Novel intracellular signaling function of prostaglandin H synthase-1 in NF-kappa B activation.
J Inflamm
; 45(4): 260-8, 1995.
Article
in En
| MEDLINE
| ID: mdl-8867670
ABSTRACT
Many potent nonsteroidal antiinflammatory drugs (NSAIDs) exert their effects by inhibiting the cyclooxygenase activity of prostaglandin H synthase-1 (PGHS1, thus disrupting prostaglandin biosynthesis. However, these drugs do not block the activation of NF-kappa B, an inducible transcription factor which regulates numerous inflammation-related genes. Here we demonstrate that PGHS1 peroxidase, a NSAID-insensitive activity of PGHS1, mediates NF-kappa B activation through an intracellular reactive oxygen signaling pathway. Overexpression of PGHS1 strongly potentiated NF-kappa B activation by phorbol esters and dramatically elevated the generation of intracellular reactive oxygen species (ROS) in response to low concentrations of t-butyl peroxide. Both functions were dependent on PGHS1 peroxidase activity and could be suppressed by the potent antioxidant pyrrolidine dithiocarbamate. In contrast, elimination of PGHS1 cyclooxygenase activity by NSAIDs or site-directed mutagenesis failed to block ROS production or NF-kappa B activation. Thus, PGHS1 peroxidase serves an intracellular signaling function leading to NF-kappa B activation, separable from its role in prostaglandin synthesis.
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Collection:
01-internacional
Database:
MEDLINE
Main subject:
Signal Transduction
/
NF-kappa B
/
Prostaglandin-Endoperoxide Synthases
Language:
En
Journal:
J Inflamm
Journal subject:
ANGIOLOGIA
/
CARDIOLOGIA
Year:
1995
Type:
Article
Affiliation country:
Canada