title: Systematic study of constitutive cyclooxygenase-2 expression: Role of NF-κB and NFAT transcriptional pathways.
abstract: Cyclooxygenase-2 (COX-2) is an inducible enzyme that drives inflammation and is the therapeutic target for widely used nonsteroidal antiinflammatory drugs (NSAIDs). However, COX-2 is also constitutively expressed, in the absence of overt inflammation, with a specific tissue distribution that includes the kidney, gastrointestinal tract, brain, and thymus. Constitutive COX-2 expression is therapeutically important because NSAIDs cause cardiovascular and renal side effects in otherwise healthy individuals. These side effects are now of major concern globally. However, the pathways driving constitutive COX-2 expression remain poorly understood. Here we show that in the kidney and other sites, constitutive COX-2 expression is a sterile response, independent of commensal microorganisms and not associated with activity of the inflammatory transcription factor NF-κB. Instead, COX-2 expression in the kidney but not other regions colocalized with nuclear factor of activated T cells (NFAT) transcription factor activity and was sensitive to inhibition of calcineurin-dependent NFAT activation. However, calcineurin/NFAT regulation did not contribute to constitutive expression elsewhere or to inflammatory COX-2 induction at any site. These data address the mechanisms driving constitutive COX-2 and suggest that by targeting transcription it may be possible to develop antiinflammatory therapies that spare the constitutive expression necessary for normal homeostatic functions, including those important to the cardiovascular-renal system.
authors.affiliation: Cardiothoracic Pharmacology, Vascular Biology, National Heart and Lung Institute, Imperial College London, London SW3 6LY, United Kingdom; n.kirkby@imperial.ac.uk j.a.mitchell@ic.ac.uk.
authors.forename: Nicholas S
authors.initials: NS
authors.lastname: Kirkby
authors.affiliation: Translational Medicine and Therapeutics, The William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Queen Mary, University of London, London EC1M 6BQ, United Kingdom; Farmcombe Family Institute of Digestive Health, McMaster University, Hamilton, ON L8S 4K1, Canada;
authors.forename: Melissa V
authors.initials: MV
authors.lastname: Chan
authors.affiliation: Department of Medical and Molecular Pharmacology, David Geffen School of Medicine, University of California, Los Angeles, CA 90095-1570;
authors.forename: Anne K
authors.initials: AK
authors.lastname: Zaiss
authors.affiliation: Department of Clinical Sciences in Malmo, Lund University, Malmo SE-205 02, Sweden;
authors.forename: Eliana
authors.initials: E
authors.lastname: Garcia-Vaz
authors.affiliation: Department of Medical and Molecular Pharmacology, David Geffen School of Medicine, University of California, Los Angeles, CA 90095-1570;
authors.forename: Jing
authors.initials: J
authors.lastname: Jiao
authors.affiliation: Department of Clinical Sciences in Malmo, Lund University, Malmo SE-205 02, Sweden;
authors.forename: Lisa M
authors.initials: LM
authors.lastname: Berglund
authors.affiliation: Farmcombe Family Institute of Digestive Health, McMaster University, Hamilton, ON L8S 4K1, Canada;
authors.forename: Elena F
authors.initials: EF
authors.lastname: Verdu
authors.affiliation: Cardiothoracic Pharmacology, Vascular Biology, National Heart and Lung Institute, Imperial College London, London SW3 6LY, United Kingdom;
authors.forename: Blerina
authors.initials: B
authors.lastname: Ahmetaj-Shala
authors.affiliation: Farmcombe Family Institute of Digestive Health, McMaster University, Hamilton, ON L8S 4K1, Canada; Antibe Therapeutics Inc., Toronto, ON M5R 1B2, Canada.
authors.forename: John L
authors.initials: JL
authors.lastname: Wallace
authors.affiliation: Department of Medical and Molecular Pharmacology, David Geffen School of Medicine, University of California, Los Angeles, CA 90095-1570;
authors.forename: Harvey R
authors.initials: HR
authors.lastname: Herschman
authors.affiliation: Department of Clinical Sciences in Malmo, Lund University, Malmo SE-205 02, Sweden;
authors.forename: Maria F
authors.initials: MF
authors.lastname: Gomez
authors.affiliation: Cardiothoracic Pharmacology, Vascular Biology, National Heart and Lung Institute, Imperial College London, London SW3 6LY, United Kingdom; n.kirkby@imperial.ac.uk j.a.mitchell@ic.ac.uk.
authors.forename: Jane A
authors.initials: JA
authors.lastname: Mitchell
mesh_terms: D000818:Animals; D051546:Cyclooxygenase 2 / Q000235:genetics* / Q000378:metabolism; D016572:Cyclosporine / Q000494:pharmacology; D016207:Cytokines / Q000378:metabolism; D005260:Female; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D005856:Germ-Free Life; D007668:Kidney / Q000187:drug effects / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology; D008156:Luciferases / Q000378:metabolism; D008297:Male; D008810:Mice, Inbred C57BL; D016328:NF-kappa B / Q000378:metabolism*; D050778:NFATC Transcription Factors / Q000235:genetics* / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D014018:Tissue Distribution / Q000187:drug effects; D014158:Transcription, Genetic / Q000187:drug effects
chemical_list: D016207:Cytokines; D008070:Lipopolysaccharides; D016328:NF-kappa B; D050778:NFATC Transcription Factors; D012333:RNA, Messenger; D016572:Cyclosporine; D008156:Luciferases; D051546:Cyclooxygenase 2
keywords: Vioxx; cardiovascular; cyclooxygenase; nonsteroidal antiinflammatory drugs; prostacyclin