IL-1β reactivity and the development of severe fatigue after military deployment: a longitudinal study.
BACKGROUND
It has been suggested that pro-inflammatory cytokine signaling to the brain may contribute to severe fatigue. We propose that not only the level of circulating cytokines, but also increased reactivity of target cells to cytokines contributes to the effect of cytokines on behavior. Based on this concept, we assessed the reactivity of peripheral blood cells to IL-1β in vitro as a novel approach to investigate whether severe fatigue is associated with increased pro-inflammatory signaling.


METHODS
We included 504 soldiers before deployment to a combat-zone. We examined fatigue severity and the response to in vitro stimulation with IL-1β prior to deployment (T0), and 1 (T1) and 6 months (T2) after deployment. IL-8 production was used as read-out. As a control we determined LPS-induced IL-8 production. The presence of severe fatigue was assessed with the Checklist Individual Strength (CIS-20R). Differences in dose-response and the longitudinal course of IL-1β and LPS-induced IL-8 production and fatigue severity were investigated using repeated measures ANOVA.


RESULTS
At T2, the group who had developed severe fatigue (n = 65) had significantly higher IL-1β-induced IL-8 production than the non-fatigued group (n = 439). This group difference was not present at T0, but developed over time. Longitudinal analysis revealed that in the non-fatigued group, IL-1β-induced IL-8 production decreased over time, while IL-1β-induced IL-8 production in the fatigued group had not decreased. To determine whether the observed group difference was specific for IL-1β reactivity, we also analyzed longitudinal LPS-induced IL-8 production. We did not observe a group difference in LPS-induced IL-8 production.


CONCLUSIONS
Collectively, our findings indicate that severe fatigue is associated with a higher reactivity to IL-1β. We propose that assessment of the reactivity of the immune system to IL-1β may represent a promising novel method to investigate the association between behavioral abnormalities and pro-inflammatory cytokine signaling.
Laboratory of Neuroimmunology and Developmental Origins of Disease, University Medical Center Utrecht, Utrecht, The Netherlands.
Mirjam
M
van Zuiden
Annemieke
A
Kavelaars
Karima
K
Amarouchi
Mirjam
M
Maas
Eric
E
Vermetten
Elbert
E
Geuze
Cobi J
CJ
Heijnen
D000328:Adult; D000704:Analysis of Variance; D001773:Blood Cells / Q000187:drug effects / Q000378:metabolism; D015331:Cohort Studies; D004305:Dose-Response Relationship, Drug; D005221:Fatigue / Q000097:blood*; D005260:Female; D006801:Humans; D053583:Interleukin-1beta / Q000097:blood* / Q000494:pharmacology; D016209:Interleukin-8 / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology; D008297:Male; D008889:Military Personnel / Q000523:psychology*; D009426:Netherlands; D013223:Statistics as Topic; D011795:Surveys and Questionnaires; D013997:Time Factors; D055815:Young Adult
D053583:Interleukin-1beta; D016209:Interleukin-8; D008070:Lipopolysaccharides