Regulation of bile canalicular barrier by a novel tight junction protein claudin-2 during cholestasis

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Hepatic tight junctions (TJs) play crucial roles in the barrier to keep bile in bile canaliculi away from the blood circulation, which we call the bloc d-billiary-barrier. Intrahepatic cholestasis or impairment of bile flow is an important manifestation of inherited and acquired liver disease. In rodent livers, integral TJ proteins claudin-1,-2,-3,-5 and-14 are detected. CLaudin-2 shows a lobular gradient increasing from periportal to pericentral hepatocytes, whereas claudin-1 and-3 are expressed in the whole liver lobule. Although claudin-2 expression induces cation-selective channels in tight junctions of epithelial cells, the physiological functions and regulation of claudin-2 in hepatocytes remain unclear. Oncostatin M (OSM) is a multifunctional cytokine implicated in the differentiation c f hepatocytes that induces formation of E-cadherin-based adherens junctions in fetal hepatocytes. In this study, we examined whether OSM could induce expression and function of claudin-2 in roden … More t hepatocytes, immortalized mouse and primary cultured proliferative rat hepatocytes. In the immortalized mouse and primary cultured proliferative rat hepatocytes, treatment with OSM markedly increased mRNA and protein of claudin-2 together with formation of developed networks of TJ strands. The increase of claudin-2 enhanced the paracellular barrier function which depended on molecular size. The increase of claudin-2 expression induced by OSM in rodent hepatocytes was regulated through distinct signaling pathways including PKC. Furthermore, we examined effects of claudin-2 on bile canaliculi formation using WIF-B9 hepatic cells which has hepatic cell polarity. In treatment with phenobarbital, bile canaliculi formation was induced and dilated together with an increase of claudin-2 expression. In treatment with siRNA of claudin-2, the bile canaliculi formation was inhibited by downregulation of claudin-2. These results suggest that expression of claudin-2 in hepatocytes may play a specific role as controlling the size of paracellular permeability in the barrier to keep bile in bile canaliculi and bile canaliculi formation. Less