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Published online before print April 12, 2007
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© by The Society for Leukocyte Biology
Journal of Leukocyte Biology, doi:10.1189/jlb.0107030

Received for publication January 16, 2007.
Revised March 15, 2007.
Accepted for publication March 16, 2007.

Article

Class III antiarrhythmic methanesulfonanilides inhibit leukocyte recruitment in zebrafish

Simon B. Brown *@, Carl S. Tucker {dagger}, Christopher Ford *, Yfe Lee *, Donald R. Dunbar {dagger}, and John J. Mullins {dagger}

*MRC Centres for Inflammation Research and {dagger}Cardiovascular Science, Queen’s Medical Research Institute, College of Medicine and Veterinary Medicine, University of Edinburgh, Edinburgh, United Kingdom

@ To whom correspondence should be addressed. E-mail: simon.brown{at}ed.ac.uk.


  Abstract

Understanding fundamental molecular mechanisms that govern the transmigration and interstitial migration of leukocytes to sites of tissue damage and infection is of potential significance in identifying novel therapeutic targets for the management of chronic inflammatory disorders. CD31 is a mammalian cell adhesion molecule that regulates the recruitment of leukocytes from the circulation. Our recent unpublished work has suggested that homophilic ligation of CD31 can negatively regulate the ether-à-go-go-related gene (ERG) current within leukocytes to regulate cell-cell adhesion. To validate and probe the functional significance of ERG in leukocytes, we developed an infected wound model of inflammation in zebrafish and assessed the efficacy of two ERG-specific inhibitors, dofetilide and E4031, as well as an ERG-specific antisense RNA morpholino on neutrophil recruitment. Our data confirm a hitherto undescribed role for ERG in leukocytes, where inhibition or translational knockdown of ERG resulted in significant attenuation of the inflammatory response to an infectious stimulus. Inhibition of ERG was verified independently by a decrease in the ventricular heart rate, where ERG also functions in the repolarization of the cardiac action potential. Our results suggest that ERG-specific Class III antiarrhythmic drugs can modulate inflammatory responses to infection.

Key Words: inflammation • infection • ether-à-go-go-related gene (ERG)




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