Interferon‐gamma signaling drives epithelial TNF‐alpha receptor‐2 expression during colonic tissue repair

Abstract Interferon‐gamma (IFNγ) is traditionally recognized for its pro‐inflammatory role during intestinal inflammation. Here, we demonstrate that IFNγ also functions as a pro‐repair molecule by increasing TNFα receptor 2 (TNFR2 protein/ TNFRSF1B gene ) expression on intestinal epithelial cells (IEC) following injury in vitro and in vivo. In silico analyses identified binding sites for the IFNγ signaling transcription factor STAT1 in the promoter region of TNFRSF1B . Scratch‐wounded IEC exposed to IFNγ exhibited a STAT1‐dependent increase in TNFR2 expression. In situ hybridization revealed elevated Tnfrsf1b mRNA levels in biopsy‐induced colonic mucosal wounds, while intraperitoneal administration of IFNγ neutralizing antibodies following mucosal injury resulted in impaired IEC Tnfrsf1b mRNA and inhibited colonic mucosal repair. These findings challenge conventional notions that “pro‐inflammatory” mediators solely exacerbate damage by highlighting latent pro‐repair functions. Moreover, these results emphasize the critical importance of timing and amount in the synthesis and release of IFNγ and TNFα during the inflammatory process, as they are pivotal in restoring tissue homeostasis.