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p38-dependent c-Jun degradation contributes to reduced PGE2 production in sodium orthovanadate-treated macrophages
Nur Aziz1, Eunji Kim1, Yanyan Yang2
1Department of Integrative Biotechnology and Biomedical Institute for Convergence at SKKU (BICS), Sungkyunkwan University, Suwon 16419, Korea.
Abstract:
In particular, the phenomenon of c-Jun degradation within the inflammatory response has not yet been fully analyzed. In order to verify this, we investigated LPS-stimulated murine macrophages pre-treated with sodium orthovanadate (SO) in order to uncover the regulatory mechanisms of the MAPKs which regulate c-Jun degradation within the inflammatory response. Through our study, we found that SO suppressed the production of prostaglandin E2 (PGE2) and the expression of COX-2 in LPS-stimulated RAW264.7 cells. Additionally, SO decreased total c-Jun levels, without altering the amount of mRNA, although the phospho-levels of p38, ERK, and JNK were strongly enhanced. Through the usage of selective MAPK inhibitors, and knockdown and overexpression strategies, p38 was revealed to be a major MAPK which regulates c-Jun degradation. Further analysis indicates that the phosphorylation of p38 is a determinant for c-Jun degradation, and is sufficient to induce ubiquitination-dependent c-Jun degradation, recovered through MG132 treatment. Therefore, our results suggest that the hyperphosphorylation of p38 by SO contributes to c-Jun degradation, which is linked to the suppression of PGE2 secretion in inflammatory responses; and thus, finding drugs to increase p38 activity could be a novel strategy for the development of anti-inflammatory drugs. [BMB Reports 2022; 55(8): 389-394].
Insights
Sodium orthovanadate (SO) enhances p38 MAPK phosphorylation, leading to c-Jun degradation and suppressed prostaglandin E2 (PGE2) production in inflammatory responses. This suggests targeting p38 activity for novel anti-inflammatory drug development.
Area of Science:
- Cellular Biology
- Molecular Biology
- Immunology
Background:
- The degradation of c-Jun, a key transcription factor in inflammatory pathways, remains incompletely understood.
- Investigating the role of mitogen-activated protein kinases (MAPKs) in c-Jun degradation during inflammation is crucial for understanding cellular responses.
- Lipopolysaccharide (LPS)-stimulated murine macrophages provide a model system to study inflammatory signaling.
Discussion:
- Sodium orthovanadate (SO) treatment suppressed prostaglandin E2 (PGE2) production and COX-2 expression in LPS-stimulated RAW264.7 cells.
- SO decreased total c-Jun levels without affecting mRNA, while significantly increasing phosphorylation of p38, ERK, and JNK.
- p38 MAPK was identified as the primary regulator of c-Jun degradation through phosphorylation-dependent ubiquitination.
Key Insights:
- p38 MAPK phosphorylation is a critical determinant for c-Jun degradation.
- SO-induced hyperphosphorylation of p38 contributes to c-Jun degradation.
- This degradation is linked to the suppression of PGE2 secretion, impacting inflammatory responses.
Outlook:
- Targeting p38 MAPK activity presents a potential therapeutic strategy for developing novel anti-inflammatory drugs.
- Further research into the precise mechanisms of p38-mediated c-Jun ubiquitination could yield new drug targets.
- Understanding this pathway may offer insights into managing inflammatory conditions characterized by aberrant c-Jun regulation.
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