Background In order to gain insight into the early effects drawn by JAK inhibitors on intra-joint JAK/STAT-dependent signaling, we sought synovial activation of STATs and their end-products, along with their modification with tofacitinib (TOFA), at flare-up in antigen induced arthritis (AIA). New Zealand rabbits were randomly assigned to four groups -healthy controls, AIA, TOFA-treated AIA, or TOFA-treated controls-. AIA was induced with 4 weekly intra-articular ovalbumin injections in sensitized animals. TOFA (10 mg·kg- 1·day- 1) was administered for the last 2 weeks. Animals were euthanized 24 h after the last injection. Results AIA animals showed high-grade synovitis, which was partially improved by TOFA. No effects of the treatment were found on serum C-reactive protein or on the synovial macrophage infiltration at this stage. Synovial MMP-1,-3 and -13 expression levels in treated AIA rabbits were found to drop to those of controls, while a downregulation of IL6, IFNγ and TNF was evident in treated versus untreated AIA rabbits. Concurrently, a reduction in pSTAT1 and SOCS1, but not in pSTAT3, SOCS3 or active NFκB-p65, was noted with TOFA. Conclusions Studying the mechanism of action of immunomodulatory drugs represents a major challenge in vivo, since drug-dependent decreases in inflammation very likely mask direct effects on disease mechanisms. This study design allowed us to prevent any confounding effect resulting from reductions in the overall inflammatory status, hence assessing the true pharmacological actions of TOFA in a very severe synovitis. Our findings point to pSTAT1 and MMPs as early molecular readouts of response to this JAK inhibitor.

中文翻译：

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托法替尼对 pSTAT1 的抑制是实验性慢性滑膜炎早期改善的原因。

背景 为了深入了解 JAK 抑制剂对关节内 JAK/STAT 依赖性信号传导的早期影响，我们寻求 STATs 及其最终产物的滑膜激活，以及它们与托法替尼 (TOFA) 的修饰。抗原诱导关节炎（AIA）。新西兰兔被随机分配到四组——健康对照组、AIA、TOFA 处理的 AIA 或 TOFA 处理的对照组。在致敏动物中通过每周 4 次的关节内卵清蛋白注射来诱导 AIA。TOFA (10 mg·kg- 1·day- 1) 在最后 2 周内给药。最后一次注射后24小时对动物实施安乐死。结果 AIA 动物表现出高度滑膜炎，TOFA 部分改善了滑膜炎。在此阶段，未发现治疗对血清 C 反应蛋白或滑膜巨噬细胞浸润有影响。滑膜 MMP-1，发现处理过的 AIA 兔中的 -3 和 -13 表达水平下降至对照组，而处理过的 AIA 兔与未处理的 AIA 兔相比，IL6、IFNγ 和 TNF 的下调是明显的。同时，TOFA 注意到 pSTAT1 和 SOCS1 减少，但 pSTAT3、SOCS3 或活性 NFκB-p65 没有减少。结论 研究免疫调节药物的作用机制在体内是一项重大挑战，因为药物依赖性炎症减少很可能掩盖了对疾病机制的直接影响。这项研究设计使我们能够防止因整体炎症状态降低而产生的任何混杂效应，从而评估 TOFA 在非常严重的滑膜炎中的真正药理作用。我们的研究结果表明 pSTAT1 和 MMPs 是对这种 JAK 抑制剂反应的早期分子读数。