Figure 8. A schematic model depicts the reciprocal regulation between REGγ and NFκB.

Inflammatory injury impairs integrity of the epithelial barrier, triggering initial activation of NFκB, which promotes expression of IκBɛ and REGγ. Elevated REGγ enhances degradation of IκBɛ protein in a ubiquitin-independent manner, neutralizing its ability to inhibit NFκB, thus leading to further elevation of REGγ and activation of NFκB. The reciprocal regulation between REGγ and NFκB via IκBɛ constitutes a novel regulatory circuit with the potential for positive feedback that can lead to run-away inflammation, the development of colitis and CAC. Notably, IκBɛ KO mice are not resistant to DSS colitis, unlike REGγ KOs. We speculate this is because of compensatory upregulation of other IκBs that takes place in the case of chronic IκBɛ deficiency (IκBɛ KO) but not acute deficiency such as in REGγ-deficient mice.