggest that endotoxin administration and subsequent immune activation may end up impacting social behavior via central nervous system mechanisms.…”

Role of Interleukin-6 in Depressive Disorder

“…Study by Engler et al directly tested the intravenous administration of low-dose endotoxin, one of the most important bacterial components contributing to the inflammatory process, in healthy male volunteers [40]. They found selective increase of IL-6 in the cerebrospinal fluid (CSF) and a strong association between the increase of CSF IL-6 levels and the endotoxin-induced mood deterioration, suggesting that increase in the central IL-6 concentrations may contribute to depression pathogenesis.…”

„Old Friends“, Immunregulation und Stressresilienz

“…Dies deckt sich mit Daten, die zeigen, dass Frauen im Vergleich zu Männern häufiger an affektiven Erkrankungen leiden [199,200]. Bedeutsam sind auch die Ergebnisse von Engler und Kollegen, die zeigen, dass die intravenöse Verabreichung von niedrig dosiertem Endotoxin (0,8 ng/kg Körpergewicht) in gesunden männlichen Probanden nicht nur einen signifikanten Anstieg der Plasmakonzentration von TNF, IL-6 und IL-10 bewirkt, sondern auch zu einem verzögerten aber verlässlichen und selektiven Anstieg von IL-6 in der Zerebrospinalflüssigkeit führt [201]. Letzterer war stark positiv mit der Schwere der Gemütsbeeinträchtigungen assoziiert [201], was darauf hindeutet, dass das Auftreten depressiver Symptome bei entzündlichen Erkrankungen in erster Linie auf einem Anstieg an IL-6 im Gehirn zurückzuführen sein könnte.…”