Defining immunological impact and therapeutic benefit of mild heating in a murine model of arthritis.
Defining immunological impact and therapeutic benefit of mild heating in a murine model of arthritis.
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DOI：
10.1371/journal.pone.0120327
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发表时间：
2015
期刊：
影响因子：
3.7
通讯作者：
Repasky EA
中科院分区：
文献类型：
--
作者：
Lee CT;Kokolus KM;Leigh ND;Capitano M;Hylander BL;Repasky EA
传统疗法，包括各种热疗，自古以来就被认为可以缓解类风湿性关节炎(RA)的症状。然而，由于普遍缺乏关于加热如何影响与RA相关的分子或免疫学靶点的信息，因此热处理(HT)仅限于被称为“替代疗法”的治疗类别。在这项研究中，我们在胶原诱导的关节炎(CIA)模型中评估了轻度羟色胺的有效性，该模型已被许多先前的研究用于评估治疗RA的新的药理方法，并测试炎症免疫活性是否发生改变。我们还比较了羟色胺和甲氨蝶呤的疗效，甲氨蝶呤是一种治疗类风湿关节炎的典型药物。CIA小鼠接受了几个小时的单一羟色胺治疗或每天30分钟的羟色胺治疗。观察病情进展和巨噬细胞浸润情况。我们发现，两种HT方案都显著降低了关节炎疾病的严重程度和炎症关节中的巨噬细胞浸润。令人惊讶的是，羟色胺在控制疾病进展方面与甲氨蝶呤一样有效。在分子水平上，羟色胺抑制肿瘤坏死因子-α，增加IL-10的产生。我们还观察到炎症组织中热休克蛋白70的诱导和核因子-κB和缺氧诱导因子-1α的减少。此外，利用体外激活的巨噬细胞，我们发现羟色胺减少了促炎细胞因子的产生，这一作用与诱导热休克蛋白-1和热休克蛋白70，抑制核因子-κB和STAT的激活有关。我们的发现表明，在临床相关的小鼠模型中，羟色胺在控制关节炎进展方面具有显著的治疗益处，其疗效与甲氨蝶呤相似。机制上，羟色胺以高度相关的抗炎通路为靶点，这有力地支持了其更多的研究，用于RA的临床试验。
Traditional treatments, including a variety of thermal therapies have been known since ancient times to provide relief from rheumatoid arthritis (RA) symptoms. However, a general absence of information on how heating affects molecular or immunological targets relevant to RA has limited heat treatment (HT) to the category of treatments known as “alternative therapies”. In this study, we evaluated the effectiveness of mild HT in a collagen-induced arthritis (CIA) model which has been used in many previous studies to evaluate newer pharmacological approaches for the treatment of RA, and tested whether inflammatory immune activity was altered. We also compared the effect of HT to methotrexate, a well characterized pharmacological treatment for RA. CIA mice were treated with either a single HT for several hours or daily 30 minute HT. Disease progression and macrophage infiltration were evaluated. We found that both HT regimens significantly reduced arthritis disease severity and macrophage infiltration into inflamed joints. Surprisingly, HT was as efficient as methotrexate in controlling disease progression. At the molecular level, HT suppressed TNF-α while increasing production of IL-10. We also observed an induction of HSP70 and a reduction in both NF-κB and HIF-1α in inflamed tissues. Additionally, using activated macrophages in vitro, we found that HT reduced production of pro-inflammatory cytokines, an effect which is correlated to induction of HSF-1 and HSP70 and inhibition of NF-κB and STAT activation. Our findings demonstrate a significant therapeutic benefit of HT in controlling arthritis progression in a clinically relevant mouse model, with an efficacy similar to methotrexate. Mechanistically, HT targets highly relevant anti-inflammatory pathways which strongly support its increased study for use in clinical trials for RA.
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