Möser Christine V, Stephan Heike, Altenrath Katharina, Kynast Katharina L, Russe Otto Q, Olbrich Katrin, Geisslinger Gerd, Niederberger Ellen
Pharmazentrum Frankfurt/ZAFES, Institut für Klinische Pharmakologie, Klinikum der Goethe-Universität Frankfurt, Theodor Stern Kai 7, 60590, Frankfurt am Main, Germany.
J Neuroinflammation. 2015 May 23;12:100. doi: 10.1186/s12974-015-0319-3.
TANK-binding kinase (TBK1) is a non-canonical IκB kinase (IKK) involved in the regulation of type I interferons and of NF-κB signal transduction. It is activated by viral infections and inflammatory mediators and has therefore been associated with viral diseases, obesity, and rheumatoid arthritis. Its role in pain has not been investigated so far. Due to the important roles of NF-κB, classical IκB Kinases and the IKK-related kinase, IKKε, in inflammatory nociception, we hypothesized that TBK1, which is suggested to form a complex with IKKε under certain conditions, might also alter the inflammatory nociceptive response.
We investigated TBK1 expression and regulation in "pain-relevant" tissues of C57BL/6 mice by immunofluorescence, quantitative PCR, and Western blot analysis. Furthermore, nociceptive responses and the underlying signal transduction pathways were assessed using TBK1(-/-) mice in two models of inflammatory nociception.
Our data show that TBK1 is expressed and regulated in the spinal cord after peripheral nociceptive stimulation and that a deletion of TBK1 alleviated the inflammatory hyperalgesia in mice while motor function and acute nociception were not altered. TBK1-mediated effects are at least partially mediated by regulation of NF-κB dependent COX-2 induction but also by alteration of expression of c-fos via modulation of MAP kinases as shown in the spinal cord of mice and in cell culture experiments.
We suggest that TBK1 exerts pronociceptive effects in inflammatory nociception which are due to both modulation of NF-κB dependent genes and regulation of MAPKs and c-fos. Inhibition of TBK1 might therefore constitute a novel effective tool for analgesic therapy.
TANK结合激酶（TBK1）是一种非典型的IκB激酶（IKK），参与I型干扰素的调节以及核因子κB（NF-κB）信号转导。它可被病毒感染和炎症介质激活，因此与病毒性疾病、肥胖症和类风湿性关节炎有关。迄今为止，尚未对其在疼痛中的作用进行研究。鉴于NF-κB、经典IκB激酶以及IKK相关激酶IKKε在炎性伤害感受中发挥重要作用，我们推测，在某些条件下可能与IKKε形成复合物的TBK1，或许也会改变炎性伤害感受反应。
我们通过免疫荧光、定量PCR和蛋白质免疫印迹分析，研究了C57BL/6小鼠“疼痛相关”组织中TBK1的表达及调控情况。此外，在两种炎性伤害感受模型中，使用TBK1基因敲除小鼠评估伤害感受反应及潜在的信号转导通路。
我们的数据表明，外周伤害性刺激后脊髓中可表达并调控TBK1，敲除TBK1可减轻小鼠的炎性痛觉过敏，而运动功能和急性伤害感受未受影响。TBK1介导的效应至少部分是通过调节NF-κB依赖的环氧化酶-2（COX-2）诱导来实现的，同时也通过调节丝裂原活化蛋白激酶（MAPK）来改变c-fos的表达，这在小鼠脊髓和细胞培养实验中均有体现。
我们认为，TBK1在炎性伤害感受中发挥促伤害感受作用，这是由于其对NF-κB依赖基因的调节以及对MAPK和c-fos的调控所致。因此，抑制TBK1可能成为一种新型有效的镇痛治疗工具。
