Department of Orthopedic Surgery, Keio University School of Medicine, 35 Shinano-machi, Shinjuku-ku, Tokyo, 160-8582, Japan.
Department of Advanced Therapy for Musculoskeletal Disorders, Keio University School of Medicine, 35 Shinano-machi, Shinjuku-ku, Tokyo, 160-8582, Japan.
Sci Rep. 2018 Oct 25;8(1):15783. doi: 10.1038/s41598-018-34173-5.
Auto-inflammatory syndrome, a condition clinically distinct from rheumatoid arthritis, is characterized by systemic inflammation in tissues such as major joints, skin, and internal organs. Autonomous innate-immune activation is thought to promote this inflammation, but underlying pathological mechanisms have not been clarified nor are treatment strategies established. Here, we newly established a mouse model in which IL-1 signaling is conditionally activated in adult mice (hIL-1 cTg) and observed phenotypes similar to those seen in auto-inflammatory syndrome patients. In serum of hIL-1 cTg mice, IL-6 and IL-17 levels significantly increased, and signal transducer and activator of transcription 3 (Stat3) was activated in joints. When we crossed hIL-1 cTg with either IL-6- or IL-17-deficient mice or with Stat3 conditional knockout mice, phenotypes seen in hIL-1 cTg mice were significantly ameliorated. Thus, IL-6, IL-17 and Stat3 all represent potential therapeutic targets for this syndrome.
自身炎症综合征与类风湿关节炎在临床上有明显区别，其特征是主要关节、皮肤和内脏等组织的全身炎症。自主先天免疫激活被认为会促进这种炎症，但尚未阐明潜在的病理机制，也没有确立治疗策略。在这里，我们新建立了一种条件性激活成年小鼠中白细胞介素-1 信号的小鼠模型（hIL-1 cTg），并观察到与自身炎症综合征患者相似的表型。在 hIL-1 cTg 小鼠的血清中，白细胞介素-6 和白细胞介素-17 水平显著增加，关节中信号转导和转录激活因子 3（Stat3）被激活。当我们将 hIL-1 cTg 与白细胞介素-6 或白细胞介素-17 缺陷小鼠或 Stat3 条件性敲除小鼠杂交时，hIL-1 cTg 小鼠的表型明显改善。因此，白细胞介素-6、白细胞介素-17 和 Stat3 均可能成为该综合征的潜在治疗靶点。
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