Novel intracellular signaling function of prostaglandin H synthase-1 in NF-kappa B activation.
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.
Munroe
D G
DG
Discovery Research, R. W. Johnson Pharmaceutical Research Institute, Don Mills, Ontario, Canada.
Wang
E Y
EY
MacIntyre
J P
JP
Tam
S S
SS
Lee
D H
DH
Taylor
G R
GR
Zhou
L
L
Plante
R K
RK
Kazmi
S M
SM
Bäuerle
P A
PA
D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology; D001483:Base Sequence; D002460:Cell Line; D007425:Intracellular Membranes / Q000378:metabolism; D008969:Molecular Sequence Data; D016328:NF-kappa B / Q000502:physiology*; D015345:Oligonucleotide Probes / Q000235:genetics; D011451:Prostaglandin-Endoperoxide Synthases / Q000502:physiology*; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology
D000894:Anti-Inflammatory Agents, Non-Steroidal; D016328:NF-kappa B; D015345:Oligonucleotide Probes; D017382:Reactive Oxygen Species; D011451:Prostaglandin-Endoperoxide Synthases; D013755:Tetradecanoylphorbol Acetate