Electric Fields and IL-18 synergistically Modulate Dendritic Cells Sensitization

Oral dendritic cells (DCs) are pivotal in mediating the oral mucosal immune response. Following oral infections, DCs migration and cytokine production are dependent on the dynamic exogenous and endogenous stimuli. IL-18 is highly expressed during infection and has been indicated as the key regulator in DC migration in vivo. Disruption of an epithelial barrier generates endogenous electric fields (EFs) instantly, which induces directed migration of cells. It is unknown how EFs act on DC to modify their response to cytokines stimulation during infection and repair. Objectives: The aim of this study is to investigate the mechanism of EF-modulated sensitization of DCs in response to IL-18. Methods: Time-lapse migration assays were performed on KG-1 cells, differentiated DCs, primary cultured DCs and skin explants, either treated with IL-18, EFs or both stimuli. IFN-γ production was analysed by a modified transwell assay. IL-18 receptor (IL-18R) polarization and actin polymerization were investigated by immunocytochemical staining. IL-18R was tagged with a GFP to track receptor redistribution in real time. IL-18R expression and p38 phosphorylation were analysed by Western Blot. Results: DCs migration induced by IL-18 from mouse skin was enhanced significantly by EFs. IL-18 and EFs also synergistically increased DC motility in vitro, associated with increased actin polymerization. IL-18Rα was required for EFs induced directional DCs migration and IFN-γ production in KG-1 cells. EFs increased IL-18 activity via p38 phosphorylation due to increased co-localisation of IL-18R α and β chains at the leading edge rather than upregulated IL-18R expression. Conclusions: EF-induced co-localisation of IL-18R serves as the mechanism of enhanced IL-18 induced DCs migration and cytokine production.  Those results demonstrate that physiological EFs may help the host immune response by promoting DC activity. Sensitization of DC has clinical implication in treatment of oral infection and cancers.