PPARγ controls I3C-mediated anti-inflammatory effects through the NF-κB/IL-6 pathway on gut inflammation models

Inflammatory bowel diseases (IBD), comprising ulcerative colitis (UC) and Crohn's disease (CD), are chronic inflammatory disorders of the gut of limited available pharmacotherapy. Continuous efforts have striven to better unravel their etiology, but mechanisms leading to disease onset and progression are still not fully comprehended. While in vivo and in vitro colitis models are invaluable for elucidating such mechanisms, they fail individually to fully represent human disease and are not necessarily easily comparable. The peroxisome proliferator-activated receptor gamma (PPARγ) is a transcription factor that has in recent years been evidenced as a key mediator of IBD progression, and better elucidating its role could advance the understanding of IBD. In the present study, we used a mouse model of chronic colitis alongside in vitro co-culture models employing THP1 macrophages combined with Caco-2 epithelial cells or human intestinal organoids. In these models, we tested the influence PPARγ on the effects of indol-3-carbinol (I3C), a well-known agonist of the aryl hydrocarbon receptor (AhR) that has been shown to be effective in ameliorating inflammation in murine colitis models, as well as how PPARγ expression is modulated in response to I3C treatment. Our results delivered clear evidence that PPARγ plays a key role in controlling the anti-inflammatory effects of I3C through the NF-κB/IL-6 axis in macrophages. Further, PPARγ is itself an indicator of I3C therapeutical efficacy in the epithelium. We suggest PPARγ as a potential biomarker for tracking disease progression and therapeutic efficacy, which could also serve as a putative target for future therapeutic interventions.