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. cyclooxygenase | nonsteroidal antiinflammatory drugs | prostacyclin | cardiovascular | Vioxx C yclooxygenase (COX) converts arachidonic acid to prostanoids, which include prostaglandins (PGs), prostacyclin, and thromboxane. Prostanoids are important mediators that regulate diverse functions in the cardiovascular, gastrointestinal, urogenital, and nervous systems, as well as playing critical roles in immunity, inflammation and resolution of inflammation. There are two COX

Spontaneous Glutamatergic Synaptic Activity Regulates Constitutive COX-2 Expression in Neurons OPPOSING ROLES FOR THE TRANSCRIPTION FACTORS CREB (cAMP RESPONSE ELEMENT BINDING) PROTEIN AND Sp1 (STIMULATORY PROTEIN-1)

“…Hence, constitutive neuronal PTGS2 transcription appears to be independent of NFB. This is in line with a recent study demonstrating both negligible constitutive NFB activity in brain and a lack of effect of NFB inhibition on PTGS2 promoter activity in knock-in reporter mice (21). Interestingly, stimulus-induced increases in neuronal COX-2 expression do appear to involve NFB binding.…”

“…This expression closely mirrored tissue mRNA levels, with the notable exception of cerebellum and spinal cord, suggesting areas of the promoter that suppress expression may be missing from our construct and/or that native expression in these tissues is influenced by elements in the COX-2 3Ј-UTR. Indeed, underscoring this point, analysis of basal expression of luciferase activity driven from the endogenous PTGS2 gene in a knock-in mouse also shows high expression in cortex and hippocampus, with little expression in cerebellum; the spinal cord was not assessed (21).…”

Apoptotic Effects of Etodolac in Breast Cancer Cell Cultures

“…COX-2, on the other hand, is hardly detectable in normal conditions but is induced upon stimulation by mitogenic agents, cytokines, growth factors, and so on. Later reports, however, demonstrated that COX-2 is also constitutively expressed in basal levels at several tissues including gastric mucosa, developing brain or kidney [3][4][5].…”

“…COX-2, on the other hand, is hardly detectable in normal conditions but is induced upon stimulation by mitogenic agents, cytokines, growth factors, and so on. Later reports, however, demonstrated that COX-2 is also constitutively expressed in basal levels at several tissues including gastric mucosa, developing brain or kidney [3][4][5].COX isoforms catalyse prostaglandin G/H (PGG2/PGH2) synthesis from arachidonic acid, and these prostaglandins are then converted to stable forms like PGD2, PGE2, PGF2, prostacyclin (PGI2) or thromboxane A2 (TXA2) depending on the cell type. Inhibition of COX enzymes, therefore, could result in improper prostaglandin activity, which in turn may cause diferent side efects.…”

Isomeric iodinated analogs of nimesulide: Synthesis, physicochemical characterization, cyclooxygenase-2 inhibitory activity, and transport across Caco-2 cells

“…COX-2 expression is induced by inflammatory stimuli, although this enzyme is also expressed constitutively in areas that are not associated with inflammation, including the brain, thymus, gut, and kidney. 1 In the brain, the cerebral cortex shows the highest COX-2 expression. 1 Recent studies have shown that central nervous system COX-2 expression is up-regulated in a variety of neuropathological diseases.…”