INTRODUCTION Primary sclerosing cholangitis (PSC) is a rare cholestatic liver disease with periductal inflammation and fibrosis. Genetic studies suggest inflammatory cytokines and IL-6-dependent activation of transcription factor STAT3 as pivotal steps in PSC pathogenesis. However, details of inflammatory regulation remain unclear. METHODS We recruited 50 patients with PSC (36 with inflammatory bowel disease, 14 without inflammatory bowel disease), 12 patients with autoimmune hepatitis, and 36 healthy controls to measure cytokines in the serum, bile, and immune cell supernatant using bead-based immunoassays and flow cytometry and immunohistochemistry to analyze phosphorylation of STATs in immune cells. Finally, we analyzed cytokines and STAT3 phosphorylation of T cells in the presence of JAK1/2 inhibitors. RESULTS In PSC, IL-6 specifically triggered phosphorylation of STAT3 in CD4 + T cells and lead to enhanced production of interferon (IFN) gamma and interleukin (IL)-17A. Phospho-STAT3-positive CD4 + T cells correlated with systemic inflammation (C-reactive protein serum levels). Combination of immunohistology and flow cytometry indicated that phospho-STAT3-positive cells were enriched in the peribiliary liver stroma and represented CD4 + T cells with prominent production of IFN gamma and IL-17A. JAK1/2 inhibitors blocked STAT3 phosphorylation and production of IFN gamma and IL-6, whereas IL-17A was apparently resistant to this inhibition. DISCUSSION Our results demonstrate systemic and local activation of the IL-6/STAT3 pathway in PSC. Resistance of IL-17A to STAT3-targeted inhibition points to a more complex immune dysregulation beyond STAT3 activation.

中文翻译：

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原发性硬化性胆管炎中 IL-6 依赖性 STAT3 激活和促炎细胞因子的诱导。

简介 原发性硬化性胆管炎 (PSC) 是一种罕见的胆汁淤积性肝病，伴有导管周围炎症和纤维化。遗传学研究表明炎症细胞因子和转录因子 STAT3 的 IL-6 依赖性激活是 PSC 发病机制的关键步骤。然而，炎症调节的细节仍不清楚。方法 我们招募了 50 名 PSC 患者（36 名患有炎症性肠病，14 名无炎症性肠病）、12 名自身免疫性肝炎患者和 36 名健康对照者，使用基于微珠的免疫测定法和流式细胞术和免疫组织化学分析免疫细胞中 STAT 的磷酸化。最后，我们分析了 JAK1/2 抑制剂存在下 T 细胞的细胞因子和 STAT3 磷酸化。结果 在 PSC 中，IL-6 特异性触发 CD4 + T 细胞中 STAT3 的磷酸化，并导致干扰素 (IFN) γ 和白细胞介素 (IL)-17A 的产生增加。磷酸化 STAT3 阳性 CD4 + T 细胞与全身炎症（C 反应蛋白血清水平）相关。免疫组织学和流式细胞术相结合表明，磷酸化 STAT3 阳性细胞在胆周肝基质中富集，代表 CD4 + T 细胞，并显着产生 IFN γ 和 IL-17A。JAK1/2 抑制剂阻断 STAT3 磷酸化以及 IFN γ 和 IL-6 的产生，而 IL-17A 显然对这种抑制有抵抗力。讨论 我们的结果表明 PSC 中 IL-6/STAT3 通路的全身和局部激活。IL-17A 对 STAT3 靶向抑制的抵抗表明除了 STAT3 激活之外还有更复杂的免疫失调。