The Pro-inflammatory Cytokine Interleukin-6 Regulates Nanoparticle Transport Across Model Follicle-Associated Epithelium Cells

Abstract

The aim of this study was to investigate whether the pro-inflammatory cytokines improved the function of the cell monolayer model of the human follicle-associated epithelium (FAE) of co-culture of Caco-2 cells on permeable filters with Raji B-cells underneath from the viewpoint of particle transport. Exposure to tumor necrosis factor-α resulted in an almost maintained epithelial integrity/paracellular permeability combined with an increased nanoparticle transport in a dose-dependent manner while the effects of interleukin (IL)-1β were limited. Exposure to IL-6 significantly enhanced the nanoparticle transport with the limited disruption of the cell monolayer integrity. The addition of IL-6 or tumor necrosis factor-α to Caco-2 monolayers without Raji B-cells did not enhance nanoparticle transport. In our IL-6 treated FAE model, the nanoparticle transport almost disappeared at 4°C or after the addition of 5-(N-ethyl-N-isopropyl) amiloride, an inhibitor of macropinocytosis. Furthermore, IgA binding, presumably by a secretory IgA receptor, a marker of M-cells was observed on the apical side of our model FAE. These results indicate that the combined effect of IL-6 with unknown factors from Raji-B cells made the FAE model more functional with regard to nanoparticle transport. The IL-6 enhanced FAE model will be a useful platform for nanoparticle drug delivery research across the intestinal epithelium.