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Systematic study of constitutive cyclooxygenase-2 expression: Role of NF-κB and NFAT transcriptional pathways.

Kirkby, Nicholas S; Chan, Melissa V; Zaiss, Anne K; Garcia Vaz, Eliana LU ; Jiao, Jing; Berglund, Lisa LU ; Verdu, Elena F; Ahmetaj-Shala, Blerina; Wallace, John L and Herschman, Harvey R, et al. (2016) In Proceedings of the National Academy of Sciences 113(2). p.434-439
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... (More)
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. (Less)
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Proceedings of the National Academy of Sciences
volume
113
issue
2
pages
434 - 439
publisher
National Acad Sciences
external identifiers
  • pmid:26712011
  • wos:000367881500058
  • scopus:84954511734
ISSN
1091-6490
DOI
10.1073/pnas.1517642113
language
English
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yes
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2927ffa4-c096-4336-9d6c-59954faf431f (old id 8500296)
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http://www.ncbi.nlm.nih.gov/pubmed/26712011?dopt=Abstract
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2016-01-06 20:05:34
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2017-10-08 03:08:03
@article{2927ffa4-c096-4336-9d6c-59954faf431f,
  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.},
  author       = {Kirkby, Nicholas S and Chan, Melissa V and Zaiss, Anne K and Garcia Vaz, Eliana and Jiao, Jing and Berglund, Lisa and Verdu, Elena F and Ahmetaj-Shala, Blerina and Wallace, John L and Herschman, Harvey R and Gomez, Maria and Mitchell, Jane A},
  issn         = {1091-6490},
  language     = {eng},
  number       = {2},
  pages        = {434--439},
  publisher    = {National Acad Sciences},
  series       = {Proceedings of the National Academy of Sciences},
  title        = {Systematic study of constitutive cyclooxygenase-2 expression: Role of NF-κB and NFAT transcriptional pathways.},
  url          = {http://dx.doi.org/10.1073/pnas.1517642113},
  volume       = {113},
  year         = {2016},
}