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First published on May 13, 2008; DOI: 10.1124/mol.107.043711

0026-895X/08/7402-432-442$20.00
Mol Pharmacol 74:432-442, 2008

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Protein Kinase C Enhances Tight Junction Barrier Function of Human Nasal Epithelial Cells in Primary Culture by Transcriptional RegulationFormula

Jun-ichi Koizumi, Takashi Kojima, Noriko Ogasawara, Ryuta Kamekura, Makoto Kurose, Mitsuru Go, Atsushi Harimaya, Masaki Murata, Makoto Osanai, Hideki Chiba, Tetsuo Himi, and Norimasa Sawada

Departments of Otolaryngology (J.K., N.O., R.K., M.K., M.G., A.H., T.H.) and Pathology (T.K., M.M., M.O., H.C., N.S.), Sapporo Medical University School of Medicine, Sapporo, Japan

The epithelium of upper respiratory tissues such as human nasal mucosa forms a continuous barrier via tight junctions, which is thought to be regulated in part through a protein kinase C (PKC) signaling pathway. To investigate the mechanisms of the regulation of PKC-mediated tight junction barrier function of human nasal epithelium in detail, primary human nasal epithelial cells were treated with the PKC activator 12-O-tetradecanoylophorbol-13-acetate (TPA). In primary human nasal epithelial cells, treatment with TPA led not only to activation of phosphorylation of PKC, myristoylated alanine-rich C kinase substrate, and mitogen-activated protein kinase but also expression of novel PKC-{delta}, PKC-{theta}, and PKC-{epsilon}. Treatment with TPA increased transepithelial electrical resistance, with tight junction barrier function more than 4-fold that of the control, together with up-regulation of tight junction proteins, occludin, zona occludens (ZO)-1, ZO-2 and claudin-1 at the transcriptional level. Furthermore, it affected the subcellular localization of the tight junction proteins and the numbers of tight junction strands. The up-regulation of barrier function and tight junction proteins was prevented by a pan-PKC inhibitor, and the inhibitors of PKC-{delta} and PKC-{theta} but not PKC-{epsilon}. In primary human nasal epithelial cells, transcriptional factors GATA-3 and -6 were detected by reverse transcription-polymerase chain reaction. The knockdown of GATA-3 using RNA interference resulted in inhibition of up-regulation of ZO-1 and ZO-2 by treatment with TPA. These results suggest that TPA-induced PKC signaling enhances the barrier function of human nasal epithelial cells via transcriptional up-regulation of tight junction proteins, and the mechanisms may contribute to a drug delivery system.

Received November 21, 2007; accepted May 2, 2008

Address correspondence to: Dr. Takashi Kojima, Department of Pathology, Sapporo Medical University School of Medicine, S1. W17. Sapporo 060-8556, Japan. E-mail: ktakashi{at}sapmed.ac.jp






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