title: Involvement of Spinal IL-6 Trans-Signaling in the Induction of Hyperexcitability of Deep Dorsal Horn Neurons by Spinal Tumor Necrosis Factor-Alpha.
abstract: During peripheral inflammation, both spinal TNF-α and IL-6 are released within the spinal cord and support the generation of inflammation-evoked spinal hyperexcitability. However, whether spinal TNF-α and IL-6 act independently in parallel or in a functionally dependent manner has not been investigated. In extracellular recordings from mechanonociceptive deep dorsal horn neurons of normal rats in vivo, we found that spinal application of TNF-α increased spinal neuronal responses to mechanical stimulation of knee and ankle joints. This effect was significantly attenuated by either sgp130, which blocks IL-6 trans-signaling mediated by IL-6 and its soluble receptor IL-6R (sIL-6R); by an antibody to the IL-6 receptor; or by minocycline, which inhibits the microglia. IL-6 was localized in neurons of the spinal cord and, upon peripheral noxious stimulation in the presence of spinal TNF-α, IL-6 was released spinally. Furthermore, TNF-α recruited microglial cells to provide sIL-6R, which can form complexes with IL-6. Spinal application of IL-6 plus sIL-6R, but not of IL-6 alone, enhanced spinal hyperexcitability similar to TNF-α and the inhibition of TNF-α-induced hyperexcitability by minocycline was overcome by coadministration of sIL-6R, showing that sIL-6R is required. Neither minocycline nor the TNF-α-neutralizing compound etanercept inhibited the induction of hyperexcitability by IL-6 plus sIL-6R. Together, these data show that the induction of hyperexcitability of nociceptive deep dorsal horn neurons by TNF-α largely depends on the formation of IL-6/sIL-6R complexes that are downstream of TNF-α and requires the interactions of neurons and microglia orchestrated by TNF-α.
  
  
  
  Both spinal TNF-α and IL-6 induce a state of spinal hyperexcitability. We present the novel finding that the full effect of TNF-α on the development of spinal hyperexcitability depends on IL-6 trans-signaling acting downstream of TNF-α. IL-6 trans-signaling requires the formation of complexes of IL-6 and soluble IL-6 receptor. Spinal TNF-α furthers the release of IL-6 from neurons in the spinal cord during peripheral noxious stimulation and recruits microglial cells to provide soluble IL-6 receptor, which can form complexes with IL-6. Therefore, a specific interaction between neurons and microglia is required for the full development of TNF-α-induced hyperexcitability of nociceptive deep horsal horn neurons.
authors.affiliation: Department of Physiology I/Neurophysiology, Jena University Hospital, Friedrich-Schiller-University of Jena, 07743 Jena, Germany, and.
authors.forename: Christian
authors.initials: C
authors.lastname: König
authors.affiliation: Department of Physiology I/Neurophysiology, Jena University Hospital, Friedrich-Schiller-University of Jena, 07743 Jena, Germany, and.
authors.forename: Eric
authors.initials: E
authors.lastname: Morch
authors.affiliation: Department of Physiology I/Neurophysiology, Jena University Hospital, Friedrich-Schiller-University of Jena, 07743 Jena, Germany, and.
authors.forename: Annett
authors.initials: A
authors.lastname: Eitner
authors.affiliation: Department of Physiology I/Neurophysiology, Jena University Hospital, Friedrich-Schiller-University of Jena, 07743 Jena, Germany, and.
authors.forename: Christian
authors.initials: C
authors.lastname: Möller
authors.affiliation: Department of Math and Computer Science, Bethel University, St. Paul, Minnesota 55112.
authors.forename: Brian
authors.identifier: 0000-0002-9988-2116
authors.initials: B
authors.lastname: Turnquist
authors.affiliation: Department of Physiology I/Neurophysiology, Jena University Hospital, Friedrich-Schiller-University of Jena, 07743 Jena, Germany, and.
authors.forename: Hans-Georg
authors.initials: HG
authors.lastname: Schaible
authors.affiliation: Department of Physiology I/Neurophysiology, Jena University Hospital, Friedrich-Schiller-University of Jena, 07743 Jena, Germany, and Andrea.Ebersberger@med.uni-jena.de.
authors.forename: Andrea
authors.initials: A
authors.lastname: Ebersberger
mesh_terms: D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D002135:Calcium-Binding Proteins / Q000378:metabolism; D045744:Cell Line, Tumor; D050822:Cytokine Receptor gp130 / Q000378:metabolism; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D015850:Interleukin-6 / Q000378:metabolism*; D008297:Male; D051379:Mice; D008840:Microfilament Proteins / Q000378:metabolism; D017628:Microglia / Q000187:drug effects / Q000378:metabolism; D008911:Minocycline / Q000494:pharmacology; D010812:Physical Stimulation; D020671:Posterior Horn Cells / Q000187:drug effects* / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D015398:Signal Transduction / Q000187:drug effects*; D013116:Spinal Cord / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*; D043222:Ubiquitin Thiolesterase / Q000378:metabolism
chemical_list: C491049:Aif1 protein, mouse; D002135:Calcium-Binding Proteins; D005904:Glial Fibrillary Acidic Protein; D015850:Interleukin-6; D008840:Microfilament Proteins; D014409:Tumor Necrosis Factor-alpha; D050822:Cytokine Receptor gp130; D043222:Ubiquitin Thiolesterase; C496976:Uchl1 protein, mouse; D008911:Minocycline
keywords: central sensitization; cytokine; electrophysiology; inflammation; microglia; soluble IL-6 receptor