Elevated interleukin-12B is associated with increased seizure susceptibility: insights from two-sample Mendelian randomization and in vivo experiment

Objective To evaluate the causality between interleukins (ILs) and epilepsy using Mendelian randomization (MR) analysis. Furthermore, in vivo experiments were conducted to validate the results. Methods All summary datasets for MR analysis were sourced from publicly available genome-wide association studies. MR analysis was utilized to assess the causal relationship between ILs and generalized epilepsy (GE). Comprehensive sensitivity analyses were carried out to verify the robustness of the findings. Additionally, seizure threshold, seizure score, and video electroencephalography recordings were conducted to evaluate the effect of IL-12B on seizure susceptibility. Results The MR results revealed a causal effect of IL-12B on GE (IVW: β = 0.17, OR = 1.18, 95% CI = 1.05–1.34, p = 0.007). Estimated effects derived from supplementary methods were consistent with this finding. The robustness of these results was confirmed by sensitivity tests. Mice pretreated with IL-12B exhibited a significantly decreased seizure threshold, higher seizure scores, shortened latency to SE, and reduced survival probability compared with those pretreated with saline. Conclusion Our study demonstrated that elevated serum levels of IL-12B are associated with an increased risk of GE. The results were validated through in vivo experiments. These results underscore the crucial role of targeted anti-inflammatory therapy in the treatment of epilepsy.