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Published ahead of print on August 20, 2007, doi:10.1165/rcmb.2007-0197OC

Am. J. Respir. Cell Mol. Biol., Volume 38, Number 2, February 2008, 176-184

A more recent version of this article appeared on February 1, 2008
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Submitted on June 4, 2007
Revised on August 15, 2007

CHOP Transcription Factor Mediates IL-8 Signaling in Cystic Fibrosis Bronchial Epithelial Cells

Neeraj Vij1, Martha O Amoako1, Steven Mazur1, and Pamela L Zeitlin1*

1 Division of Pediatric Respiratory Sciences, Johns Hopkins School of Medicine, Baltimore, MD, USA

* To whom correspondence should be addressed. E-mail: pzeitlin{at}jhmi.edu.

Interleukin (IL)-8 is a potent neutrophil chemo-attractant that drives the inflammatory response in cystic fibrosis. Traditional approaches to the pathophysiology of this inflammation have focused on targeting NF{kappa}B-dependent signaling and therapy with glucocorticoids. We test the hypothesis that an alternative pathway, independent of NF{kappa}B, operates through prostaglandin E2 (PGE-2) receptor EP-2 and stimulates IL-8 chemokine secretion. Using CF bronchial epithelial cells (IB3-1) in vitro, exogenous PGE-2 induces IL-8 release in a dose dependent manner. These events are associated with elevation in the EP-2 receptors. Inhibition of cyclo-oxygenase (Cox)-2 with NS-398 was associated with reductions in Cox-2 (2-fold) and IL-6 (1.3 fold) mRNA transcripts, and in IL-8 and PGE-2 chemokine secretion. The inhibition of Cox-2 signaling led to down-regulation of the downstream CHOP (C/EBP homologous protein) transcription factor resulting in a decrease in IL-8 activation. We confirmed the regulation of IL-8 promoter by CHOP in CF cells using the IL-8 reporter assay. We conclude that PGE-2 stimulates IL-8 production through the CHOP transcription factor in CF cells.




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