Neurotoxic prostaglandin J2 enhances cyclooxygenase-2 expression in neuronal cells through the p38MAPK pathway: A death wish?

The role of the proinflammatory and inducible form of cyclooxygenases (COX-2) in neurodegeneration is not well defined. Some of its metabolic products, such as prostaglandins (PG) of the J2 series, are known to be neurotoxic. Here we demonstrate that PGJ2 enhances COX-2 gene expression without elevating COX-1 levels in neuronal cells. PGJ2 also increased PGE2 production, establishing that the de novo synthesized COX-2 is enzymatically active. PGJ2 derivatives, such as 15d-PGJ2, are known activators of PPARgamma, a nuclear receptor that activates gene expression. However, the selective PPARgamma agonist ciglitazone failed to up-regulate COX-2, indicating that the PGJ2 effect on COX-2 is PPARgamma independent. Furthermore, PGJ2 stabilized IkappaBalpha levels, indicating that NFkappaB is not active under these conditions. The blocking of neuronal NFkappaB activity by PGJ2 may be an important contributor to its neurotoxicity, insofar as NFkappaB transactivation seems to be required for neuronal survival in the CNS. Interleukin-1 (IL1) is a proinflammatory cytokine known to stimulate the expression of genes associated with inflammation, including COX-2. Notably, IL1 mRNA levels in the neuronal cells were increased by PGJ2 treatment. The proinflammatory cytokine may mediate COX-2 up-regulation by PGJ2 through p38MAPK and not JNK activation, in that only an inhibitor of the former prevented the COX-2 increase. Thiol-reducing agents, such as N-acetylcysteine, protected the neuronal cells from the deleterious effects of PGJ2, whereas ascorbic acid did not. Collectively, our findings suggest that proinflammatory conditions that lead to COX-2 upregulation and the concomitant production of PGJ2 initiate a mechanism of self-destruction through an autotoxic loop between PGJ2 and COX-2 that may exacerbate neurodegeneration beyond a point of no return. Thiol-reducing antioxidants may offer an optimal strategy for halting this neurodegenerative process. (C) 2004 Wiley-Liss, Inc.