Blocking AHR signaling curbs IL-8 in lab model of gut inflammation

Inhibiting the aryl hydrocarbon receptor (AHR) with a pharmacological blocker reduced expression of the inflammatory mediator IL-8 in a laboratory model of intestinal inflammation, according to a study published in Molecular Biology Reports. The work, led by Gilda Parsamanesh, Farshid Noorbakhsh, Kaveh Baghaei and Nima Rezaei, provides functional evidence that AHR signaling contributes to inflammatory responses in intestinal epithelial cells, although the protein-level effect did not reach statistical significance.

The AHR is an important regulator of intestinal homeostasis, and altered AHR expression has been linked to inflammatory bowel disease (IBD). However, its precise role in epithelial inflammatory responses has remained unclear. The researchers set out to evaluate AHR signaling in two in vitro models of intestinal inflammation and to test what happens when the receptor is pharmacologically inhibited.

Two inflammatory systems were compared. The first was a differentiated Caco-2/THP-1 co-culture, pairing intestinal epithelial cells with immune cells. The second was a Caco-2 epithelial model stimulated with the inflammatory triggers TNF-α and lipopolysaccharide (LPS). AHR expression was measured by real-time PCR in both settings, and the model whose AHR expression pattern best matched the team’s previous findings in pediatric IBD tissues was selected for the inhibition experiments.

The two models behaved in opposite ways. AHR expression was significantly reduced in the Caco-2/THP-1 co-culture, whereas it increased following TNF-α/LPS stimulation. Because the stimulated epithelial model reproduced the expression pattern seen in the earlier tissue work, it was chosen for further testing with BAY2416964, a selective AHR inhibitor.

To confirm that the drug was working, the researchers measured TIPARP, whose expression reflects AHR activity. BAY2416964 significantly reduced TIPARP expression, supporting effective inhibition of AHR signaling in the stimulated cells.

The clearest downstream effect appeared in IL-8, one of the inflammatory mediators examined in the study. AHR inhibition significantly reduced IL-8 mRNA expression in the TNF-α/LPS-stimulated Caco-2 model. By contrast, reductions in IL-6 and TNF-α messenger RNA after treatment did not reach statistical significance, indicating that IL-8 was the most responsive of the inflammatory mediators tested.

Protein measurements added nuance to the picture. TNF-α/LPS stimulation significantly increased IL-8 production, confirming that the model mounted a robust secretory response. BAY2416964 lowered IL-8 protein levels in the expected direction, but this reduction did not reach statistical significance. The authors therefore describe IL-8 as showing the most consistent response to AHR inhibition across the endpoints tested, while stopping short of claiming a significant protein-level effect.

The study’s conclusions are carefully bounded. The findings suggest that AHR contributes to inflammatory signaling in intestinal epithelial cells and extend the team’s earlier observations of altered AHR expression by adding functional evidence from a controlled experimental system. The authors emphasize that further studies using complementary approaches and more physiologically relevant models are needed to define the broader functional significance of AHR inhibition in intestinal inflammation.

Because the work relied on cell culture rather than patient tissue or animal models, its findings are preliminary with respect to human disease. The contrast between the two in vitro systems also highlights how model choice can shape apparent AHR behavior, with expression falling in the co-culture and rising under direct TNF-α/LPS stimulation. Even so, the identification of IL-8 as a consistent transcriptional target of AHR inhibition offers a concrete lead for future research into how this receptor shapes epithelial inflammation in IBD.

Subject of Research: Attenuation of IL-8 expression following AHR inhibition in an in vitro model of intestinal inflammation

Article Title: Attenuation of IL-8 expression following AHR inhibition in an in vitro model of intestinal inflammation

Article References: Parsamanesh, G., Noorbakhsh, F., Baghaei, K., & Rezaei, N. (2026). Attenuation of IL-8 expression following AHR inhibition in an in vitro model of intestinal inflammation. Molecular Biology Reports, 53(1), Article 1783. https://doi.org/10.1007/s11033-026-12970-w

Image Credits: AI Generated

DOI: 10.1007/s11033-026-12970-w

Keywords: Attenuation, IL-8, expression, following, inhibition, vitro, model, intestinal, inflammation, scientific research