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

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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.