NOVEL INTRACELLULAR SIGNALING FUNCTION OF PROSTAGLANDIN-H SYNTHASE-1 IN NF-KAPPA-B ACTIVATION

Many potent nonsteroidal antiinflammatory drugs (NSAIDs) exert their e ffects by inhibiting the cyclooxygenase activity of prostaglandin H sy nthase-1 (PGHS1), thus disrupting prostaglandin biosynthesis. However, these drugs no not block the activation of NF-kappa B, an inducible t ranscription factor which regulates numerous inflammation-related gene s. Here toe demonstrate that PGHS1 peroxidase, a NSAID-insensitive act ivity of PGHS1, mediates NF-kappa B activation through an intracellula r reactive oxygen signaling pathway. Overexpression of PGHS1 strongly potentiated NF-kappa B activation by phorbol esters and dramatically e levated 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, elim ination of PGHS1 cyclooxygenase activity by NSAIDs or site-directed mu tagenesis failed to block ROS production or NF-kappa B activation. Thu s, PGHS1 peroxidase serves an intracellular signaling function leading to NF-kappa B activation, separable from its role in prostaglandin sy nthesis. (C) 1995 Wiley-Liss, Inc.