The balance of inhibitory and excitatory cytokines is differently regulated in vivo and in vitro among therapy resistant epilepsy patients

Purpose: Excessive neuronal activity and seizures directly stimulate cytokine expression. In this study we investigated cytokine production in circulating blood and peripheral blood mononuclear cells (PBMC) in order to assess the cellular origin of these cytokines in patients with therapy resistant epilepsy. Methods: We compared the levels of plasma IL-1beta, IL-1Ra and IL-6 in 10 patients with therapy resistant localization-related epilepsy and in healthy volunteers. The spontaneous and exogenously stimulated production of these cytokines was studied in PBMC cultures using EIA. Moreover, cell-specific cytokine production was studied using flow cytometry. Results: Highly pro-inflammatory cytokine profile (high IL-6, low IL-1Ra and low IL-1Ra/IL-1beta ratio) was observed in plasma from patients with epilepsy. Spontaneous and LPS stimulated cytokine release was similar in PBMC cultures of patients and control subjects. When cells were stimulated with OKT3 the cytokine response profiles in patients with epilepsy were almost opposite (anti-inflammatory) to the profile which was observed in circulating blood. Low IL-6 was observed in cell cultures of patients when stimulated with PDBu + A23187. Flow cytometric analysis revealed that the percentages of IL-1beta, IL-1Ra and IL-6 positive monocytes were similar in patients and control subjects. Conclusions: Patients with therapy resistant epilepsy display a pro-inflammatory profile of plasma cytokines without any evidence of increased production from PBMC. These results suggest that the most likely origin for these cytokines is the brain, where cytokines can exert neuromodulatory functions. (C) 2004 Elsevier B.V. All rights reserved.