An autocrine neuronal interleukin-6 loop mediates chloride accumulation and NKCC1 phosphorylation in axotomized sensory neurons

J Neurosci. 2011 Sep 21;31(38):13516-26. doi: 10.1523/JNEUROSCI.3382-11.2011.


The cation-chloride cotransporter NKCC1 plays a fundamental role in the central and peripheral nervous systems by setting the value of intracellular chloride concentration. Following peripheral nerve injury, NKCC1 phosphorylation-induced chloride accumulation contributes to neurite regrowth of sensory neurons. However, the molecules and signaling pathways that regulate NKCC1 activity remain to be identified. Functional analysis of cotransporter activity revealed that inhibition of endogenously produced cytokine interleukin-6 (IL-6), with anti-mouse IL-6 antibody or in IL-6⁻/⁻ mice, prevented chloride accumulation in a subset of axotomized neurons. Nerve injury upregulated the transcript and protein levels of IL-6 receptor in myelinated, TrkB-positive sensory neurons of murine lumbar dorsal root ganglia. Expression of phospho-NKCC1 was observed mainly in sensory neurons expressing IL-6 receptor and was absent from IL-6⁻/⁻ dorsal root ganglia. The use of IL-6 receptor blocking-function antibody or soluble IL-6 receptor, together with pharmacological inhibition of Janus kinase, confirmed the role of neuronal IL-6 signaling in chloride accumulation and neurite growth of a subset of axotomized sensory neurons. Cell-specific expression of interleukin-6 receptor under pathophysiological conditions is therefore a cellular response by which IL-6 contributes to nerve regeneration through neuronal NKCC1 phosphorylation and chloride accumulation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Axotomy / methods
  • Cells, Cultured
  • Chlorides / metabolism
  • Chlorides / physiology*
  • Enzyme Inhibitors / pharmacology
  • Female
  • Ganglia, Spinal / metabolism
  • Interleukin-6 / genetics
  • Interleukin-6 / physiology*
  • Janus Kinases / antagonists & inhibitors
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Nerve Regeneration / drug effects
  • Nerve Regeneration / physiology
  • Neurites / drug effects
  • Neurites / physiology
  • Patch-Clamp Techniques
  • Phosphorylation
  • Receptors, Interleukin-6 / biosynthesis
  • Receptors, Interleukin-6 / physiology
  • Sensory Receptor Cells / drug effects
  • Sensory Receptor Cells / metabolism*
  • Sensory Receptor Cells / physiology
  • Sodium-Potassium-Chloride Symporters / metabolism*
  • Sodium-Potassium-Chloride Symporters / physiology
  • Solute Carrier Family 12, Member 2
  • Up-Regulation


  • Chlorides
  • Enzyme Inhibitors
  • Interleukin-6
  • Receptors, Interleukin-6
  • Slc12a2 protein, mouse
  • Sodium-Potassium-Chloride Symporters
  • Solute Carrier Family 12, Member 2
  • Janus Kinases