AhR-Induced Anti-Inflammatory Effects on a Caco-2/THP-1 Co-Culture Model of Intestinal Inflammation Are Mediated by PPARγ
Gustavo Henrique Oliveira da Rocha, Claudia Mueller, Susanne Przybylski-Wartner, H.‐G. Schaller, Sina Riemschneider, Jörg Lehmann
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.