Department of Biophysics, Division of Clinical of Immunology, Kobe University Graduate School of Health Sciences, Tomogaoka 7-10-2, Suma, Kobe 654-0142, Japan.
Department of Orthopaedic Surgery, Kobe Kaisei Hospital, Shinohara-Kita 3-11-15, Nada, Kobe 657-0068, Japan.
Int Immunopharmacol. 2020 Jul;84:106549. doi: 10.1016/j.intimp.2020.106549. Epub 2020 May 18.
Diurnal variation of symptoms are observed in rheumatoid arthritis, especially in productions of cytokines that show peak concentrations during mid night. In contrast, cytokines of collagen-induced arthritis (CIA) mice increase in daytimes under Mid-light condition. By using chronotherapy, differences in drug efficacies according to administration time of Baricitinib, a wide ranged cytokine blocker, were examined in CIA mice.
CIA mice were administered a dose of 3 mg/kg of Baricitinib once a day at zeitgeber time (ZT) 0 or ZT12 for 21 days. Arthritis scores, histopathology and factors related to joint destruction in sera were examined. Phosphorylation of STAT3 in liver, expressions of cytokines in spleen, and Interleukin (IL)-6 and tumor necrosis factor (TNF)-α in sera were measured.
In CIA mice, diurnal variations were observed both in expressions of cytokines and phosphorylation of STAT3. Arthritis scores of ZT0/12 group decreased from day3 as compared to untreated mice, and those of ZT0 group significantly decreased as compared to ZT12 group from day12. Pathological findings, immunohistochemistry of cytokines and Receptor activator of nuclear factor kappa-Β ligand (RANKL)/osteoprotegerin ratio in sera well reflected results of arthritis scores. Diurnal variation of STAT3 phosphorylation was suppressed in ZT0 group. At ZT2, expressions of IL-6/Interferon-γ/TNF/granulocyte-macrophage colony-stimulating factor in ZT0 group were significantly decreased as compared to untreated mice, though not in ZT12 group. In ZT0 group, IL-6 and TNF-α in sera were decreased for longer time than that in ZT12 group.
Chronotherapy using Baricitinib targeting cytokine secretions is effective in CIA mice. Clinical applications of chronotherapy can be expected to enhance the drug efficacy.
类风湿关节炎患者的症状存在昼夜变化，尤其是细胞因子的产生在午夜达到峰值。相比之下，胶原诱导性关节炎（CIA）小鼠的细胞因子在中光期白天增加。通过时间治疗学，我们在 CIA 小鼠中检查了广泛的细胞因子阻滞剂巴瑞替尼给药时间不同的药物疗效差异。
CIA 小鼠每天在 Zeitgeber 时间（ZT）0 或 ZT12 时给予 3mg/kg 巴瑞替尼一次，共 21 天。检查关节炎评分、组织病理学和血清中与关节破坏相关的因子。测量肝脏中 STAT3 的磷酸化、脾脏中细胞因子的表达以及血清中白细胞介素（IL）-6 和肿瘤坏死因子（TNF）-α。
在 CIA 小鼠中，细胞因子的表达和 STAT3 的磷酸化均存在昼夜变化。ZT0/12 组的关节炎评分从第 3 天开始比未治疗的小鼠下降，而 ZT0 组从第 12 天开始比 ZT12 组显著下降。病理学发现、细胞因子的免疫组织化学和血清中核因子 kappa-B 受体激活剂配体（RANKL）/骨保护素的比率很好地反映了关节炎评分的结果。ZT0 组 STAT3 磷酸化的昼夜变化受到抑制。在 ZT2 时，ZT0 组的 IL-6/干扰素-γ/TNF/粒细胞-巨噬细胞集落刺激因子的表达明显低于未治疗的小鼠，而 ZT12 组则没有。在 ZT0 组中，血清中的 IL-6 和 TNF-α的减少时间比 ZT12 组长。
针对细胞因子分泌的巴瑞替尼时间治疗在 CIA 小鼠中是有效的。时间治疗的临床应用有望提高药物疗效。
