title: CHOP transcription factor mediates IL-8 signaling in cystic fibrosis bronchial epithelial cells.
abstract: 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-kappaB-dependent signaling and therapy with glucocorticoids. We test the hypothesis that an alternative pathway, independent of NF-kappaB, 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.
authors: Division of Pediatric Respiratory Sciences, Johns Hopkins School of Medicine, 200 N. Wolfe St., Baltimore, MD 21287, USA.
authors: Neeraj
authors: N
authors: Vij
authors: Martha O
authors: MO
authors: Amoako
authors: Steven
authors: S
authors: Mazur
authors: Pamela L
authors: PL
authors: Zeitlin
mesh_terms: D001483:Base Sequence; D015153:Blotting, Western; D001980:Bronchi / Q000378:metabolism* / Q000473:pathology; D002460:Cell Line; D047369:Chromatin Immunoprecipitation; D000242:Cyclic AMP / Q000378:metabolism; D051546:Cyclooxygenase 2 / Q000187:drug effects; D003550:Cystic Fibrosis / Q000378:metabolism*; D017931:DNA Primers; D015232:Dinoprostone / Q000378:metabolism; D004847:Epithelial Cells / Q000378:metabolism; D006801:Humans; D007052:Ibuprofen / Q000494:pharmacology; D016209:Interleukin-8 / Q000378:metabolism*; D016328:NF-kappa B / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000502:physiology*; D051742:Transcription Factor CHOP / Q000502:physiology*
chemical_list: D017931:DNA Primers; D016209:Interleukin-8; D016328:NF-kappa B; D051742:Transcription Factor CHOP; D000242:Cyclic AMP; D051546:Cyclooxygenase 2; D015232:Dinoprostone; D007052:Ibuprofen
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