The Cytokine Interleukin-6 Is Sufficient But Not Necessary to Mimic the Peripheral Conditioning Lesion Effect on Axonal Growth

Abstract

Lesioning the peripheral branch of a dorsal root ganglion (DRG) neuron before injury of the central branch of the same neuron enables spontaneous regeneration of these spinal axons. This effect is cAMP and transcription dependent. Here, we show that the cytokine interleukin-6 (IL-6) is upregulated in DRG neurons after either a conditioning lesion or treatment with dibutyryl-cAMP. In culture, IL-6 allows neurons to grow in the presence of inhibitors of regeneration present in myelin. Importantly, intrathecal delivery of IL-6 to DRG neurons blocks inhibition by myelin both in vitro and in vivo, effectively mimicking the conditioning lesion. Blocking IL-6 signaling has no effect on the ability of cAMP to overcome myelin inhibitors. Consistent with this, IL-6-deficient mice respond to a conditioning lesion as effectively as wild-type mice. We conclude that IL-6 can mimic both the cAMP effect and the conditioning lesion effect but is not an essential component of either response.

An Autocrine Neuronal Interleukin-6 Loop Mediates Chloride Accumulation and NKCC1 Phosphorylation in Axotomized Sensory Neurons

“…To assess the neuronal contribution to IL-6 secretion relative to nonneuronal cells, we performed IL-6 measurements in axotomized culture at 4 DIV in the absence and the presence of 1 M (␤-Darabinofuranosyl)cytosine, AraC, to reduce non-neuronal cell proliferation. In agreement with a continuous IL-6 production and secretion in vitro with time (Cao et al, 2006), the amount of IL-6 was increased to 397 Ϯ 33 pg/ml (n ϭ 3) at 4 DIV. In the presence of AraC, it was reduced to 277 Ϯ 10 pg/ml (n ϭ 3) ( Fig.…”

“…In agreement with other studies, we show that IL-6 is one of the factors promoting neurite growth (Cafferty et al, 2004;Cao et al, 2006). In addition, we provide evidence that inhibition of IL-6R signaling specifically reduced total primary neurite length of NF-200-positive medium to large sensory neurons.…”

“…In addition, we provide evidence that inhibition of IL-6R signaling specifically reduced total primary neurite length of NF-200-positive medium to large sensory neurons. Contradictory results concerning the effects of IL-6 on neurite growth of conditioned axotomized neurons have been reported using IL-6 Ϫ/Ϫ mice (Cafferty et al, 2004;Cao et al, 2006). In our culture conditions, we did also get contradictory results as only mild changes in neurite length were obtained in IL-6 Ϫ/Ϫ axotomized sensory neurons.…”

“…Combined overexpression of IL-6 and its ␣ receptor IL-6R, IL-6R, resulted in faster regeneration of the hypoglossal nerve (Hirota et al, 1996). Furthermore, peripheral injury-induced IL-6 is able to promote regeneration within the CNS (Cafferty et al, 2004;Cao et al, 2006). Since the IL-6 signal-transducing ␤ receptor, gp130, is ubiquitously expressed in sensory neurons, the specificity of IL-6 signaling is mainly mediated by tissue-specific constitutive IL-6 ␣ receptor, IL-6R, expression and/or local actions of soluble IL-6R (Gardiner et al, 2002;Andratsch et al, 2009).…”

Boosting Central Nervous System Axon Regeneration by Circumventing Limitations of Natural Cytokine Signaling

“…To test their responsiveness towards hIL-6, we exposed dissociated DRG neurons to different concentrations of hIL-6 (Figure 4). We used only recombinant IL-6 as positive control in these experiments, 34 as CNTF did not significantly increase axon growth of murine DRG neurons. Both IL-6 and hIL-6 elicited a pronounced and concentration-dependent growth response.…”