Key Laboratory of Gastroenterology and Hepatology, Ministry of Health, Division of Gastroenterology and Hepatology, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai Institute of Digestive Disease, Shanghai, China.
Inflamm Bowel Dis. 2015 Feb;21(2):241-50. doi: 10.1097/MIB.0000000000000267.
High SOCS3 expression in intestinal epithelial cells (IECs) of patients with ulcerative colitis (UC) in remission reflects the shorter time to relapse. We investigated whether high SOCS3 increased risk for relapse through violating STAT3-dependent protective effects of interleukin (IL)-22 during UC remission.
Expression of IL-22 and c-Myc in UC remission mucosa was analyzed by immunohistochemistry. Effects of IL-22 on migration and proliferation of IEC cell lines with enforced SOCS3 expression were assessed with wounding assay and CCK-8 assay, respectively. Influence of STAT3 interference and SOCS3 overexpression on IL-22-regulated expression of antimicrobial peptide and proliferation-related molecules, including DMBT1, c-Myc, Survivin, Bcl-2, and Bcl-xL, were performed with quantitative real-time polymerase chain reaction or Western blot.
Patients with UC in remission showed significantly more IL-22-positive immune cells, but no difference of epithelial c-Myc levels, in mucosa compared with healthy controls. Overexpression of SOCS3 nearly abolished IL-22-induced activation of STAT3. By inhibiting STAT3 signaling, SOCS3 influenced IL-22-induced expression of DMBT1, c-Myc, Survivin, and Bcl-2 as well as proliferation and migration processes in cultured IEC cell line.
SOCS3 overexpression impairs IL-22-mediated epithelial homeostasis and mucosal wound healing, which could be the mechanism for high SOCS3 IEC expression contributed early relapse of mucosal inflammation. Prevention of SOCS3 expression or enhancement of IL-22/STAT3 signaling in IEC seems to be rational therapeutic strategies for UC remission maintenance.
缓解期溃疡性结肠炎（UC）患者肠上皮细胞（IEC）中 SOCS3 高表达反映了复发时间更短。我们研究了 SOCS3 是否通过在 UC 缓解期间破坏 STAT3 依赖性白细胞介素（IL）-22 的保护作用而增加复发风险。
通过免疫组织化学分析 UC 缓解期黏膜中 IL-22 和 c-Myc 的表达。通过划痕试验和 CCK-8 试验分别评估 IL-22 对 SOCS3 过表达的 IEC 细胞系迁移和增殖的影响。采用定量实时聚合酶链反应或 Western blot 检测 STAT3 干扰和 SOCS3 过表达对 IL-22 调节的抗菌肽和增殖相关分子（包括 DMBT1、c-Myc、Survivin、Bcl-2 和 Bcl-xL）表达的影响。
与健康对照相比，缓解期 UC 患者的黏膜中显示出更多的 IL-22 阳性免疫细胞，但上皮细胞 c-Myc 水平没有差异。SOCS3 的过表达几乎消除了 IL-22 诱导的 STAT3 激活。通过抑制 STAT3 信号转导，SOCS3 影响了 IL-22 诱导的 DMBT1、c-Myc、Survivin 和 Bcl-2 的表达以及培养的 IEC 细胞系中的增殖和迁移过程。
SOCS3 过表达会损害 IL-22 介导的上皮稳态和黏膜伤口愈合，这可能是 SOCS3 在 IEC 中高表达导致黏膜炎症早期复发的机制。预防 SOCS3 表达或增强 IEC 中的 IL-22/STAT3 信号似乎是 UC 缓解维持的合理治疗策略。
