Brain Advance Access originally published online on April 7, 2005
Brain 2005 128(7):1634-1641; doi:10.1093/brain/awh490
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Fast modulation of heat-activated ionic current by proinflammatory interleukin 6 in rat sensory neurons
1 Institut für Physiologie und Experimentelle Pathophysiologie, Friedrich-Alexander Universität, Erlangen-Nürnberg, 2 Institut für Anatomie und Zellbiologie, Justus-Liebig Universität, Giessen, 3 Institut für Biochemie, Christian-Albrecht Universität, Kiel, Germany and 4 Department für Physiologie und Medizinische Physik, Division Physiologie, Medizinische Universität, Innsbruck, Austria
Correspondence to: Prof. Dr M. Kress, Division Physiologie Fritz-Pregl-Str. 3, A-6020 Innsbruck, Austria E-mail: michaela.kress{at}uibk.ac.at
The pro-inflammatory cytokine interleukin-6 (IL-6) together with its soluble receptor (sIL-6R) induces and maintains thermal hyperalgesia. It facilitates the heat-induced release of calcitonin gene-related peptide from rat cutaneous nociceptors in vivo and in vitro. Here we report that exposure of nociceptive neurons to the IL-6–sIL-6R complex or the gp130-stimulating designer IL-6–sIL-6R fusion protein Hyper-IL-6 (HIL-6) resulted in a potentiation of heat-activated inward currents (Iheat) and a shift of activation thresholds towards lower temperatures without affecting intracellular calcium levels. The Janus tyrosine kinase inhibitor AG490, the selective protein kinase C (PKC) inhibitor, bisindolylmaleimide 1 (BIM1), as well as rottlerin, a selective blocker of the PKC
isoform, but not the cyclooxygenase inhibitor indomethacin, effectively reduced the effect. Reverse transcription–polymerase chain reaction (RT–PCR) and in situ hybridization revealed expression of mRNA for the signal-transducing ß subunit of the receptor gp130 in neuronal somata, rather than satellite cells in rat dorsal root ganglia. Together, the results suggest that IL-6–sIL-6R acts directly on sensory neurons. It increases their susceptibility to noxious heat via the gp130/Jak/PKC signalling pathway.
Key Words: thermal hyperalgesia; neuropathic pain; TRPV-1; vanilloid receptor; protein kinase
Abbreviations: BIM = bisindolylmaleimide; DRG = dorsal root ganglion; HIL-6 = Hyper-IL-6; Iheat = heat-activated ionic current; IL-6 = interleukin-6; LIFR = leukaemia inhibitory factor receptor; PKC = protein kinase C; RT–PCR = reverse transcription–polymerase chain reaction; sIL-6R = interleukin-6 soluble receptor; TRPV = vallinoid receptor
Received July 6, 2004. Revised December 23, 2004. Accepted February 28, 2005.
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