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AhR-Induced Anti-Inflammatory Effects on a Caco-2/THP-1 Co-Culture Model of Intestinal Inflammation Are Mediated by
Gustavo Henrique Oliveira da Rocha1, Claudia Müller1, Susanne Przybylski-Wartner1
1Department of Preclinical Development and Validation, Fraunhofer Institute for Cell Therapy and Immunology, 04103 Leipzig, Germany.
Abstract:
The aryl hydrocarbon receptor (AhR) and the peroxisome proliferator-activated receptor γ (PPARγ) are ligand-activated transcription factors that have in recent years been investigated for their anti-inflammatory properties for treatment of inflammatory bowel diseases (IBDs). These are globally prevalent chronic maladies of the gut that lack cost-efficient therapeutical options capable of inducing long-term remission. In the present study, we used an in vitro Transwell® co-culture model composed of Caco-2 epithelial cells in the apical compartment and lipopolysaccharide-treated (LPS) THP-1 macrophages in the basolateral compartment. Secretion of cytokines, disruption of epithelial integrity, and expression of surface markers and junctional proteins were assessed in order to investigate interactions between AhR and PPARγ on the ligand-elicited effects on the control of inflammation. The results revealed that the potent AhR ligand 6-formylindolo[3,2-b]carbazole (FICZ) attenuated LPS-induced IL-6 release by macrophages, which then stabilized Caco-2 monolayer permeability by decreasing claudin-2 expression. These effects were disrupted by GW9662 and to some extent by CH223191, inhibitors of PPARγ and AhR, respectively. Our main findings evidence PPARγ might be a downstream regulator of AhR activation essential for its ligand-based anti-inflammatory effects, suggesting it might be employed as either an auxiliary target or as a biomarker of therapeutical efficacy on AhR-based IBD pharmacotherapy.
Insights
The aryl hydrocarbon receptor (AhR) pathway, when activated by FICZ, reduces inflammation in inflammatory bowel diseases (IBDs). Peroxisome proliferator-activated receptor γ (PPARγ) appears crucial for these anti-inflammatory effects, suggesting it as a therapeutic target.
Area of Science:
- Immunology
- Gastroenterology
- Pharmacology
Background:
- Inflammatory bowel diseases (IBDs) are chronic gut conditions with limited effective treatments.
- Aryl hydrocarbon receptor (AhR) and peroxisome proliferator-activated receptor γ (PPARγ) show potential anti-inflammatory properties for IBD therapy.
Purpose of the Study:
- To investigate the interaction between AhR and PPARγ in controlling inflammation within an in vitro IBD model.
- To determine if PPARγ is a downstream mediator of AhR's anti-inflammatory effects.
Main Methods:
- Utilized a Transwell® co-culture model with Caco-2 epithelial cells and LPS-treated THP-1 macrophages.
- Assessed cytokine secretion, epithelial integrity, and protein expression following AhR ligand (FICZ) and inhibitor treatments.
Main Results:
- FICZ treatment reduced macrophage IL-6 release and stabilized Caco-2 monolayer permeability by decreasing claudin-2.
- Inhibitors of PPARγ (GW9662) and AhR (CH223191) disrupted these anti-inflammatory effects.
Conclusions:
- PPARγ may act as a downstream regulator of AhR activation, essential for its anti-inflammatory actions in IBD.
- PPARγ could serve as an auxiliary therapeutic target or a biomarker for AhR-based IBD pharmacotherapy.
