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Di-n-butyl phthalate modifies PMA-induced macrophage differentiation of THP-1 monocytes via PPARγ
Vegard Sæter Grytting1, Bergitte Pearl Olderbø2, Jørn A Holme1
1Department of Air Pollution and Noise, Division of Infection Control and Environmental Health, Norwegian Institute of Public Health, PO Box 4404, Nydalen, N-0403 Oslo, Norway.
Abstract:
The present study examined the effects of di-n-butyl phthalate (DBP) on phorbol myristate acetate (PMA)-induced macrophage differentiation of THP-1 monocytes, determined by morphological classification and flow cytometry. Focusing on the expression of the surface marker CD36, the potential role of peroxisome proliferator-activated receptor gamma (PPARγ) was examined using various PPARγ agonists and antagonists. As the PPARγ ligand-binding domain contains multiple ligand-binding sites (LBS), agonist and antagonists targeting the different sites were used. DBP accelerated PMA-induced morphological changes and increased expression of CD36, although to a lesser degree than the PPARγ agonists rosiglitazone and 15-deoxy-Δ12,14-prostaglandin J2 (15d-PGJ2). A proteomics screening revealed that DBP enhanced the expression of PPARγ-regulated proteins. During combined exposures, DBP partly attenuated the effect of rosiglitazone, an agonist binding reversibly to PPARγ's canonical LBS. In contrast, DBP increased expression of CD36 in combination with 15d-PGJ2 which binds irreversibly to the canonical LBS. Thus, DBP appears to interact with both the canonical and alternative LBS. Accordingly, the antagonist GW9662, which binds to the canonical LBS, only partly reduced the DBP-induced CD36 expression, while the dual-site antagonist SR16832 completely blocked the effects of DBP. Overall, the results show that DBP modifies PMA-induced differentiation of THP-1 cells through interaction with PPARγ.
Insights
Di-n-butyl phthalate (DBP) influences macrophage differentiation by interacting with peroxisome proliferator-activated receptor gamma (PPARγ). DBP modulates CD36 expression, suggesting a role in cellular processes via PPARγ ligand-binding sites.
Area of Science:
- Endocrinology
- Cell Biology
- Toxicology
Background:
- Macrophage differentiation is crucial for immune responses.
- Phthalates are environmental contaminants with potential endocrine-disrupting effects.
- Peroxisome proliferator-activated receptor gamma (PPARγ) is a key regulator of differentiation.
Purpose of the Study:
- To investigate the effects of di-n-butyl phthalate (DBP) on macrophage differentiation.
- To explore the role of PPARγ in DBP-mediated effects on THP-1 monocytes.
- To elucidate the interaction of DBP with PPARγ ligand-binding sites.
Main Methods:
- THP-1 monocytes were induced to differentiate using phorbol myristate acetate (PMA).
- Morphological classification and flow cytometry were used to assess differentiation and CD36 expression.
- PPARγ agonists, antagonists, and proteomics were employed to study molecular mechanisms.
Main Results:
- DBP accelerated PMA-induced macrophage differentiation and CD36 expression.
- Proteomics revealed DBP enhanced expression of PPARγ-regulated proteins.
- DBP's interaction with both canonical and alternative PPARγ ligand-binding sites was demonstrated.
Conclusions:
- DBP modulates PMA-induced THP-1 cell differentiation through interaction with PPARγ.
- DBP affects CD36 expression, a marker of macrophage differentiation.
- The findings suggest phthalates can interfere with nuclear receptor signaling pathways.
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