The role of interleukin-17 and interferon-gamma in the generation of arthritic pain

慢性疼痛的常见原因是关节紊乱，其中包括炎症性关节疾病，如风湿性关节炎。我们以疾病为导向的方法探讨关节炎疼痛的机制。由于促炎细胞因子在类风湿关节炎的发病机制中起着关键作用，我们研究它们在关节炎疼痛的产生和维持中的作用。我们发现，促炎细胞因子如肿瘤坏死因子- α和白细胞介素-6通过感觉神经元上的细胞因子受体使痛觉神经元敏感，从而显著促进关节炎疼痛的产生。最近的研究表明，细胞因子白介素-17 （IL-17）和干扰素- γ (ifn - γ)在类风湿关节炎等自身免疫性疾病中起着重要的致病作用。由于感觉神经元表达这些细胞因子受体的比例，我们建议探索IL-17和ifn - γ在关节疼痛产生中的作用和机制。初步数据表明，IL-17以前觉性方式起作用，而ifn - γ则抑制伤害性。基于这些发现，我们提出假设，IL-17和ifn - γ显著影响关节伤害感觉神经元对机械刺激的敏感性，并参与长期调节机械性痛觉过敏，这是关节炎疼痛的一个主要特征。由于体内IL-17和ifn - γ可能由相同的Th细胞释放，并且由于这些细胞因子可能以相反的方式作用于感觉神经元，我们还将特别讨论这些细胞因子在感觉神经元中的相互作用。此外，我们将探讨这些细胞因子如何在伤害感觉中发挥作用。我们假设这两种细胞因子都调节了痛觉感觉神经元中特定瞬时受体电位离子通道（有害刺激的主要转导分子）的表达和功能。此外，我们假设IL-17和ifn - γ对感觉神经元的兴奋性有不同的影响，对短期和长期兴奋性的影响差异可能是由于这些细胞因子对不同类型的电压门控钠通道的影响不同。为了解决这些问题，我们将对培养的背根神经节神经元进行行为实验、体内电生理记录、膜片夹持和钙成像实验，并利用免疫组织化学方法研究瞬时受体电位离子通道在体内和培养的感觉神经元中的表达和调控。该项目的总体目标是进一步了解IL-17和ifn - γ介导的神经免疫相互作用，了解关节炎期间关节疼痛的机制，以及了解细胞因子的神经生物学作用。

Very frequent causes of chronic pain are disorders of the joint, and amongst them are inflammatory joint diseases such as rheumatoid arthritis. We explore the mechanisms of arthritic pain in a disease-oriented approach. Because proinflammatory cytokines play a pivotal role in the pathogenesis of rheumatoid arthritis we investigate their role in the generation and maintenance of arthritic pain. We showed that proinflammatory cytokines such as tumor necrosis factor-alpha and interleukin-6 significantly contribute to pain generation in arthritis by sensitizing nociceptive neurons through cytokine receptors on sensory neurons. Recent research shows that the cytokines interleukin-17 (IL-17) and interferon-gamma (IFN-gamma) play a significant pathogenic role in autoimmune diseases such as rheumatoid arthritis. Since proportions of sensory neurons express receptors for these cytokines, we propose to explore the role and mechanisms of IL-17 and IFN-gamma in the generation of joint pain. Preliminary data suggest that IL-17 acts in a pronociceptive manner whereas IFN-gamma rather inhibits nociception. Based on these findings we put forward the hypothesis that both IL-17 and IFN-gamma significantly influence the sensitivity of nociceptive sensory neurons of the joint for mechanical stimuli and are involved in the long-term regulation of mechanical hyperalgesia, a major feature of pain in arthritis. Because in vivo IL-17 and IFN-gamma may be released by the same Th cells and because these cytokines may act on sensory neurons in an opposite manner, we will also particularly address the interactions of these cytokines at sensory neurons. Furthermore we will explore how these cytokines exert their effects in nociception. We hypothesize that both cytokines regulate the expression and function of particular Transient Receptor Potential ion channels (major transduction molecules for noxious stimuli) in nociceptive sensory neurons. Furthermore, we hypothesize that IL-17 and IFN-gamma differently influence the excitability of sensory neurons and that differences in the effect on short and long-term excitability may result from different effects of these cytokines on different types of voltage-gated sodium channels. In order to address these questions we will carry out behavioral experiments, electrophysiological recordings in vivo, patch clamping and calcium imaging experiments in cultured dorsal root ganglion neurons, and we will study the expression and regulation of Transient Receptor Potential ion channels in vivo and in cultured sensory neurons using immunohistochemistry. The overall aim of the project is to further our understanding of neuroimmune interactions mediated by IL-17 and IFN-gamma, our understanding of the mechanisms of joint pain during arthritis, and our understanding of the neurobiological actions of cytokines.