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.
[1]Fudan Univ, Hosp & Inst Obstet & Gynecol, Shanghai 200011, Peoples R China;
[2]East China Normal Univ, 500 Dongchuan Rd, Shanghai 200241, Peoples R China;
[3]East China Normal Univ, Shanghai Key Lab Regulatory Biol, Sch Life Sci, Shanghai Fengxian Dist Cent Hosp,Joint Ctr Transl, 500 Dongchuan Rd, Shanghai 200241, Peoples R China;
[4]Fudan Univ, Shanghai Peoples Hosp 5, Shanghai 200240, Peoples R China;
[5]Southern Med Univ, Fengxian Hosp, 6600 Nan Feng Rd, Shanghai 201499, Peoples R China;
[6]Northwest Univ, Coll Life Sci, Xian 710069, Shanxi, Peoples R China
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