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

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

Correspondence and requests for reprints should be addressed to Pamela L. Zeitlin, Professor of Pediatrics, Division of Pediatric Respiratory Sciences, Johns Hopkins School of Medicine, 200 N. Wolfe St., Baltimore, MD 21287. E-mail: pzeitlin{at}jhmi.edu

Interleukin (IL)-8 is a potent neutrophil chemoattractant that drives the inflammatory response in cystic fibrosis (CF). Traditional approaches to the pathophysiology of this inflammation have focused on targeting NF-B–dependent signaling and therapy with glucocorticoids. We test the hypothesis that an alternative pathway, independent of NF-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 cyclooxygenase (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 C/EBP homologous protein (CHOP) 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.

Key Words: PGE-2 • chemokine • cAMP • ibuprofen • CFTR

CLINICAL RELEVANCE IL-8 drives the inflammatory response in cystic fibrosis (CF). We show an alternative, non–NF-B, signaling pathway for prostaglandin E2–induced IL-8 stimulation in CF. We provide additional data regarding the potential of cyclooxygenase-2 inhibition for CF lung disease.