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Infection and Immunity, May 2007, p. 2562-2571, Vol. 75, No. 5
0019-9567/07/$08.00+0     doi:10.1128/IAI.01656-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

Jun N-Terminal Protein Kinase Enhances Middle Ear Mucosal Proliferation during Bacterial Otitis Media

Department of Surgery/Otolaryngology, UCSD School of Medicine, and Veterans Affairs Medical Center, La Jolla, California,¹ Department of Medicine, UCSD School of Medicine, and Veterans Affairs Medical Center, La Jolla, California,² Department of Otorhinolaryngology—Head & Neck Surgery, Tohoku University School of Medicine, Sendai, Japan,³ Department of Otorhinolaryngology—Head & Neck Surgery, Bayerische Julius Maximilians Universität, Würzburg, Germany,⁴ Department of Microbiology, University of Lund, Lund, Sweden⁵

Received 16 October 2006/ Returned for modification 19 December 2006/ Accepted 14 February 2007

Mucosal hyperplasia is a characteristic component of otitis media. The present study investigated the participation of signaling via the Jun N-terminal protein kinase (JNK) mitogen-activated protein kinase in middle ear mucosal hyperplasia in animal models of bacterial otitis media. Otitis media was induced by the inoculation of nontypeable Haemophilus influenzae into the middle ear cavity. Western blotting revealed that phosphorylation of JNK isoforms in the middle ear mucosa preceded but paralleled mucosal hyperplasia in this in vivo rat model. Nuclear JNK phosphorylation was observed in many cells of both the mucosal epithelium and stroma by immunohistochemistry. In an in vitro model of primary rat middle ear mucosal explants, bacterially induced mucosal growth was blocked by the Rac/Cdc42 inhibitor Clostridium difficile toxin B, the mixed-lineage kinase inhibitor CEP11004, and the JNK inhibitor SP600125. Finally, the JNK inhibitor SP600125 significantly inhibited mucosal hyperplasia during in vivo bacterial otitis media in guinea pigs. Inhibition of JNK in vivo resulted in a diminished proliferative response, as shown by a local decrease in proliferating cell nuclear antigen protein expression by immunohistochemistry. We conclude that activation of JNK is a critical pathway for bacterially induced mucosal hyperplasia during otitis media, influencing tissue proliferation.

Published ahead of print on 26 February 2007.

Editor: J. N. Weiser