Andratsch Manfred, Mair Norbert, Constantin Cristina E, Scherbakov Nadja, Benetti Camilla, Quarta Serena, Vogl Christian, Sailer Claudia A, Uceyler Nurcan, Brockhaus Johannes, Martini Rudolf, Sommer Claudia, Zeilhofer Hanns Ulrich, Müller Werner, Kuner Rohini, Davis John B, Rose-John Stefan, Kress Michaela
Department of Physiology and Medical Physics, Division of Physiology, Innsbruck Medical University, Innsbruck, Austria.
J Neurosci. 2009 Oct 28;29(43):13473-83. doi: 10.1523/JNEUROSCI.1822-09.2009.
Interleukin-6 (IL-6) is a key mediator of inflammation. Inhibitors of IL-6 or of its signal transducing receptor gp130 constitute a novel class of anti-inflammatory drugs, which raise great hopes for improved treatments of painful inflammatory diseases such as rheumatoid arthritis. IL-6 and gp130 may enhance pain not only indirectly through their proinflammatory actions but also through a direct action on nociceptors (i.e., on neurons activated by painful stimuli). We found indeed that the IL-6/gp130 ligand-receptor complex induced heat hypersensitivity both in vitro and in vivo. This process was mediated by activation of PKC-delta via Gab1/2/PI(3)K and subsequent regulation of TRPV1, a member of the transient receptor potential (TRP) family of ion channels. To assess the relevance of this direct pain promoting effect of IL-6, we generated conditional knock-out mice, which lack gp130 specifically in nociceptors, and tested them in models of inflammatory and tumor-induced pain. These mice showed significantly reduced levels of inflammatory and tumor-induced pain but no changes in immune reactions or tumor growth. Our results uncover the significance of gp130 expressed in peripheral pain sensing neurons in the pathophysiology of major clinical pain disorders and suggest their use as novel pain relieving agents in inflammatory and tumor pain.
白细胞介素-6（IL-6）是炎症的关键介质。IL-6或其信号转导受体gp130的抑制剂构成了一类新型抗炎药物，为改善类风湿关节炎等疼痛性炎症疾病的治疗带来了巨大希望。IL-6和gp130不仅可以通过其促炎作用间接增强疼痛，还可以通过对伤害感受器（即对由疼痛刺激激活的神经元）的直接作用来增强疼痛。我们确实发现，IL-6/gp130配体-受体复合物在体外和体内均诱导热超敏反应。这一过程是通过Gab1/2/PI(3)K激活蛋白激酶C-δ（PKC-δ）以及随后对瞬时受体电位（TRP）离子通道家族成员TRPV1的调节来介导的。为了评估IL-6这种直接促进疼痛作用的相关性，我们构建了条件性敲除小鼠，其伤害感受器中特异性缺乏gp130，并在炎症性疼痛和肿瘤诱导性疼痛模型中对它们进行了测试。这些小鼠的炎症性疼痛和肿瘤诱导性疼痛水平显著降低，但免疫反应或肿瘤生长没有变化。我们的研究结果揭示了外周疼痛感知神经元中表达的gp130在主要临床疼痛疾病病理生理学中的重要性，并表明它们可作为炎症性疼痛和肿瘤性疼痛的新型止痛剂。
