Tumor formation at ileocecal junction associated with interleukin-1β upregulation in aryl hydrocarbon...

Aryl hydrocarbon receptor (AhR) is a ligand-dependent transcription factor. We previously reported spontaneous ileocecal tumorigenesis in AhR-deficient mice after the age of 10 weeks, which originated in the confined area between ileum and cecum. This study aimed to investigate the underlying mechanism that causes tumor development at this particular location. To observe mucosal architecture in detail, tissues of ileocecal region were stained with methylene blue. Gene expression profile in the ileocecal tissue was compared with cecum. Immunohistochemical analysis was performed with ileocecal tissues using antibodies against ileum-specific Reg3β or cecum-specific Pitx2. In AhR^+/+ mice and AhR^+/- mice, that do not develop lesions, methylene blue staining revealed the gradually changing shape and arrangement of villi from ileum to cecum. It was also observed in AhR-deficient mice before developing lesions. Microarray-based analysis revealed abundant antimicrobial genes, such as Reg3, in the ileocecal tissue while FGFR2 and Pitx2 were specific to cecum. Immunohistochemical analysis of AhR-deficient mice indicated that lesions originated from the ileocecal junction, a boundary area between different epithelial types. Site-specific gene expression analysis revealed higher expression of IL-1β at the ileocecal junction compared with the ileum or cecum of 9-11-week-old AhR-deficient mice. These findings indicate that AhR plays a vital function in the ileocecal junction. Regulating AhR activity can potentially manage the stability of ileocecal tissue possessing cancer-prone characteristics. This investigation contributes to understanding homeostasis in different epithelial transitional tissues, frequently associated with pathological states.