Local intracellular signaling cascades following peripheral nerve injury lead to robust axon regeneration and neuropathic pain induction. Cytokines are classic injury-induced mediators. We used sciatic nerve ligature (ScNL) to investigate temporal changes in IL-6 and its receptor gp130 in both ipsilateral and contralateral lumbal (L4-L5) dorsal root ganglia (DRG). Rats were operated aseptically on unilateral ScNL and allowed to survive for 1, 3, 7, and 14 days. Immunohistochemistry and Western blot analysis were used to determine levels of IL-6 and gp130 in DRG. A distinct increase in immunostaining for IL-6 was found in the neuronal cell bodies of sections through both ipsilateral and contralateral DRG at 1 and 3 days after operation. After 7 and 14 days, the DRG sections displayed only a moderate elevation in immunostaining when compared with sections of naïve DRG. The levels of IL-6 protein increased in both ipsilateral and contralateral lumbal DRG following peripheral nerve injury. The elevation of IL-6 protein was significant in both ipsilateral and contralateral DRG 1, 3, 7, and 14 days after operation. On the other hand, the levels of gp130 receptor did not change significantly. The data provide evidence for changes in IL-6 levels not only in the DRG associated with the damaged nerve but also in those unassociated with nerve injury during the experimental neuropathic pain model.

Department of Anatomy Division of Neuroanatomy Faculty of Medicine Masaryk University 62500 Brno Czech Republic

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Arruda JL, Colburn RW, Rickman AJ, Rutkowski MD, DeLeo JA (1998) Increase of interleukin-6 mRNA in the spinal cord following peripheral nerve injury in the rat: potential role of IL-6 in neuropathic pain. Brain Res Mol Brain Res 62:228–235. doi:10.1016/S0169-328X(98)00257-5 PubMed

Bolin LM, Verity AN, Silver JE, Shooter EM, Abrams JS (1995) Interleukin-6 production by Schwann cells and induction in sciatic nerve injury. J Neurochem 64:850–858 PubMed

Brazda V, Muller P, Brozkova K, Vojtesek B (2006) Restoring wild-type conformation and DNA-binding activity of mutant p53 is insufficient for restoration of transcriptional activity. Biochem Biophys Res Commun 351:499–506. doi:10.1016/j.bbrc.2006.10.065 PubMed

Cafferty WB, Gardiner NJ, Gavazzi I, Powell J, McMahon SB, Heath JK, Munson J, Cohen J, Thompson SW (2001) Leukemia inhibitory factor determines the growth status of injured adult sensory neurons. J Neurosci 21:7161–7170 PubMed PMC

Cafferty WB, Gardiner NJ, Das P, Qiu J, McMahon SB, Thompson SW (2004) Conditioning injury-induced spinal axon regeneration fails in interleukin-6 knock-out mice. J Neurosci 24:4432–4443 PubMed PMC

Chao T, Pham K, Steward O, Gupta R (2008) Chronic nerve compression injury induces a phenotypic switch of neurons within the dorsal root ganglia. J Comp Neurol 506:180–193. doi:10.1002/cne.21537 PubMed

Chudler EH, Anderson LC, Byers MR (1997) Nerve growth factor depletion by autoimmunization produces thermal hypoalgesia in adult rats. Brain Res 765:327–330. doi:10.1016/S0006-8993(97)00681-1 PubMed

De Jongh RF, Vissers KC, Meert TF, Booij LH, De Deyne CS, Heylen RJ (2003) The role of interleukin-6 in nociception and pain. Anesth Analg 96:1096–1103. doi:10.1213/01.ANE.0000055362.56604.78 (table of contents) PubMed

DeLeo JA, Colburn RW, Nichols M, Malhotra A (1996) Interleukin-6-mediated hyperalgesia/allodynia and increased spinal IL-6 expression in a rat mononeuropathy model. J Interferon Cytokine Res 16:695–700 PubMed

De Martino C, Zamboni L (1967) Silver methenamine stain for electron microscopy. J Ultrastruct Res 19:273–282 PubMed

Dubovy P, Jancalek R, Klusakova I, Svizenska I, Pejchalova K (2006) Intra- and extraneuronal changes of immunofluorescence staining for TNF-alpha and TNFR1 in the dorsal root ganglia of rat peripheral neuropathic pain models. Cell Mol Neurobiol 26:1205–1217. doi:10.1007/s10571-006-9006-3 PubMed PMC

Dubovy P, Tuckova L, Jancalek R, Svizenska I, Klusakova I (2007) Increased invasion of ED-1 positive macrophages in both ipsi- and contralateral dorsal root ganglia following unilateral nerve injuries. Neurosci Lett 427:88–93. doi:10.1016/j.neulet.2007.09.012 PubMed

Gadient RA, Otten UH (1997) Interleukin-6 (IL-6)–a molecule with both beneficial and destructive potentials. Prog Neurobiol 52:379–390. doi:10.1016/S0301-0082(97)00021-X PubMed

Gardiner NJ, Cafferty WB, Slack SE, Thompson SW (2002) Expression of gp130 and leukaemia inhibitory factor receptor subunits in adult rat sensory neurones: regulation by nerve injury. J Neurochem 83:100–109. doi:10.1046/j.1471-4159.2002.01101.x PubMed

Grothe C, Heese K, Meisinger C, Wewetzer K, Kunz D, Cattini P, Otten U (2000) Expression of interleukin-6 and its receptor in the sciatic nerve and cultured Schwann cells: relation to 18-kD fibroblast growth factor-2. Brain Res 885:172–181. doi:10.1016/S0006-8993(00)02911-5 PubMed

Hanani M (2005) Satellite glial cells in sensory ganglia: from form to function. Brain Res Brain Res Rev 48:457–476. doi:10.1016/j.brainresrev.2004.09.001 PubMed

Hirota H, Kiyama H, Kishimoto T, Taga T (1996) Accelerated Nerve Regeneration in Mice by upregulated expression of interleukin (IL) 6 and IL-6 receptor after trauma. J Exp Med 183:2627–2634. doi:10.1084/jem.183.6.2627 PubMed PMC

Jacobs JM, Macfarlane RM, Cavanagh JB (1976) Vascular leakage in the dorsal root ganglia of the rat, studied with horseradish peroxidase. J Neurol Sci 29:95–107. doi:10.1016/0022-510X(76)90083-6 PubMed

Kidd BL, Cruwys SC, Garrett NE, Mapp PI, Jolliffe VA, Blake DR (1995) Neurogenic influences on contralateral responses during experimental rat monoarthritis. Brain Res 688:72–76. doi:10.1016/0006-8993(95)00512-O PubMed

Kieseier BC, Tani M, Mahad D, Oka N, Ho T, Woodroofe N, Griffin JW, Toyka KV, Ransohoff RM, Hartung HP (2002) Chemokines and chemokine receptors in inflammatory demyelinating neuropathies: a central role for IP-10. Brain 125:823–834. doi:10.1093/brain/awf070 PubMed

Kishimoto TK, Springer TA (1989) Human leukocyte adhesion deficiency: molecular basis for a defective immune response to infections of the skin. Curr Probl Dermatol 18:106–115 PubMed

Kishimoto T, Akira S, Narazaki M, Taga T (1995) Interleukin-6 family of cytokines and gp130. Blood 86:1243–1254 PubMed

Kleinschnitz C, Brinkhoff J, Sommer C, Stoll G (2005) Contralateral cytokine gene induction after peripheral nerve lesions: dependence on the mode of injury and NMDA receptor signaling. Brain Res Mol Brain Res 136:23–28. doi:10.1016/j.molbrainres.2004.12.015 PubMed

Koltzenburg M, Wall PD, McMahon SB (1999) Does the right side know what the left is doing? Trends Neurosci 22:122–127. doi:10.1016/S0166-2236(98)01302-2 PubMed

Liu RY, Snider WD (2001) Different signaling pathways mediate regenerative versus developmental sensory axon growth. J Neurosci 21:RC164 PubMed PMC

Liu CN, Wall PD, Ben-Dor E, Michaelis M, Amir R, Devor M (2000) Tactile allodynia in the absence of C-fiber activation: altered firing properties of DRG neurons following spinal nerve injury. Pain 85:503–521. doi:10.1016/S0304-3959(00)00251-7 PubMed

Marchand F, Perretti M, McMahon SB (2005) Role of the immune system in chronic pain. Nat Rev Neurosci 6:521–532. doi:10.1038/nrn1700 PubMed

Markus A, Zhong J, Snider WD (2002) Raf and akt mediate distinct aspects of sensory axon growth. Neuron 35:65–76. doi:10.1016/S0896-6273(02)00752-3 PubMed

McMahon SB, Cafferty WB, Marchand F (2005) Immune and glial cell factors as pain mediators and modulators. Exp Neurol 192:444–462. doi:10.1016/j.expneurol.2004.11.001 PubMed

Mellick RS, Cavanagh JB (1968) Changes in blood vessel permeability during degeneration and regeneration in peripheral nerves. Brain 91:141–160. doi:10.1093/brain/91.1.141 PubMed

Mullberg J, Geib T, Jostock T, Hoischen SH, Vollmer P, Voltz N, Heinz D, Galle PR, Klouche M, Rose-John S (2000) IL-6 receptor independent stimulation of human gp130 by viral IL-6. J Immunol 164:4672–4677 PubMed

Murphy PG, Grondin J, Altares M, Richardson PM (1995) Induction of interleukin-6 in axotomized sensory neurons. J Neurosci 15:5130–5138 PubMed PMC

Murphy P, Topilko P, Schneider-Maunoury S, Seitanidou T, Baron-Van Evercooren A, Charnay P (1996) The regulation of Krox-20 expression reveals important steps in the control of peripheral glial cell development. Development 122:2847–2857 PubMed

Murphy PG, Ramer MS, Borthwick L, Gauldie J, Richardson PM, Bisby MA (1999) Endogenous interleukin-6 contributes to hypersensitivity to cutaneous stimuli and changes in neuropeptides associated with chronic nerve constriction in mice. Eur J Neurosci 11:2243–2253. doi:10.1046/j.1460-9568.1999.00641.x PubMed

Oka T, Oka K, Hosoi M, Hori T (1995) Intracerebroventricular injection of interleukin-6 induces thermal hyperalgesia in rats. Brain Res 692:123–128. doi:10.1016/0006-8993(95)00691-I PubMed

Olsson R (1966) Partial hepatectomy in experimental carbon tetrachloride-induced liver fibrosis. A histological and biochemical study in rats. Acta Chir Scand Suppl 366:3–85 PubMed

Oppenhheim JJ, Feldman M (2001) Cytokine reference. Academic Press, New York

Qiu J, Cafferty WB, McMahon SB, Thompson SW (2005) Conditioning injury-induced spinal axon regeneration requires signal transducer and activator of transcription 3 activation. J Neurosci 25:1645–1653. doi:10.1523/JNEUROSCI.3269-04.2005 PubMed PMC

Reichert F, Levitzky R, Rotshenker S (1996) Interleukin 6 in intact and injured mouse peripheral nerves. Eur J Neurosci 8:530–535. doi:10.1111/j.1460-9568.1996.tb01237.x PubMed

Ryoke K, Ochi M, Iwata A, Uchio Y, Yamamoto S, Yamaguchi H (2000) A conditioning lesion promotes in vivo nerve regeneration in the contralateral sciatic nerve of rats. Biochem Biophys Res Commun 267:715–718. doi:10.1006/bbrc.1999.2017 PubMed

Shamash S, Reichert F, Rotshenker S (2002) The cytokine network of Wallerian degeneration: tumor necrosis factor-alpha, interleukin-1alpha, and interleukin-1beta. J Neurosci 22:3052–3060 PubMed PMC

Sheth K, Friel J, Nolan B, Miller-Graziano C, Bankey P (2002) Down-regulated circulating PMN function after injury despite enhanced p38 MAPK activity. Surg Infect (Larchmt) 3:151–157. doi:10.1089/109629602760105826 (discussion 157–158) PubMed

Simpson RJ, Hammacher A, Smith DK, Matthews JM, Ward LD (1997) Interleukin-6: structure-function relationships. Protein Sci 6:929–955. doi:10.1002/pro.5560060501 PubMed PMC

Stoll G, Muller HW (1999) Nerve injury, axonal degeneration and neural regeneration: basic insights. Brain Pathol 9:313–325 PubMed PMC

Svensson P, Wang K, Arendt-Nielsen L, Cairns BE, Sessle BJ (2005) Pain effects of glutamate injections into human jaw or neck muscles. J Orofac Pain 19:109–118 PubMed

Taga T, Kishimoto T (1997) Gp130 and the interleukin-6 family of cytokines. Annu Rev Immunol 15:797–819. doi:10.1146/annurev.immunol.15.1.797 PubMed

Thomson AW (1991) Immunomodulation: suppression, enhancement and autoimmunity. Curr Opin Biotechnol 2:247–253. doi:10.1016/0958-1669(91)90017-Y PubMed

Ueda H (2006) Molecular mechanisms of neuropathic pain-phenotypic switch and initiation mechanisms. Pharmacol Ther 109:57–77. doi:10.1016/j.pharmthera.2005.06.003 PubMed

Yamaguchi H, Ochi M, Mori R, Ryoke K, Yamamoto S, Iwata A, Uchio Y (1999) Unilateral sciatic nerve injury stimulates contralateral nerve regeneration. NeuroReport 10:1359–1362. doi:10.1097/00001756-199904260-00037 PubMed

Zhong J, Heumann R (1995) Lesion-induced interleukin-6 mRNA expression in rat sciatic nerve. Ann N Y Acad Sci 762:488–490 PubMed

Zhong H, Zhang M, Nurse CA (1999) Electrophysiological characterization of 5-HT receptors on rat petrosal neurons in dissociated cell culture. Brain Res 816:544–553 PubMed

The Intrinsic Neuronal Activation of the CXCR4 Signaling Axis Is Associated with a Pro-Regenerative State in Cervical Primary Sensory Neurons Conditioned by a Sciatic Nerve Lesion

Bilateral activation of glial cells and cellular distribution of the chemokine CCL2 and its receptor CCR2 in the trigeminal subnucleus caudalis of trigeminal neuropathic pain model

Dynamic response to peripheral nerve injury detected by in situ hybridization of IL-6 and its receptor mRNAs in the dorsal root ganglia is not strictly correlated with signs of neuropathic pain

Bilateral changes of cannabinoid receptor type 2 protein and mRNA in the dorsal root ganglia of a rat neuropathic pain model

Bilateral elevation of interleukin-6 protein and mRNA in both lumbar and cervical dorsal root ganglia following unilateral chronic compression injury of the sciatic nerve