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Neurotoxic prostaglandin J2 enhances cyclooxygenase‐2 expression in neuronal cells through the p38MAPK pathway
Author(s) -
Li Zongmin,
FigueiredoPereira Maria
Publication year - 2008
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.22.2_supplement.308
Subject(s) - cyclooxygenase , prostaglandin , microbiology and biotechnology , prostaglandin e2 receptor , chemistry , pharmacology , biology , enzyme , biochemistry , receptor , agonist
The objective of this study is to investigate the cell signaling pathway that leads to COX‐2 upregulation in stressed neuronal cells. Here we demonstrate that neurotoxic prostaglandins (PG) of the J2 series enhance 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. The selective PPARγ agonist ciglitazone failed to up‐regulate COX‐2, indicating that the PGJ2 effect on COX‐2 is PPARγ independent. Furthermore, PGJ2 stabilized IκBα levels, indicating that NFκB is not active under these conditions. The proinflammatory cytokine Interleukin‐1 (IL1) 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.