Interleukin-1 beta induces cyclooxygenase-2 and prostaglandin E-2 synthesis in human neuroblastoma cells: Involvement of p38 mitogen-activated protein kinase and nuclear factor-kappa B

Prostaglandins (PGs), which are generated by the enzymatic activity of cycl ooxygenase (COX)-1 and -2, modulate several functions in the CNS such as th e generation of fever, the sleep/wake cycle, and the perception of pain. Mo reover, the neuronal induction of COX-2 has been linked to neuroinflammator y aspects of Alzheimer's disease (AD). The regulation of COX expression in neuronal cells is only partly understood and has been mainly linked to syna ptic activity. In pathophysiological situations, however, cytokines may be potent stimulators of neuronal COX expression. Here we show that interleuki n (IL)-1 beta induces COX-2 mRNA and protein synthesis and the release of P GE(2) in the human neuroblastoma cell line SK-N-SH. We further demonstrate that both a free radical scavenger and an inhibitor of p38 mitogen-activate d protein kinase (MAPK) reduce IL-1 beta-induced synthesis of COX-2. IL-1 b eta induces p38 MAPK phosphorylation and activation of the nuclear factor-k appa B independently from each other. Our data suggest that IL-1 beta-induc ed COX-2 expression in SK-N-SH cells is regulated by different mechanisms, presumably involving mRNA transcription and mRNA stability. The ability of p38 MAPK to augment COX-2 expression in human neuroblastoma cells, as shown here, suggests that p38 MAPK may be involved in neuronal expression of COX -2 in AD.