The Protein Kinase IKKε Is a Potential Target for the Treatment of Inflammatory Hyperalgesia
The Protein Kinase IKKε Is a Potential Target for the Treatment of Inflammatory Hyperalgesia
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DOI：
10.4049/jimmunol.1004088
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发表时间：
2011-09-01
影响因子：
4.4
通讯作者：
Niederberger, Ellen
中科院分区：
文献类型：
--
作者：
Moeser, Christine V.;Kynast, Katharina;Niederberger, Ellen
抑制剂-κ B激酶A（IKK α）最近才被鉴定为与经典的I-κ B激酶亚基IKK α和IKK β具有高度同源性的酶。尽管有这种相似性，但它主要被讨论为通过调节I型IFN抑制病毒感染。然而，体外研究也表明IKK β在NF-κ B活性的调节中起作用，但IKK β介导的NF-κ B活化的独特机制尚不清楚。鉴于NF-κ B在炎症中的重要作用，我们研究了IKK κ B在小鼠炎症性痛觉过敏模型中的调节和功能。我们发现IKK β在脊髓和背根神经节的伤害性感受神经元中大量表达。在注射酵母多糖或福尔马林引起的后爪炎症过程中，脊髓和背根神经节中IKK β mRNA和蛋白水平迅速增加。IKK β基因敲除小鼠对急性热或机械刺激表现出正常的伤害性反应。然而，在炎性疼痛模型中，IKK β缺陷小鼠与野生型小鼠相比表现出显著降低的伤害性行为，表明IKK β有助于炎性痛觉过敏的发展。抗伤害作用与NF-κ B B活化减少和NF-κ B依赖性环氧化酶-2、诱导型NO合酶和金属蛋白酶-9诱导减弱有关。相反，IRF-3是病毒感染中重要的IKK β靶点，在炎性伤害性刺激后不受调节。因此，我们得出结论，调节炎症伤害性敏感性的激活NF-κ B依赖性基因转录，并可能是一个有用的治疗目标，在治疗炎症性疼痛。免疫学杂志，2011，187：2617-2625。
Inhibitor-kB kinase epsilon (IKK epsilon) was only recently identified as an enzyme with high homology to the classical I-kappa B kinase subunits, IKK alpha and IKK beta. Despite this similarity, it is mainly discussed as a repressor of viral infections by modulating type I IFNs. However, in vitro studies also showed that IKK epsilon plays a role in the regulation of NF-kappa B activity, but the distinct mechanisms of IKK epsilon -mediated NF-kappa B activation are not clear. Given the paramount role of NF-kappa B in inflammation, we investigated the regulation and function of IKK epsilon in models of inflammatory hyperalgesia in mice. We found that IKK epsilon was abundantly expressed in nociceptive neurons in the spinal cord and in dorsal root ganglia. IKK epsilon mRNA and protein levels rapidly increased in spinal cord and dorsal root ganglia during hind paw inflammation evoked by injection of zymosan or formalin. IKK epsilon knockout mice showed normal nociceptive responses to acute heat or mechanical stimulation. However, in inflammatory pain models, IKK epsilon deficient mice exhibited a significantly reduced nociceptive behavior in comparison with wild type mice, indicating that IKK epsilon contributed to the development of inflammatory hyperalgesia. Antinociceptive effects were associated with reduced activation of NF-kappa B and attenuated NF-kappa B-dependent induction of cyclooxygenase-2, inducible NO synthase, and metalloproteinase-9. In contrast, IRF-3, which is an important IKK epsilon target in viral infections, was not regulated after inflammatory nociceptive stimulation. Therefore, we concluded that modulates inflammatory nociceptive sensitivity by activation of NF-kappa B-dependent gene transcription and may be useful as a therapeutic target in the treatment of inflammatory pain. The Journal of Immunology, 2011, 187: 2617-2625.