The interleukin 22–oncostatin M axis promotes intestinal inflammation and tumorigenesis [Epithelial_cells_BulkRNA-seq]

Multicellular cytokine networks regulate the onset of intestinal inflammation and colitis-associated cancer (CAC). Interleukin 22 (IL-22) promotes epithelial cell recovery but can also drive inflammation and tumorigenesis. We demonstrate that IL-22 from innate lymphoid cells activates STAT3 and increases OSM receptor expression in intestinal epithelial cells. This activation leads to sustained STAT3 activity via OSM, promoting inflammation and tumorigenesis. Deleting the OSM receptor or blocking OSM pharmacologically mitigates colitis and CAC. Our findings highlight the IL-22-OSM axis as a potential therapeutic target for these conditions. Col1a2creERT2 and VillincreERT2 Osmr^fl/fl mice were treated with 75 mg/kg body weight of tamoxifen intraperitoneally daily for one week, following the Jackson Laboratory protocol. Control mice, either cre+ Osmr^fl/wt or Osmr^fl/fl without creERT2, also received tamoxifen. Colitis was induced by orally inoculating the mice with 1 × 10^8 CFU of H. hepaticus for two days, followed by weekly 1 mg injections of anti-IL10R antibody.

多细胞细胞因子网络调控肠道炎症与结肠炎相关癌症（colitis-associated cancer, CAC）的发生。白细胞介素22（Interleukin 22, IL-22）可促进上皮细胞修复，但同时也可诱发炎症与肿瘤发生。本研究证实，先天淋巴样细胞分泌的IL-22可激活肠道上皮细胞中的信号转导与转录激活因子3（signal transducer and activator of transcription 3, STAT3），并上调抑瘤素M受体（oncostatin M receptor, OSMR）的表达；该激活通路通过抑瘤素M（Oncostatin M, OSM）介导维持STAT3的持续活化，进而促进炎症发生与肿瘤进展。敲除OSMR或通过药理学手段阻断OSM均可缓解结肠炎及CAC的病情。本研究结果表明，IL-22-OSM信号轴可作为上述疾病的潜在治疗靶点。按照杰克逊实验室（Jackson Laboratory）的实验方案，对Col1a2creERT2及VillincreERT2 Osmr^fl/fl小鼠每日腹腔注射75 mg/kg体重的他莫昔芬，连续给药一周。对照组小鼠（包括cre+ Osmr^fl/wt小鼠及未携带creERT2的Osmr^fl/fl小鼠）同样接受他莫昔芬处理。通过经口接种1×10^8 CFU的肝螺杆菌（Helicobacter hepaticus, H. hepaticus）以诱导小鼠结肠炎，随后每周腹腔注射1 mg抗IL10R抗体。