Celecoxib paradoxically induces COX-2 expression and astrocyte activation through the ERK/JNK/AP-1 signaling pathway in the cerebral cortex of rats

Kai-Che Wei; Jun-Ting Lin; Chia-Ho Lin

doi:10.1016/j.neuint.2024.105926

Celecoxib paradoxically induces COX-2 expression and astrocyte activation through the ERK/JNK/AP-1 signaling pathway in the cerebral cortex of rats

Neurochem Int. 2024 Dec 27:183:105926. doi: 10.1016/j.neuint.2024.105926. Online ahead of print.

Authors

Kai-Che Wei¹, Jun-Ting Lin², Chia-Ho Lin³

Affiliations

¹ Department of Dermatology, Kaohsiung Veterans General Hospital, Kaoshiung, 813, Taiwan; College of Medicine, National Yang-Ming Chiao Tung University, Taipei, 112, Taiwan.
² Master and PhD Programs in Pharmacology and Toxicology, School of Medicine, Tzu Chi University, Hualien, 970, Taiwan.
³ Master and PhD Programs in Pharmacology and Toxicology, School of Medicine, Tzu Chi University, Hualien, 970, Taiwan; Department of Pharmacology, School of Medicine, Tzu Chi University, Hualien, 970, Taiwan. Electronic address: chlin97@mail.tcu.edu.tw.

PMID: 39734024
DOI: 10.1016/j.neuint.2024.105926

Abstract

Previous studies have shown that celecoxib or NSAID may paradoxically induce cyclooxygenase-2 (COX-2) expression and trigger inflammation-like responses in airway smooth muscle cells and renal mesangial cells. Despite the extensive research on celecoxib, its atypical biological effect on the induction of COX-2 in astroglial cells within the central nervous system (CNS) remains unexplored. In the present study, we investigated the impact of celecoxib on COX-2 and Glial Fibrillary Acidic Protein (GFAP) expression and explored the mechanisms underlying celecoxib-regulated COX-2 expression in cortical astrocytes of rats. Cortical astrocytes were treated with celecoxib (20 μM) for 24 h, resulting in a significant increase in COX-2 expression and up-regulation of GFAP, a marker of astrocyte activation, and the COX-2 induced by celecoxib is functionally active in prostaglandin E2 (PGE2) synthesis. Celecoxib also enhanced LPS-induced COX-2 expression, but its ability to inhibit PGE2 synthesis decreased at higher concentrations. Celecoxib induced phosphorylation of Extracellular signal-regulated Kinase (ERK) and c-Jun N-terminal Kinase (JNK) but not p38 Mitogen-Activated Protein Kinase (p38 MAPK), and inhibition of activity of ERK and JNK by U0126 and SP600125 effectively blocked COX-2 and GFAP induction by celecoxib. Celecoxib increased the accumulation of transcription factor AP-1 (composed of phosphorylated c-Jun and c-fos) in the nucleus. Inhibition of AP-1 activity with SR11302 significantly prevented celecoxib-induced COX-2 and GFAP expression. Additionally, the inhibiting activity of ERK and JNK can effectively suppress AP-1 expression and activity induced by celecoxib. These findings demonstrated that celecoxib induces COX-2 expression and astrocyte activation through the ERK/JNK/AP-1 signaling pathway, highlighting its potential effect in modulating inflammatory responses in the central nervous system.

Keywords: Astrocyte activation; COX-2; Celecoxib; GFAP; NSAID; Transcription factor AP-1.