Guillot Xavier, Martin Hélène, Seguin-Py Stéphanie, Maguin-Gaté Katy, Moretto Johnny, Totoson Perle, Wendling Daniel, Demougeot Céline, Tordi Nicolas
PEPITE EA4267, FHU INCREASE, Univ. Bourgogne Franche-Comté, Besançon, France.
Service de Rhumatologie, CHRU Besançon, France.
PLoS One. 2017 Jul 31;12(7):e0178668. doi: 10.1371/journal.pone.0178668. eCollection 2017.
Local cryotherapy is widely and empirically used in the adjuvant setting in rheumatoid arthritis treatment, however its own therapeutic and anti-inflammatory effects are poorly characterized. We aimed to evaluate the effects of local cryotherapy on local and systemic inflammation in Adjuvant-induced arthritis, a murine model of rheumatoid arthritis.
The effects of mild hypothermia (30°C for 2 hours) on cytokine protein levels (Multiplex/ELISA) were evaluated in vitro in cultured rat adjuvant-induced arthritis patellae. In vivo, local cryotherapy was applied twice a day for 14 days in arthritic rats (ice: n = 10, cold gas: n = 9, non-treated: n = 10). At day 24 after the induction of arthritis, cytokine expression levels were measured in grinded hind paws (Q-RT-PCR) and in the plasma (Multiplex/ELISA).
In vitro, punctual mild hypothermia down-regulated IL-6 protein expression. In vivo, ice showed a better efficacy profile on the arthritis score and joint swelling and was better tolerated, while cold gas induced a biphasic response profile with initial, transient arthritis worsening. Local cryotherapy also exerted local and systemic anti-inflammatory effects, both at the gene and the protein levels: IL-6, IL-17A and IL-1β gene expression levels were significantly down-regulated in hind paws. Both techniques decreased plasma IL-17A while ice decreased plasma IL-6 protein levels. By contrast, we observed no effect on local/systemic TNF-α pathway.
We demonstrated for the first time that sub-chronically applied local cryotherapy (ice and cold gas) is an effective and well-tolerated treatment in adjuvant-induced arthritis. Furthermore, we provided novel insights into the cytokine pathways involved in Local cryotherapy's local and systemic anti-inflammatory effects, which were mainly IL-6/IL-17A-driven and TNF-α independent in this model.
局部冷冻疗法在类风湿关节炎治疗的辅助环境中被广泛且经验性地使用，然而其自身的治疗和抗炎作用却鲜有明确描述。我们旨在评估局部冷冻疗法对佐剂性关节炎（一种类风湿关节炎的小鼠模型）局部和全身炎症的影响。
在体外培养的大鼠佐剂性关节炎髌骨中评估轻度低温（30°C，持续2小时）对细胞因子蛋白水平（多重检测/酶联免疫吸附测定）的影响。在体内，对患有关节炎的大鼠每天进行两次局部冷冻疗法，持续14天（冰敷组：n = 10，冷气体组：n = 9，未治疗组：n = 10）。在诱导关节炎后的第24天，测量研磨后的后爪（实时定量聚合酶链反应）和血浆（多重检测/酶联免疫吸附测定）中的细胞因子表达水平。
在体外，局部轻度低温下调了白细胞介素-6（IL-6）蛋白表达。在体内，冰敷在关节炎评分和关节肿胀方面显示出更好的疗效，且耐受性更好，而冷气体诱导了双相反应，初期会出现短暂的关节炎恶化。局部冷冻疗法在基因和蛋白水平上也发挥了局部和全身抗炎作用：后爪中IL-6、白细胞介素-17A（IL-17A）和白细胞介素-1β（IL-1β）基因表达水平显著下调。两种技术均降低了血浆IL-17A水平，而冰敷降低了血浆IL-6蛋白水平。相比之下，我们观察到对局部/全身肿瘤坏死因子-α（TNF-α）途径没有影响。
我们首次证明，亚慢性应用局部冷冻疗法（冰敷和冷气体）在佐剂性关节炎中是一种有效且耐受性良好的治疗方法。此外，我们对局部冷冻疗法局部和全身抗炎作用所涉及的细胞因子途径提供了新的见解，在该模型中，这些作用主要由IL-6/IL-17A驱动且独立于TNF-α。
