Abstract
Interleukin‑22 (IL‑22) has both pro‑inflammatory and anti‑inflammatory properties in a number tissues depending on the environment. Epithelial cells usually have a rapid turnover and are fueled by tissue stem cells. However, the question of whether IL‑22 regulates tissue homeostasis through the modulation of stem cells remains unanswered. In this study, we investigated the role of IL‑22 in the homeostasis of intestinal epithelial cells (IECs) during inflammation through a 3D organoid culture system. qPCR was performed to detect the changes in important gene transcriptions, and immunohistochemistry and western blot analysis were carried out to determine protein expression. As a result, we found that the expression of IL‑22 was synchronously altered with the damage of the intestine. IL‑22 treatment promoted cell proliferation and suppressed the cell differentiation of intestinal organoids. Surprisingly, IL‑22 also led to self‑renewal defects of intestinal stem cells (ISCs), thereby eventually resulting in the death of organoids. In examining the underlying mechanisms, we found that IL‑22 activated signal transducer and activator of transcription 3 (Stat3) phosphorylation and suppressed the Wnt and Notch signaling pathways. Importantly, Wnt3a treatment attenuated the organoid defects caused by IL‑22, which consolidated the importance of Wnt pathway at the downstream of IL‑22. Collectively, the findings of this study indicate that IL‑22 regulates the homeostasis of the intestinal epithelium and is critical for the regeneration of the intestine during inflammation. Thus, the data of this study may provide a potential strategy and a basis for the treatment of diseases of intestinal inflammation in clinical practice.