da Rocha Gustavo Henrique Oliveira, Müller Claudia, Przybylski-Wartner Susanne, Schaller Heidrun, Riemschneider Sina, Lehmann Jörg
Department of Preclinical Development and Validation, Fraunhofer Institute for Cell Therapy and Immunology, 04103 Leipzig, Germany.
Fraunhofer Cluster of Excellence Immune-Mediated Diseases [CIMD], 04103 Leipzig, Germany.
Int J Mol Sci. 2024 Dec 5;25(23):13072. doi: 10.3390/ijms252313072.
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.
芳烃受体（AhR）和过氧化物酶体增殖物激活受体γ（PPARγ）是配体激活的转录因子，近年来人们对其抗炎特性进行了研究，以用于治疗炎症性肠病（IBD）。这些疾病是全球普遍存在的肠道慢性疾病，缺乏能够诱导长期缓解的经济高效的治疗选择。在本研究中，我们使用了一种体外Transwell共培养模型，其顶端隔室由Caco-2上皮细胞组成，基底外侧隔室由脂多糖处理（LPS）的THP-1巨噬细胞组成。为了研究AhR和PPARγ之间在配体引发的炎症控制效应上的相互作用，我们评估了细胞因子的分泌、上皮完整性的破坏以及表面标志物和连接蛋白的表达。结果显示，强效AhR配体6-甲酰基吲哚并[3,2-b]咔唑（FICZ）可减弱LPS诱导的巨噬细胞IL-6释放，进而通过降低claudin-2表达来稳定Caco-2单层的通透性。这些效应分别被PPARγ抑制剂GW9662和AhR抑制剂CH223191破坏，且在一定程度上被后者破坏。我们的主要发现证明，PPARγ可能是AhR激活的下游调节因子，对其基于配体的抗炎作用至关重要，这表明它可能被用作基于AhR的IBD药物治疗的辅助靶点或治疗效果的生物标志物。
