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

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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; Jiao, Jing; Berglund, Lisa; Verdu, Elena F; Ahmetaj-Shala, Blerina; Wallace, John L; Herschman, Harvey R; Gomez, Maria; Mitchell, Jane A.

In: Proceedings of the National Academy of Sciences, Vol. 113, No. 2, 2016, p. 434-439.

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Kirkby, Nicholas S ; Chan, Melissa V ; Zaiss, Anne K ; Garcia Vaz, Eliana ; Jiao, Jing ; Berglund, Lisa ; Verdu, Elena F ; Ahmetaj-Shala, Blerina ; Wallace, John L ; Herschman, Harvey R ; Gomez, Maria ; Mitchell, Jane A. / Systematic study of constitutive cyclooxygenase-2 expression: Role of NF-κB and NFAT transcriptional pathways. In: Proceedings of the National Academy of Sciences. 2016 ; Vol. 113, No. 2. pp. 434-439.

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TY - JOUR

T1 - Systematic study of constitutive cyclooxygenase-2 expression: Role of NF-κB and NFAT transcriptional pathways.

AU - Kirkby, Nicholas S

AU - Chan, Melissa V

AU - Zaiss, Anne K

AU - Garcia Vaz, Eliana

AU - Jiao, Jing

AU - Berglund, Lisa

AU - Verdu, Elena F

AU - Ahmetaj-Shala, Blerina

AU - Wallace, John L

AU - Herschman, Harvey R

AU - Gomez, Maria

AU - Mitchell, Jane A

PY - 2016

Y1 - 2016

N2 - 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.

AB - 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.

U2 - 10.1073/pnas.1517642113

DO - 10.1073/pnas.1517642113

M3 - Article

VL - 113

SP - 434

EP - 439

JO - Proceedings of the National Academy of Sciences

T2 - Proceedings of the National Academy of Sciences

JF - Proceedings of the National Academy of Sciences

SN - 1091-6490

IS - 2

ER -