Journal Article

Systematic study of constitutive cyclooxygenase-2 expression

Garcia-Vaz, Eliana, Ahmetaj-Shala, Blerina, Verdu, Elena F., Gomez, Maria F., Jiao, Jing, Chan, Melissa V., Kirkby, Nicholas S., Wallace, John L., Zaiss, Anne K., Berglund, Lisa M., Herschman, Harvey R., Mitchell, Jane A.

2016

Overview

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.

• Publisher: National Academy of Sciences
• Subject: Animals / Biological Sciences / Cardiology and Cardiovascular Disease / Clinical Medicine / Cyclooxygenase 2 - genetics / Cyclooxygenase 2 - metabolism / Cyclosporine - pharmacology / Cytokines - metabolism / Female / Gene Expression Regulation, Enzymologic - drug effects / Germ-Free Life / Kardiologi och kardiovaskulära sjukdomar / Kidney - drug effects / Kidney - metabolism / Klinisk medicin / Lipopolysaccharides - pharmacology / Luciferases - metabolism / Male / Medical and Health Sciences / Medicin och hälsovetenskap / Mice, Inbred C57BL / NF-kappa B - metabolism / NFATC Transcription Factors - genetics / NFATC Transcription Factors - metabolism / Pharmacology / RNA, Messenger - genetics / RNA, Messenger - metabolism / Signal Transduction - drug effects / Tissue Distribution - drug effects / Transcription, Genetic - drug effects