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Abstract
Previous results demonstrated that capsaicin induces the reversible tight junctions (TJ) opening via cofilin activation. The present study investigated the mechanisms underlying the reversible TJ opening and compared the effect to the irreversible opening induced by actin inhibitors. Capsaicin treatment induced the F-actin alteration unique to capsaicin compared to actin-interacting agents such as latrunculin A, which opens TJ irreversibly. Along with TJ opening, capsaicin decreased the level of F-actin at bicellular junctions but increased it at tricellular junctions accompanied with its concentration on the apical side of the lateral membrane. No change in TJ protein localization was observed upon exposure to capsaicin, but the amount of occludin was decreased significantly. In addition, cosedimentation analyses suggested a decrease in the interactions forming TJ, thereby weakening TJ tightness. Introduction of cofilin, LIMK and occludin into the cell monolayers confirmed their contribution to the transepithelial electrical resistance decrease. Finally, exposure of monolayers to capsaicin augmented the paracellular passage of both charged and uncharged compounds, as well as of insulin, indicating that capsaicin can be employed to modulate epithelial permeability. Our results demonstrate that capsaicin induces TJ opening through a unique mechanism, and suggest that it is a new type of paracellular permeability enhancer.
Highlights
The oral route of drug administration is considered to be the most convenient and the preferred choice for patients
We previously showed that capsaicin decreases the transepithelial electrical resistance (TER) in human intestinal Caco-2 cell monolayers
To investigate whether capsaicin is capable of opening tight junctions (TJ) in other types of cells, Mandin Darby Canine Kidney (MDCK) monolayers were used and the degree of tightness of the TJ was measured by assessing the TER
Summary
The oral route of drug administration is considered to be the most convenient and the preferred choice for patients. Oral administration of peptide/protein drugs encounters several obstacles. It is a great challenge to deliver hydrophilic macromolecules, as they cannot diffuse across through the lipid bilayer of the cell membrane because of their high molecular weight and hydrophilicity [1]. Enhancing the paracellular delivery of hydrophilic functional molecules including protein/peptide drugs has received considerable attention [2]. Polarized epithelial cells form tight junctions (TJ) that restrict the paracellular movement of solutes and macromolecules across epithelia. TJ are located at the apicolateral plasma membranes of adjacent cells [3] and are composed of a complex combination of transmembrane integral proteins including occludin, claudins and tricellulin, along with several intracellular proteins such as zonula occludens-1 (Zo-1), which connects the transmembrane proteins to the actin cytoskeleton [4]. TJ proteins and the cytoskeleton are key regulators of the TJ, and TJ proteins are connected to a belt-like cytoskeleton structure to form the structural support for the TJ [5]
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