Prostaglandin I2 is responsible for ameliorating prostaglandin E2 stress in stimulating the expression of tumor necrosis factor ? in a ?-amyloid protein -dependent mechanism.

ABSTRACT: Cyclooxygenase-2 (COX-2) has been found to be induced during the early stage of Alzheimer's disease (AD). Using mouse-derived astrocyte and APP/PS1 transgenic (Tg) mice as model systems, we firstly elucidated the mechanisms underlying COX-2 metabolic production including prostaglandin (PG)E2- and PGI2-mediated tumor necrosis factor ? (TNF-?) regulation. Specifically, PGE2 accumulation in astrocyte activated the p38 and JNK/c-Jun signaling pathways via phosphorylation, resulting in TNF-? expression. In contrast, the administration of PGI2 attenuated the effects of PGE2 in stimulating the production of TNF-? by inhibiting the activity of TNF-? promoter and the binding activity of AP1 on the promoter of TNF-?. Moreover, our data also showed that not only A?1-42 oligomers but also A?1-42 fibrils have the ability to involve in mediating the antagonistic effects of PGE2 and PGI2 on regulating the expression of TNF-? via a p38- and JNK/c-Jun-dependent, AP1-transactivating mechanism. Reciprocally, the production of TNF-? finally accelerated the deposition of ?-amyloid protein (A?)1-42 in ?-amyloid plaques (APs), which contribute to the cognitive decline of AD.

SUBMITTER: Zheng SQ 

PROVIDER: S-EPMC5732691 | biostudies-literature | 2017 Nov

REPOSITORIES: biostudies-literature