CHOP transcription factor mediates IL-8 signaling in cystic fibrosis bronchial epithelial cells.
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.
Vij
Neeraj
N
Division of Pediatric Respiratory Sciences, Johns Hopkins School of Medicine, 200 N. Wolfe St., Baltimore, MD 21287, USA.
Amoako
Martha O
MO
Mazur
Steven
S
Zeitlin
Pamela L
PL
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*
D017931:DNA Primers; D016209:Interleukin-8; D016328:NF-kappa B; D051742:Transcription Factor CHOP; D000242:Cyclic AMP; D051546:Cyclooxygenase 2; D015232:Dinoprostone; D007052:Ibuprofen
J Pediatr. 1991 Jun;118(6):956-64
2040934
J Clin Invest. 1990 Dec;86(6):1945-53
2254454
J Allergy Clin Immunol. 1992 May;89(5):1001-9
1583242
Lancet. 1993 Mar 13;341(8846):643-7
8095568
J Clin Invest. 1994 Jan;93(1):26-32
8282796
Am J Respir Crit Care Med. 1994 Jul;150(1):207-13
7912987
Mol Cell Biol. 1994 Aug;14(8):5300-8
8035808
Am J Respir Crit Care Med. 1994 Aug;150(2):448-54
8049828
J Leukoc Biol. 1994 Nov;56(5):554-8
7525815
N Engl J Med. 1995 Mar 30;332(13):848-54
7503838
BMJ. 1995 Jun 17;310(6994):1571-2
7787647
J Clin Invest. 1995 Nov;96(5):2204-10
7593606
J Infect Dis. 1996 Aug;174(2):262-7
8699053
J Rheumatol. 1996 May;23(5):862-8
8724299
Proc Natl Acad Sci U S A. 1996 Aug 20;93(17):9090-5
8799159
J Biol Chem. 1997 Jan 24;272(4):2396-403
8999951
J Biol Chem. 1998 Feb 6;273(6):3562-73
9452483
J Clin Invest. 1998 Aug 15;102(4):679-87
9710435
J Immunol. 1998 Oct 1;161(7):3746-52
9759900
Genes Dev. 2004 Dec 15;18(24):3066-77
15601821
Nat Struct Mol Biol. 2005 Jan;12(1):10-6
15619636
J Biol Chem. 2005 Apr 15;280(15):14433-42
15659384
N Engl J Med. 2005 May 12;352(19):1992-2001
15888700
J Cyst Fibros. 2005 Aug;4 Suppl 2:15-23
15967736
Am J Physiol Lung Cell Mol Physiol. 2005 Nov;289(5):L816-24
15964894
Am J Respir Cell Mol Biol. 2006 Jun;34(6):754-9
16456185
J Biol Chem. 2006 Jun 23;281(25):17369-78
16621797
J Biol Chem. 1984 Jun 10;259(11):6752-6
6427221
Am J Physiol Cell Physiol. 2000 Feb;278(2):C259-67
10666020
J Biol Chem. 2001 Oct 19;276(42):38658-64
11509575
Mol Ther. 2002 Jul;6(1):119-26
12095312
Am J Physiol Lung Cell Mol Physiol. 2002 Sep;283(3):L612-8
12169581
Lancet. 2003 Feb 22;361(9358):681-9
12606185
Life Sci. 2003 Dec 5;74(2-3):143-53
14607241
J Biol Chem. 2004 Jan 2;279(1):177-87
14561754
Biochem Biophys Res Commun. 2004 Apr 30;317(2):463-71
15063780
Proc Natl Acad Sci U S A. 2004 May 18;101(20):7693-8
15136726
Clin Diagn Lab Immunol. 2004 Sep;11(5):819-24
15358638
Clin Sci Mol Med. 1975 May;48(5):421-30
1126133
Am J Physiol. 1986 Jan;250(1 Pt 2):F47-53
3079967
Proc Natl Acad Sci U S A. 1987 Dec;84(24):9233-7
3480540
Am Rev Respir Dis. 1988 Oct;138(4):780-3
3202451
Arthritis Rheum. 1989 Jan;32(1):1-9
2643434
J Clin Invest. 1992 May;89(5):1478-84
1569186