The Pro-inflammatory Cytokine Interleukin-6 Regulates Nanoparticle Transport Across Model Follicle-Associated Epithelium Cells.
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.
Department of Pharmacy, Uppsala University, Husargatan 3, Box 580, Uppsala 751 23, Sweden; BA Project, Formulation Research Institute, Otsuka Pharmaceutical Company, Ltd., 224-18 Ebino, Hiraishi, Kawauchi-cho, Tokushima 771-0182, Japan. Electronic address: Miyake.Masateru@otsuka.jp.
Masateru
M
Miyake
Department of Pharmacy, Uppsala University, Husargatan 3, Box 580, Uppsala 751 23, Sweden.
Eva
E
Ragnarsson
Department of Pharmacy, Uppsala University, Husargatan 3, Box 580, Uppsala 751 23, Sweden.
Daisuke
D
Nakai
Department of Pharmacy, Uppsala University, Husargatan 3, Box 580, Uppsala 751 23, Sweden.
Per
P
Artursson
D000584:Amiloride / Q000031:analogs & derivatives / Q000494:pharmacology; D001402:B-Lymphocytes / Q000378:metabolism; D018938:Caco-2 Cells; D004305:Dose-Response Relationship, Drug; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism*; D018859:Hair Follicle / Q000378:metabolism; D006801:Humans; D007070:Immunoglobulin A / Q000378:metabolism; D015850:Interleukin-6 / Q000494:pharmacology*; D007413:Intestinal Mucosa / Q000378:metabolism; D008353:Mannitol / Q000378:metabolism; D053758:Nanoparticles / Q000378:metabolism*; D010539:Permeability; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
C508600:IL6 protein, human; D007070:Immunoglobulin A; D015850:Interleukin-6; D014409:Tumor Necrosis Factor-alpha; D008353:Mannitol; D000584:Amiloride; C039614:ethylisopropylamiloride
IL-6; M-cells; absorption improving; nanoparticle; pro-inflammatory cytokine; sIgA receptor