Differential effects of locally and systemically administered soluble glycoprotein 130 on pain and inflammation in experimental arthritis.
Differential effects of locally and systemically administered soluble glycoprotein 130 on pain and inflammation in experimental arthritis.
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DOI：
10.1186/ar3079
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发表时间：
2010
影响因子：
4.9
通讯作者：
Schaible HG
中科院分区：
文献类型：
--
作者：
Boettger MK;Leuchtweis J;Kümmel D;Gajda M;Bräuer R;Schaible HG
白细胞介素-6（IL-6）是全身性关节炎的关键参与者，参与炎症和关节破坏。在神经细胞中也发现了IL-6信号传导。最近，IL-6，特别是IL-6与其可溶性IL-6受体（sIL-6 R）一起显示出诱导关节伤害感受器对机械刺激的持久的强烈敏化，这是难以逆转的，这表明IL-6信号传导在关节炎疼痛的产生和维持中起着重要作用。在这里，我们测试了在关节炎的临床前模型，抗原诱导的关节炎（AIA）的大鼠，是否全身或局部中和IL-6/sIL-6 R复合物与可溶性糖蛋白130（sgp 130）改变关节炎疼痛和sgp 130如何影响AIA的炎症过程。用sgp 130或盐水腹膜内或关节内处理患有AIA的大鼠（每组n = 9）。然后，在21天的观察期内测量疼痛相关和运动行为以及关节肿胀，然后进行炎症和破坏性变化的组织病理学终点分析。在AIA诱导时单一关节内应用sgp 130几乎没有减少AIA的发展，但显著减弱了疼痛相关行为，即AIA急性期的原发性机械性痛觉过敏。相比之下，反复全身应用sgp 130发作后的AIA只有轻微衰减疼痛的晚期阶段的AIA。没有治疗减少继发性痛觉过敏。此外，在本研究中，关节内sgp 130治疗后21天的关节破坏显著减弱，但全身sgp 130治疗后没有。除了其在慢性炎症中的作用之外，关节中的IL-6在AIA的急性和慢性阶段的关节炎性关节疼痛的产生和维持中起重要作用。关节内注射sgp 130的特别有效性表明，首先，发炎关节中的IL-6/sIL-6 R，而不是循环IL-6/sIL-6 R，是痛觉过敏产生的原因，其次，IL-6/sIL-6 R的早期中和在产生抗伤害感受方面特别成功。此外，直接在关节炎症部位中和IL-6/sIL-6 R（以及可能使用跨膜信号转导亚基gp 130的其他细胞因子）似乎可有效预防关节破坏。
Interleukin-6 (IL-6) is a key player in systemic arthritis, involved in inflammation and joint destruction. IL-6 signalling has also been revealed in nerve cells. Recently, IL-6 and in particular IL-6 together with its soluble IL-6 receptor (sIL-6R) were shown to induce a long-lasting robust sensitization of joint nociceptors for mechanical stimuli which was difficult to reverse, suggesting that IL-6 signalling plays a significant role in the generation and maintenance of arthritic pain. Here we tested in a preclinical model of arthritis, antigen-induced arthritis (AIA) in the rat, whether systemic or local neutralization of IL-6/sIL-6R complexes with soluble glycoprotein 130 (sgp130) alters arthritic pain and how sgp130 influences the inflammatory process in AIA. Rats with AIA were either treated with sgp130 or saline intra-peritoneally or intra-articularly (each group n = 9). Then, pain-related and locomotor behaviour, as well as joint swelling, were measured during an observation period of 21 days, followed by histopathological end-point analysis for inflammatory and destructive changes. A single intra-articular application of sgp130 at the time of AIA induction barely reduced the development of AIA, but significantly attenuated pain-related behaviour, that is, primary mechanical hyperalgesia in the acute phase of AIA. By contrast, repeated systemic application of sgp130 after onset of AIA only slightly attenuated pain at a late stage of AIA. None of the treatments reduced secondary hyperalgesia. Furthermore, in the present study joint destruction at 21 days was significantly attenuated after intra-articular sgp130 treatment, but not after systemic sgp130. In addition to its role in chronic inflammation, IL-6 in the joint plays a significant role in the generation and maintenance of arthritic joint pain at acute and chronic stages of AIA. The particular effectiveness of intra-articular injection of sgp130 indicates, first, that IL-6/sIL-6R in the inflamed joint, rather than circulating IL-6/sIL-6R, is responsible for the generation of hyperalgesia, and, second, that early neutralization of IL-6/sIL-6R is particularly successful in producing antinociception. Furthermore, neutralization of IL-6/sIL-6R (and possibly other cytokines which use the transmembrane signal-transducing subunit gp130) directly at the site of joint inflammation seems to be effective in the prevention of joint destruction.
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影响因子：
15.1
作者：
Boettger, Michael Karl;Weber, Konstanze;Schaible, Hans-Georg
通讯作者：
Schaible, Hans-Georg
影响因子：
15.3
作者：
NOVICK, D;ENGELMANN, H;WALLACH, D;RUBINSTEIN, M
通讯作者：
RUBINSTEIN, M
影响因子：
7.3
作者：
Whiteside, GT;Harrison, J;Walker, K
通讯作者：
Walker, K
影响因子：
13.6
作者：
Fonseca, J. E.;Santos, M. J.;Choy, E.
通讯作者：
Choy, E.
影响因子：
--
作者：
Boettger, Michael K.;Hensellek, Susanne;Schaible, Hans-Georg
通讯作者：
Schaible, Hans-Georg