GP130 cytokines, leukemia inhibitory factor and interleukin-6, induce neuropeptide expression in intact adult rat sensory neuronsin vivo: Time-course, specificity and comparison with sciatic nerve axotomy

doi:10.1016/S0306-4522(97)00553-8

Neuroscience

Volume 84, Issue 4, June 1998, Pages 1247-1255

https://doi.org/10.1016/S0306-4522(97)00553-8 Get rights and content

Abstract

The gp130 cytokines leukemia inhibitory factor and interleukin-6 are neuroactive cytokines associated with peripheral nerve injury. Here we show that exogenous administration of these factors selectively regulates neuropeptide phenotype in intact sensory neurons in a manner consistent with their role as injury-induced factors. Intraneural injection of leukemia inhibitory factor into the intact sciatic nerve of adult rats induces a significant increase in the percentage of neuronal profiles immunoreactive for galanin in the L4 and L5 dorsal root ganglia without altering the percentage profiles immunoreactive for vasoactive intestinal polypeptide or neuropeptide Y. Galanin-immunoreactivity was predominantly confined to those neurons which retrogradely transported and accumulated leukemia inhibitory factor. The up-regulation of galanin-immunoreactivity observed in L4 and L5 dorsal root ganglia following unilateral axotomy of the sciatic nerve was significantly reduced following continuous treatment for two weeks with a monoclonal antibody against the gp130 receptor motif. Intraneural injection of interleukin-6 into the intact sciatic nerve also significantly increased the percentage of neuronal profiles which displayed galanin-immunoreactivity but not vasoactive intestinal polypeptide or neuropeptide Y-immunoreactivity.

Our results indicate that cytokines which interact with the gp130 receptor at the site of peripheral nerve injury contribute to the cell body response to axotomy. Changes in the levels of such cytokines however are insufficient to account for the complete repertoire of neuropeptide phenotypic changes associated with peripheral nerve injury.

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Indeed, Shadiack et al. (1998) found that galanin expression in sympathetic and sensory neurons is dependent on the induction of the cytokine LIF. Injection of LIF and IL6 into the intact sciatic nerve of adult rats significantly increases the percentage of immunoreactive galanin neurons after sciatic nerve axotomy in the L4 and L5 DRGs (Thompson et al., 1998). Furthermore, IL6 knockout mice show decreased galanin expression in the spinal cord (Ramer et al., 1998).
We utilized a transgenic mouse model where nuclear factor kappa B (NF-κB) is selectively inhibited in glial fibrillary acidic protein (GFAP) expressing cells. The transgene, GFAP-IκBα-dn, overexpresses a dominant negative form of the inhibitor of NF-κB (IκBα) under the control of the GFAP promoter. In the present work, we sought to understand the impact of glial NF-κB inhibition on the expression of pain mediating sensory neuropeptides galanin and calcitonin gene related peptide (CGRP) in a model of neuropathic pain in mice. Chronic constriction injury (CCI) of the left sciatic nerve was performed on wild type (WT) and GFAP-IκBα-dn transgenic mice. RT-PCR and immunohistological staining were performed in sciatic nerve and/or L4-L5 DRG tissue for galanin, CGRP and macrophage marker CD11b. GFAP-IκBα-dn mice had less mechanical and thermal hyperalgesia compared to WT mice post-CCI. After CCI, we observed galanin upregulation in DRG and sciatic nerve, which was less in GFAP-IκBα-dn mice. CGRP gene expression in the DRG increased transiently on day 1 post-CCI in WT but not in GFAP-IκBα-dn mice, and no evidence of CGRP upregulation in sciatic nerve post-CCI was found. After CCI, upregulation of CD11b in sciatic nerve was less in GFAP-IκBα-dn mice compared to WT mice, indicative of less macrophage infiltration. Our results showed that glial NF-κB inhibition reduces galanin and CGRP expression, which are neuropeptides that correlate with pain behavior and inflammation after peripheral nerve injury.
Interleukin-6 upregulates the expression of PMP22 in cultured rat Schwann cells via a JAK2-dependent pathway
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The interleukin-6 (IL-6) family of cytokines is thought to be involved in the development and regeneration of peripheral nerves; however, their roles in myelination remain unclear. In this study, we examined the effects of IL-6 on the expression of genes for compact myelin proteins using Schwann cell cultures prepared by multiple explantation of adult rat sciatic nerves. In semi-quantitative reverse transcription-polymerase chain reaction analysis, stimulation of Schwann cells with IL-6 significantly increased the mRNA level of peripheral myelin protein 22 (PMP22), but not those of myelin protein zero and myelin basic protein. The increase in PMP22 mRNA was markedly suppressed by AG490, a Janus kinase 2 (JAK2) inhibitor, but not significantly by PD098059, a mitogen-activated protein kinase inhibitor. Immunocytochemical staining revealed that IL-6 enhanced immunoreactivities for the phosphorylated forms of both JAK2 and signal transducer and activator of transcription 3 (STAT3), as well as that for PMP22. These results indicate that IL-6 can enhance PMP22 production in Schwann cells via a JAK2-dependent pathway by probably activating STAT3 and thus may contribute to myelination.
Reg-2 expression in dorsal root ganglion neurons after adjuvant-induced monoarthritis
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Reg-2 is a secreted protein that is expressed de novo in motoneurons, sympathetic neurons, and dorsal root ganglion (DRG) neurons after nerve injury and which can act as a Schwann cell mitogen. We now show that Reg-2 is also upregulated by DRG neurons in inflammation with a very unusual expression pattern. In a rat model of monoarthritis, Reg-2 immunoreactivity was detected in DRG neurons at 1 day, peaked at 3 days (in 11.6% of DRG neurons), and was still present at 10 days (in 5%). Expression was almost exclusively in the population of DRG neurons that expresses the purinoceptor P2X₃ and binding sites for the lectin Griffonia simplicifolia IB4, and which is known to respond to glial cell line–derived neurotrophic factor (GDNF). Immunoreactivity was present in DRG cell bodies and central terminals in the dorsal horn of the spinal cord. In contrast, very little expression was seen in the nerve growth factor (NGF) responsive and substance P expressing population. However intrathecal delivery of GDNF did not induce Reg-2 expression, but leukemia inhibitory factor (LIF) had a dramatic effect, inducing Reg-2 immunoreactivity in 39% of DRG neurons and 62% of P2X₃ cells.
Changes in inflammation have previously been observed predominantly in the neuropeptide expressing, NGF responsive, DRG neurons. Our results show that changes also take place in the IB4 population, possibly driven by members of the LIF family of neuropoietic cytokines. In addition, the presence of Reg-2 in central axon terminals implicates Reg-2 as a possible modulator of second order dorsal horn cells.
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Many experimental studies have provided evidence that pro-inflammatory cytokines induce or increase neuropathic pain. Direct receptor-mediated actions of cytokines have been demonstrated in addition to those involving further mediators. In spite of the redundancy and pleiotropy of the cytokine network, specific actions of individual cytokines have been identified. Preliminary clinical data point to a possible beneficial role of cytokine inhibition in patients with painful neuropathy or radiculopathy.
Exogenous leukaemia inhibitory factor enhances nerve regeneration after late secondary repair using a bioartificial nerve conduit
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Citation Excerpt :
It meets the criteria for an injury factor: its time-course of expression is intimately related to injury, it acts by specific receptor-mediated uptake and retrograde transport, and it has trophic and tropic actions.16,28 Furthermore, LIF enhances neurite outgrowth in vitro, and pre-treatment with antibodies against the gp-130 neurocytokine receptor moiety inhibits the response of sensory neurons to axotomy.26 As a therapeutic agent, LIF also has the potential benefit over traditional neurotrophic factors, such as nerve growth factor, that it acts upon both motor and sensory neurons after injury, and is synergistic with other neurotrophic factors, such as nerve growth factor.16
The clinical outcome of peripheral nerve injuries remains disappointing, even in the ideal situation of a primary repair performed with optimal microsurgical techniques. Primary repair is appropriate for only about 85% of injuries, and outcome is worse following secondary nerve repair, partly owing to the reduced regenerative potential of chronically axotomised neurons. Leukaemia inhibitory factor (LIF) is a gp-130 neurocytokine that is thought to act as an ‘injury factor’, triggering the early-injury phenotype within neurons and potentially boosting their regenerative potential after secondary nerve repair. At 2–4 months after sciatic nerve axotomy in the rat, 1 cm gaps were repaired using either nerve isografts or poly-3-hydroxybutyrate conduits containing a calcium alginate and fibronectin hydrogel.
Regeneration was determined by quantitative immunohistochemistry 6 weeks after repair, and the effect of incorporating recombinant LIF (100 ng/ml) into the conduits was assessed. LIF increased the regeneration distance in repairs performed after both 2 months (69%, P=0.019) and 4 months (123%, P=0.021), and was statistically comparable to nerve graft. The total area of axonal immunostaining increased by 21% (P>0.05) and 63% (P>0.05), respectively. Percentage immunostaining area was not increased in the 2 months group, but increased by 93% in the repairs performed 4 months after axotomy. Exogenous LIF, therefore, has a potential role in promoting peripheral nerve regeneration after secondary repair, and can be effectively delivered within poly-3-hydroxybutyrate bioartificial conduits used for nerve repair.

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GP130 cytokines, leukemia inhibitory factor and interleukin-6, induce neuropeptide expression in intact adult rat sensory neuronsin vivo: Time-course, specificity and comparison with sciatic nerve axotomy

Abstract

Neuron

Brain Res.

Trends Neurosci.