title: Deletion of interleukin-6 signal transducer gp130 in small sensory neurons attenuates mechanonociception and down-regulates TRPA1 expression.
abstract: Glycoprotein 130 (gp130) is the signal transducing receptor subunit for cytokines of the interleukin-6 (IL-6) family, and it is expressed in a multitude of cell types of the immune and nervous system. IL-6-like cytokines are not only key regulators of innate immunity and inflammation but are also essential factors for the differentiation and development of the somatosensory system. Mice with a null mutation of gp130 in primary nociceptive afferents (SNS-gp130(-/-)) are largely protected from hypersensitivity to mechanical stimuli in mouse models of pathological pain. Therefore, we set out to investigate how neuronal gp130 regulates mechanonociception. SNS-gp130(-/-) mice revealed reduced mechanosensitivity to high mechanical forces in the von Frey assay in vivo, and this was associated with a reduced sensitivity of nociceptive primary afferents in vitro. Together with these findings, transient receptor potential ankyrin 1 (TRPA1) mRNA expression was significantly reduced in DRG from SNS-gp130(-/-) mice. This was also reflected by a reduced number of neurons responding with calcium transients to TRPA1 agonists in primary DRG cultures. Downregulation of Trpa1 expression was predominantly discovered in nonpeptidergic neurons, with the deficit becoming evident during stages of early postnatal development. Regulation of Trpa1 mRNA expression levels downstream of gp130 involved the classical Janus kinase family-signal transducer and activator of transcription pathway. Our results closely link proinflammatory cytokines to the expression of TRPA1, both of which have been shown to contribute to hypersensitive pain states. We suggest that gp130 has an essential role in mechanonociception and in the regulation of TRPA1 expression.
authors: Department of Physiology and Medical Physics, Division of Physiology, Medical University of Innsbruck, A-6020 Innsbruck, Austria.
authors: Philipp
authors: P
authors: Malsch
authors: Department of Physiology and Medical Physics, Division of Physiology, Medical University of Innsbruck, A-6020 Innsbruck, Austria.
authors: Manfred
authors: M
authors: Andratsch
authors: Department of Physiology and Medical Physics, Division of Physiology, Medical University of Innsbruck, A-6020 Innsbruck, Austria.
authors: Christian
authors: C
authors: Vogl
authors: Institute of Physiology and Pathophysiology, Friedrich-Alexander University Erlangen-Nuremberg, 91054 Erlangen, Germany.
authors: Andrea S
authors: AS
authors: Link
authors: Institute of Physiology and Pathophysiology, Friedrich-Alexander University Erlangen-Nuremberg, 91054 Erlangen, Germany.
authors: Christian
authors: C
authors: Alzheimer
authors: Nerve-Gut Research Laboratory, Discipline of Medicine, Faculty of Health Sciences, University of Adelaide, Adelaide, South Australia, Australia 5000, Department of Gastroenterology and Hepatology, Royal Adelaide Hospital, Adelaide, South Australia, Australia 5000, Discipline of Physiology, Faculty of Health Sciences, University of Adelaide, Adelaide, South Australia, Australia 5000, and.
authors: Stuart M
authors: SM
authors: Brierley
authors: Discipline of Physiology, Faculty of Health Sciences, University of Adelaide, Adelaide, South Australia, Australia 5000, and Leukocyte Biology Department, Women's and Children's Health Research Institute, North Adelaide, Australia 5006.
authors: Patrick A
authors: PA
authors: Hughes
authors: Department of Physiology and Medical Physics, Division of Physiology, Medical University of Innsbruck, A-6020 Innsbruck, Austria, michaela.kress@i-med.ac.at.
authors: Michaela
authors: M
authors: Kress
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D050822:Cytokine Receptor gp130 / Q000037:antagonists & inhibitors / Q000172:deficiency* / Q000235:genetics; D015536:Down-Regulation / Q000235:genetics*; D005260:Female; D017353:Gene Deletion; D008297:Male; D008465:Mechanoreceptors / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D012333:RNA, Messenger / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D011984:Sensory Receptor Cells / Q000378:metabolism*; D015398:Signal Transduction / Q000235:genetics; D000074025:TRPA1 Cation Channel; D050051:Transient Receptor Potential Channels / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000235:genetics*
chemical_list: D012333:RNA, Messenger; D000074025:TRPA1 Cation Channel; D050051:Transient Receptor Potential Channels; C475685:Trpa1 protein, mouse; D050822:Cytokine Receptor gp130
keywords: Il-6 signal transducer; JAK/STAT signaling; cytokine; mechanonociceptor; mechanotransduction; pain