Feedback control of cyclooxygenase-2 expression through PPARγ
Open accessAbstract
Cyclooxygenase-2 (COX-2), a rate-limiting enzyme for prostaglandins (PG), plays a key role in inflammation, tumorigenesis, development, and circulatory homeostasis. The PGD(2) metabolite 15-deoxy-Delta(12, 14) PGJ(2) (15d-PGJ(2)) was identified as a potent natural ligand for the peroxisome proliferator-activated receptor-gamma (PPARgamma). PPARgamma expressed in macrophages has been postulated as a negative regulator of inflammation and a positive regulator of differentiation into foam cell associated with atherogenesis. Here, we show that 15d-PGJ(2) suppresses the lipopolysaccharide (LPS)-induced expression of COX-2 in the macrophage-like differentiated U937 cells but not in vascular endothelial cells. PPARgamma mRNA abundantly expressed in the U937 cells, not in the endothelial cells, is down-regulated by LPS. In contrast, LPS up-regulates mRNA for the glucocorticoid receptor which ligand anti-inflammatory steroid dexamethasone (DEX) strongly suppresses the LPS-induced expression of COX-2, although both 15d-PGJ(2) and DEX suppressed COX-2 promoter activity by interfering with the NF-kappaB signaling pathway. Transfection of a PPARgamma expression vector into the endothelial cells acquires this suppressive regulation of COX-2 gene by 15d-PGJ(2) but not by DEX. A selective COX-2 inhibitor, NS-398, inhibits production of PGD(2) in the U937 cells. Taking these findings together, we propose that expression of COX-2 is regulated by a negative feedback loop mediated through PPARgamma, which makes possible a dynamic production of PG, especially in macrophages, and may be attributed to various expression patterns and physiological functions of COX-2.
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COX-2 expression is regulated by a negative feedback loop mediated through PPARγ, especially in macrophages.
“On the other hand, Inoue et al. (2000) [136] consider that COX-2 expression is regulated by a negative feedback loop, mediated through PPARγ, especially in macrophages, indicating that PPARγ participates in cell type-specific control of COX-2 expression.”
From Antioxidant and Anti-Inflammatory Activities of Essential Oils: A Short Review (2010) · cites this paper as [136]
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- Authors
- Inoue, H., Tanabe, T., & Umesono, K.
- Affiliations
- National Cerebral and Cardiovascular Center (JP)
- Kyoto University (JP)
- Corresponding author
- Inoue, Hiroyasu
- ORCID
- Inoue, Hiroyasu
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 2000-09
- Volume
- 275
- Issue
- 36
- Pages
- 28028-28032
- ISSN
- 0021-9258 (ISSN-L)
- OpenAlex
- W2136385901
- Cited by
- 276
- References
- 49
- Citations by year
- 2026: 2 · 2024: 1 · 2023: 2 · 2022: 3 · 2021: 7 · 2020: 7 · 2019: 3 · 2018: 2 · 2017: 3 · 2016: 3 · 2015: 2 · 2014: 6 · 2013: 11 · 2012: 14
- FWCI
- 7.96
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Biological Chemistry (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Funders
- Japan Cardiovascular Research Foundation
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Peroxisome Proliferator-Activated Receptors
- Health Sciences › Medicine › Pharmacology › Inflammatory mediators and NSAID effects
- Health Sciences › Medicine › Oncology › Cytokine Signaling Pathways and Interactions
- Keywords
- cyclooxygenase-2, PPARγ, 15-deoxy-Δ12,14-prostaglandin J2, prostaglandin D2, macrophages, lipopolysaccharide, glucocorticoid receptor, dexamethasone, NF-κB signaling, negative feedback regulation, atherogenesis, foam cells, inflammation, endothelial cells, U937 cells, NS-398
- MeSH terms
- Animals, Aorta, Cattle, Cell Differentiation, Cells, Cultured, Endothelium, Vascular, Feedback, Humans, Isoenzymes, Kinetics, Lipopolysaccharides, Luciferases, Macrophages, Membrane Proteins, Prostaglandin-Endoperoxide Synthases, Recombinant Fusion Proteins, Tetradecanoylphorbol Acetate, Transcription Factors, Transcription, Genetic, Transfection, Prostaglandin D2, Dinoprostone, Gene Expression Regulation, Enzymologic, Genes, Reporter, Receptors, Cytoplasmic and Nuclear, U937 Cells, Cyclooxygenase 2
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