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Mesial temporal lobe epilepsy (mTLE) is a chronic and often treatment-refractory brain disorder characterized by recurrent seizures originating from the hippocampus. The pathogenic mechanisms underlying mTLE remain largely unknown. Recent clinical and experimental evidence supports a role of various inflammatory mediators in mTLE. Here, we performed protein expression profiling of 40 inflammatory mediators in surgical resection material from mTLE patients with and without hippocampal sclerosis, and autopsy controls using a multiplex bead-based immunoassay. In mTLE patients we identified 21 upregulated inflammatory mediators, including 10 cytokines and 7 chemokines. Many of these upregulated mediators have not previously been implicated in mTLE (for example, CCL22, IL-7 and IL-25). Comparing the three patient groups, two main hippocampal expression patterns could be distinguished, pattern I (for example, IL-10 and IL-25) showing increased expression in mTLE + HS patients compared to mTLE-HS and controls, and pattern II (for example, CCL4 and IL-7) showing increased expression in both mTLE groups compared to controls. Upregulation of a subset of inflammatory mediators (for example, IL-25 and IL-7) could not only be detected in the hippocampus of mTLE patients, but also in the neocortex. Principle component analysis was used to cluster the inflammatory mediators into several components. Follow-up analyses of the identified components revealed that the three patient groups could be discriminated based on their unique expression profiles. Immunocytochemistry showed that IL-25 IR (pattern I) and CCL4 IR (pattern II) were localized in astrocytes and microglia, whereas IL-25 IR was also detected in neurons. Our data shows co-activation of multiple inflammatory mediators in hippocampus and neocortex of mTLE patients, indicating activation of multiple pro- and anti-epileptogenic immune pathways in this disease.

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.