Low-Dose Pulsatile Interleukin-6 As a Treatment Option for Diabetic Peripheral Neuropathy

April Ann Cox, Yves Sagot, Gael Hedou, Christina Grek, Travis Wilkes, Aaron I Vinik, Gautam Ghatnekar, April Ann Cox, Yves Sagot, Gael Hedou, Christina Grek, Travis Wilkes, Aaron I Vinik, Gautam Ghatnekar

Abstract

Diabetic peripheral neuropathy (DPN) remains one of the most common and serious complications of diabetes. Currently, pharmacological agents are limited to treating the pain associated with DPN, and do not address the underlying pathological mechanisms driving nerve damage, thus leaving a significant unmet medical need. Interestingly, research conducted using exercise as a treatment for DPN has revealed interleukin-6 (IL-6) signaling to be associated with many positive benefits such as enhanced blood flow and lipid metabolism, decreased chronic inflammation, and peripheral nerve fiber regeneration. IL-6, once known solely as a pro-inflammatory cytokine, is now understood to signal as a multifunctional cytokine, capable of eliciting both pro- and anti-inflammatory responses in a context-dependent fashion. IL-6 released from muscle in response to exercise signals as a myokine and as such has a unique kinetic profile, whereby levels are transiently elevated up to 100-fold and return to baseline levels within 4 h. Importantly, this kinetic profile is in stark contrast to long-term IL-6 elevation that is associated with pro-inflammatory states. Given exercise induces IL-6 myokine signaling, and exercise has been shown to elicit numerous beneficial effects for the treatment of DPN, a causal link has been suggested. Here, we discuss both the clinical and preclinical literature related to the application of IL-6 as a treatment strategy for DPN. In addition, we discuss how IL-6 may directly modulate Schwann and nerve cells to explore a mechanistic understanding of how this treatment elicits a neuroprotective and/or regenerative response. Collectively, studies suggest that IL-6, when administered in a low-dose pulsatile strategy to mimic the body's natural response to exercise, may prove to be an effective treatment for the protection and/or restoration of peripheral nerve function in DPN. This review highlights the studies supporting this assertion and provides rationale for continued investigation of IL-6 for the treatment of DPN.

Keywords: diabetic peripheral neuropathy; interleukin-6; myokine; nerve regeneration; neurocytokine.

Figures

Figure 1
Figure 1
Therapeutic targets of interleukin-6 (IL-6) in diabetic peripheral neuropathy (DPN). Exogenous administration of low-dose IL-6 to treat DPN  may be beneficial due to (1) increased insulin sensitivity in muscle (49), (2) decreased systemic inflammation (43, 44), (3) increased remyelination of axons (–83), (4) increased nerve regeneration (–98), (5) increased lipolysis (47, 48), and (6) decreased insulin secretion (34, 47).

References

    1. Tesfaye S, Selvarajah D. Advances in the epidemiology, pathogenesis and management of diabetic peripheral neuropathy. Diabetes Metab Res Rev (2012) 28(Suppl 1):8–14.10.1002/dmrr.2239
    1. Harati Y. Diabetic neuropathies: unanswered questions. Neurol Clin (2007) 25(1):303–17.10.1016/j.ncl.2007.01.002
    1. Deli G, Bosnyak E, Pusch G, Komoly S, Feher G. Diabetic neuropathies: diagnosis and management. Neuroendocrinology (2013) 98(4):267–80.10.1159/000358728
    1. Amin N, Doupis J. Diabetic foot disease: from the evaluation of the “foot at risk” to the novel diabetic ulcer treatment modalities. World J Diabetes (2016) 7(7):153–64.10.4239/wjd.v7.i7.153
    1. Juster-Switlyk K, Smith AG. Updates in diabetic peripheral neuropathy. F1000Res (2016) 5:3.10.12688/f1000research.7898.1
    1. Landowski LM, Dyck PJ, Engelstad J, Taylor BV. Axonopathy in peripheral neuropathies: mechanisms and therapeutic approaches for regeneration. J Chem Neuroanat (2016) 76(Pt A):19–27.10.1016/j.jchemneu.2016.04.006
    1. Lauria G, Cornblath DR, Johansson O, McArthur JC, Mellgren SI, Nolano M, et al. EFNS guidelines on the use of skin biopsy in the diagnosis of peripheral neuropathy. Eur J Neurol (2005) 12(10):747–58.10.1111/j.1468-1331.2005.01260.x
    1. Vincent AM, Callaghan BC, Smith AL, Feldman EL. Diabetic neuropathy: cellular mechanisms as therapeutic targets. Nat Rev Neurol (2011) 7(10):573–83.10.1038/nrneurol.2011.137
    1. Habib AA, Brannagan TH., III Therapeutic strategies for diabetic neuropathy. Curr Neurol Neurosci Rep (2010) 10(2):92–100.10.1007/s11910-010-0093-7
    1. Hussain N, Adrian TE. Diabetic neuropathy: update on pathophysiological mechanism and the possible involvement of glutamate pathways. Curr Diabetes Rev (2016) 12:1–10.
    1. Sinnreich M, Taylor BV, Dyck PJ. Diabetic neuropathies. Classification, clinical features, and pathophysiological basis. Neurologist (2005) 11(2):63–79.10.1097/01.nrl.0000156314.24508.ed
    1. Kaku M, Vinik A, Simpson DM. Pathways in the diagnosis and management of diabetic polyneuropathy. Curr Diab Rep (2015) 15(6):609.10.1007/s11892-015-0609-2
    1. Boyd A, Casselini C, Vinik E, Vinik A. Quality of life and objective measures of diabetic neuropathy in a prospective placebo-controlled trial of ruboxistaurin and topiramate. J Diabetes Sci Technol (2011) 5(3):714–22.10.1177/193229681100500326
    1. Boyd AL, Barlow PM, Pittenger GL, Simmons KF, Vinik AI. Topiramate improves neurovascular function, epidermal nerve fiber morphology, and metabolism in patients with type 2 diabetes mellitus. Diabetes Metab Syndr Obes (2010) 3:431–7.10.2147/DMSOTT.S13699
    1. Boulton AJ, Vinik AI, Arezzo JC, Bril V, Feldman EL, Freeman R, et al. Diabetic neuropathies: a statement by the American Diabetes Association. Diabetes Care (2005) 28(4):956–62.10.2337/diacare.28.4.956
    1. The Diabetes Control and Complications Trial Research Group. The effect of intensive diabetes therapy on the development and progression of neuropathy. Ann Intern Med (1995) 122(8):561–8.10.7326/0003-4819-122-8-199504150-00001
    1. Duckworth W, Abraira C, Moritz T, Reda D, Emanuele N, Reaven PD, et al. Glucose control and vascular complications in veterans with type 2 diabetes. N Engl J Med (2009) 360(2):129–39.10.1056/NEJMoa0808431
    1. Ismail-Beigi F, Craven T, Banerji MA, Basile J, Calles J, Cohen RM, et al. Effect of intensive treatment of hyperglycaemia on microvascular outcomes in type 2 diabetes: an analysis of the ACCORD randomised trial. Lancet (2010) 376(9739):419–30.10.1016/S0140-6736(10)60576-4
    1. Streckmann F, Zopf EM, Lehmann HC, May K, Rizza J, Zimmer P, et al. Exercise intervention studies in patients with peripheral neuropathy: a systematic review. Sports Med (2014) 44(9):1289–304.10.1007/s40279-014-0207-5
    1. Karstoft K, Pedersen BK. Exercise and type 2 diabetes: focus on metabolism and inflammation. Immunol Cell Biol (2016) 94(2):146–50.10.1038/icb.2015.101
    1. Kluding PM, Pasnoor M, Singh R, Jernigan S, Farmer K, Rucker J, et al. The effect of exercise on neuropathic symptoms, nerve function, and cutaneous innervation in people with diabetic peripheral neuropathy. J Diabetes Complications (2012) 26(5):424–9.10.1016/j.jdiacomp.2012.05.007
    1. Singleton JR, Marcus RL, Lessard MK, Jackson JE, Smith AG. Supervised exercise improves cutaneous reinnervation capacity in metabolic syndrome patients. Ann Neurol (2015) 77(1):146–53.10.1002/ana.24310
    1. English AW, Wilhelm JC, Ward PJ. Exercise, neurotrophins, and axon regeneration in the PNS. Physiology (Bethesda) (2014) 29(6):437–45.10.1152/physiol.00028.2014
    1. Peake JM, Della Gatta P, Suzuki K, Nieman DC. Cytokine expression and secretion by skeletal muscle cells: regulatory mechanisms and exercise effects. Exerc Immunol Rev (2015) 21:8–25.
    1. Singleton JR, Smith AG, Marcus RL. Exercise as therapy for diabetic and prediabetic neuropathy. Curr Diab Rep (2015) 15(12):120.10.1007/s11892-015-0682-6
    1. Yasukawa K, Hirano T, Watanabe Y, Muratani K, Matsuda T, Nakai S, et al. Structure and expression of human B cell stimulatory factor-2 (BSF-2/IL-6) gene. EMBO J (1987) 6(10):2939–45.
    1. Hirano T, Taga T, Nakano N, Yasukawa K, Kashiwamura S, Shimizu K, et al. Purification to homogeneity and characterization of human B-cell differentiation factor (BCDF or BSFp-2). Proc Natl Acad Sci U S A (1985) 82(16):5490–4.10.1073/pnas.82.16.5490
    1. Rothaug M, Becker-Pauly C, Rose-John S. The role of interleukin-6 signaling in nervous tissue. Biochim Biophys Acta (2016) 1863(6 Pt A):1218–27.10.1016/j.bbamcr.2016.03.018
    1. Febbraio MA, Pedersen BK. Contraction-induced myokine production and release: is skeletal muscle an endocrine organ? Exerc Sport Sci Rev (2005) 33(3):114–9.10.1097/00003677-200507000-00003
    1. Pedersen BK, Febbraio MA. Muscle as an endocrine organ: focus on muscle-derived interleukin-6. Physiol Rev (2008) 88(4):1379–406.10.1152/physrev.90100.2007
    1. Pal M, Febbraio MA, Whitham M. From cytokine to myokine: the emerging role of interleukin-6 in metabolic regulation. Immunol Cell Biol (2014) 92(4):331–9.10.1038/icb.2014.16
    1. Cron L, Allen T, Febbraio MA. The role of gp130 receptor cytokines in the regulation of metabolic homeostasis. J Exp Biol (2016) 219(Pt 2):259–65.10.1242/jeb.129213
    1. Fisman EZ, Tenenbaum A. The ubiquitous interleukin-6: a time for reappraisal. Cardiovasc Diabetol (2010) 9:62.10.1186/1475-2840-9-62
    1. Petersen AM, Pedersen BK. The anti-inflammatory effect of exercise. J Appl Physiol (1985) (2005) 98(4):1154–62.10.1152/japplphysiol.00164.2004
    1. Ostrowski K, Rohde T, Asp S, Schjerling P, Pedersen BK. Pro- and anti-inflammatory cytokine balance in strenuous exercise in humans. J Physiol (1999) 515(Pt 1):287–91.10.1111/j.1469-7793.1999.287ad.x
    1. Helge JW, Stallknecht B, Pedersen BK, Galbo H, Kiens B, Richter EA. The effect of graded exercise on IL-6 release and glucose uptake in human skeletal muscle. J Physiol (2003) 546(Pt 1):299–305.10.1113/jphysiol.2002.030437
    1. Leggate M, Nowell MA, Jones SA, Nimmo MA. The response of interleukin-6 and soluble interleukin-6 receptor isoforms following intermittent high intensity and continuous moderate intensity cycling. Cell Stress Chaperones (2010) 15(6):827–33.10.1007/s12192-010-0192-z
    1. Ostrowski K, Hermann C, Bangash A, Schjerling P, Nielsen JN, Pedersen BK. A trauma-like elevation of plasma cytokines in humans in response to treadmill running. J Physiol (1998) 513(Pt 3):889–94.10.1111/j.1469-7793.1998.889ba.x
    1. Sarvas JL, Khaper N, Lees SJ. The IL-6 paradox: context dependent interplay of SOCS3 and AMPK. J Diabetes Metab (2013) (Suppl 13):7–9.10.4172/2155-6156.S13-003
    1. Nadeau KJ, Zeitler PS, Bauer TA, Brown MS, Dorosz JL, Draznin B, et al. Insulin resistance in adolescents with type 2 diabetes is associated with impaired exercise capacity. J Clin Endocrinol Metab (2009) 94(10):3687–95.10.1210/jc.2008-2844
    1. Derosa G, Maffioli P, Ferrari I, Mereu R, Ragonesi PD, Querci F, et al. Effects of one year treatment of vildagliptin added to pioglitazone or glimepiride in poorly controlled type 2 diabetic patients. Horm Metab Res (2010) 42(9):663–9.10.1055/s-0030-1255036
    1. Tantiwong P, Shanmugasundaram K, Monroy A, Ghosh S, Li M, DeFronzo RA, et al. NF-kappaB activity in muscle from obese and type 2 diabetic subjects under basal and exercise-stimulated conditions. Am J Physiol Endocrinol Metab (2010) 299(5):E794–801.10.1152/ajpendo.00776.2009
    1. Steensberg A, Fischer CP, Keller C, Møller K, Pedersen BK. IL-6 enhances plasma IL-1ra, IL-10, and cortisol in humans. Am J Physiol Endocrinol Metab (2003) 285(2):E433–7.10.1152/ajpendo.00074.2003
    1. Starkie R, Ostrowski SR, Jauffred S, Febbraio M, Pedersen BK. Exercise and IL-6 infusion inhibit endotoxin-induced TNF-alpha production in humans. FASEB J (2003) 17(8):884–6.10.1096/fj.02-0670fje
    1. Wolsk E, Mygind H, Grøndahl TS, Pedersen BK, van Hall G. IL-6 selectively stimulates fat metabolism in human skeletal muscle. Am J Physiol Endocrinol Metab (2010) 299(5):E832–40.10.1152/ajpendo.00328.2010
    1. Harder-Lauridsen NM, Krogh-Madsen R, Holst JJ, Plomgaard P, Leick L, Pedersen BK, et al. Effect of IL-6 on the insulin sensitivity in patients with type 2 diabetes. Am J Physiol Endocrinol Metab (2014) 306(7):E769–78.10.1152/ajpendo.00571.2013
    1. Watt MJ, Carey AL, Wolsk-Petersen E, Kraemer FB, Pedersen BK, Febbraio MA. Hormone-sensitive lipase is reduced in the adipose tissue of patients with type 2 diabetes mellitus: influence of IL-6 infusion. Diabetologia (2005) 48(1):105–12.10.1007/s00125-004-1598-x
    1. van Hall G, Steensberg A, Sacchetti M, Fischer C, Keller C, Schjerling P, et al. Interleukin-6 stimulates lipolysis and fat oxidation in humans. J Clin Endocrinol Metab (2003) 88(7):3005–10.10.1210/jc.2002-021687
    1. Ikeda S, Tamura Y, Kakehi S, Sanada H, Kawamori R, Watada H. Exercise-induced increase in IL-6 level enhances GLUT4 expression and insulin sensitivity in mouse skeletal muscle. Biochem Biophys Res Commun (2016) 473(4):947–52.10.1016/j.bbrc.2016.03.159
    1. Pradhan AD, Manson JE, Rifai N, Buring JE, Ridker PM. C-reactive protein, interleukin 6, and risk of developing type 2 diabetes mellitus. JAMA (2001) 286(3):327–34.10.1001/jama.286.3.327
    1. Hu FB, Meigs JB, Li TY, Rifai N, Manson JE. Inflammatory markers and risk of developing type 2 diabetes in women. Diabetes (2004) 53(3):693–700.10.2337/diabetes.53.3.693
    1. Sima AA. New insights into the metabolic and molecular basis for diabetic neuropathy. Cell Mol Life Sci (2003) 60(11):2445–64.10.1007/s00018-003-3084-x
    1. Jakobsen J. Axonal dwindling in early experimental diabetes. II. A study of isolated nerve fibres. Diabetologia (1976) 12(6):547–53.10.1007/BF01220629
    1. Cameron NE, Cotter MA. The neurocytokine, interleukin-6, corrects nerve dysfunction in experimental diabetes. Exp Neurol (2007) 207(1):23–9.10.1016/j.expneurol.2007.05.009
    1. Cotter MA, Gibson TM, Nangle MR, Cameron NE. Effects of interleukin-6 treatment on neurovascular function, nerve perfusion and vascular endothelium in diabetic rats. Diabetes Obes Metab (2010) 12(8):689–99.10.1111/j.1463-1326.2010.01221.x
    1. Kimura K, Tsuda K, Moriwaki C, Kawabe T, Hamada M, Obana M, et al. Leukemia inhibitory factor relaxes arteries through endothelium-dependent mechanism. Biochem Biophys Res Commun (2002) 294(2):359–62.10.1016/S0006-291X(02)00493-X
    1. Enkhjargal B, Godo S, Sawada A, Suvd N, Saito H, Noda K, et al. Endothelial AMP-activated protein kinase regulates blood pressure and coronary flow responses through hyperpolarization mechanism in mice. Arterioscler Thromb Vasc Biol (2014) 34(7):1505–13.10.1161/ATVBAHA.114.303735
    1. Kane MO, Sene M, Anselm E, Dal S, Schini-Kerth VB, Augier C. Role of AMP-activated protein kinase in NO- and EDHF-mediated endothelium-dependent relaxations to red wine polyphenols. Indian J Physiol Pharmacol (2015) 59(4):369–79.
    1. Kelly M, Gauthier MS, Saha AK, Ruderman NB. Activation of AMP-activated protein kinase by interleukin-6 in rat skeletal muscle: association with changes in cAMP, energy state, and endogenous fuel mobilization. Diabetes (2009) 58(9):1953–60.10.2337/db08-1293
    1. Kelly M, Keller C, Avilucea PR, Keller P, Luo Z, Xiang X, et al. AMPK activity is diminished in tissues of IL-6 knockout mice: the effect of exercise. Biochem Biophys Res Commun (2004) 320(2):449–54.10.1016/j.bbrc.2004.05.188
    1. Biensø RS, Knudsen JG, Brandt N, Pedersen PA, Pilegaard H. Effects of IL-6 on pyruvate dehydrogenase regulation in mouse skeletal muscle. Pflugers Arch (2014) 466(8):1647–57.10.1007/s00424-013-1399-5
    1. Gao H, Tian Y, Wang W, Yao D, Zheng T, Meng Q. Levels of interleukin-6, superoxide dismutase and malondialdehyde in the lung tissue of a rat model of hypoxia-induced acute pulmonary edema. Exp Ther Med (2016) 11(3):993–7.10.3892/etm.2015.2962
    1. Song XM, Li JG, Wang YL, Zhou Q, Du ZH, Jia BH, et al. Effects of ketamine on proinflammatory cytokines and nuclear factor kappaB in polymicrobial sepsis rats. World J Gastroenterol (2006) 12(45):7350–4.10.3748/wjg.v12.i45.7350
    1. Dai LL, Gong JP, Zuo GQ, Wu CX, Shi YJ, Li XH, et al. Synthesis of endotoxin receptor CD14 protein in Kupffer cells and its role in alcohol-induced liver disease. World J Gastroenterol (2003) 9(3):622–6.10.3748/wjg.v9.i3.622
    1. Cartmell T, Poole S, Turnbull AV, Rothwell NJ, Luheshi GN. Circulating interleukin-6 mediates the febrile response to localised inflammation in rats. J Physiol (2000) 526(Pt 3):653–61.10.1111/j.1469-7793.2000.00653.x
    1. Paudel YN, Ali MR, Shah S, Adil M, Akhtar MS, Wadhwa R, et al. 2-[(4-Chlorobenzyl) amino]-4-methyl-1,3-thiazole-5-carboxylic acid exhibits antidiabetic potential and raises insulin sensitivity via amelioration of oxidative enzymes and inflammatory cytokines in streptozotocin-induced diabetic rats. Biomed Pharmacother (2017) 89:651–9.10.1016/j.biopha.2017.02.043
    1. Liao D, Liu YQ, Xiong LY, Zhang L. Renoprotective effect of atorvastatin on STZ-diabetic rats through inhibiting inflammatory factors expression in diabetic rat. Eur Rev Med Pharmacol Sci (2016) 20(9):1888–93.
    1. Sandireddy R, Yerra VG, Komirishetti P, Areti A, Kumar A. Fisetin imparts neuroprotection in experimental diabetic neuropathy by modulating Nrf2 and NF-kappaB pathways. Cell Mol Neurobiol (2016) 36(6):883–92.10.1007/s10571-015-0272-9
    1. Kumar A, Sharma SS. NF-kappaB inhibitory action of resveratrol: a probable mechanism of neuroprotection in experimental diabetic neuropathy. Biochem Biophys Res Commun (2010) 394(2):360–5.10.1016/j.bbrc.2010.03.014
    1. Callizot N, Andriambeloson E, Glass J, Revel M, Ferro P, Cirillo R, et al. Interleukin-6 protects against paclitaxel, cisplatin and vincristine-induced neuropathies without impairing chemotherapeutic activity. Cancer Chemother Pharmacol (2008) 62(6):995–1007.10.1007/s00280-008-0689-7
    1. Taga T, Kishimoto T. Gp130 and the interleukin-6 family of cytokines. Annu Rev Immunol (1997) 15:797–819.10.1146/annurev.immunol.15.1.797
    1. Holtmann B, Wiese S, Samsam M, Grohmann K, Pennica D, Martini R, et al. Triple knock-out of CNTF, LIF, and CT-1 defines cooperative and distinct roles of these neurotrophic factors for motoneuron maintenance and function. J Neurosci (2005) 25(7):1778–87.10.1523/JNEUROSCI.4249-04.2005
    1. Saleh A, Roy Chowdhury SK, Smith DR, Balakrishnan S, Tessler L, Martens C, et al. Ciliary neurotrophic factor activates NF-kappaB to enhance mitochondrial bioenergetics and prevent neuropathy in sensory neurons of streptozotocin-induced diabetic rodents. Neuropharmacology (2013) 65:65–73.10.1016/j.neuropharm.2012.09.015
    1. Lesbordes JC, Cifuentes-Diaz C, Miroglio A, Joshi V, Bordet T, Kahn A, et al. Therapeutic benefits of cardiotrophin-1 gene transfer in a mouse model of spinal muscular atrophy. Hum Mol Genet (2003) 12(11):1233–9.10.1093/hmg/ddg143
    1. Mitsumoto H, Klinkosz B, Pioro EP, Tsuzaka K, Ishiyama T, O’Leary RM, et al. Effects of cardiotrophin-1 (CT-1) in a mouse motor neuron disease. Muscle Nerve (2001) 24(6):769–77.10.1002/mus.1068
    1. Thier M, Hall M, Heath JK, Pennica D, Weis J. Trophic effects of cardiotrophin-1 and interleukin-11 on rat dorsal root ganglion neurons in vitro. Brain Res Mol Brain Res (1999) 64(1):80–4.10.1016/S0169-328X(98)00329-5
    1. Lara-Ramírez R, Segura-Anaya E, Martínez-Gómez A, Dent MA. Expression of interleukin-6 receptor alpha in normal and injured rat sciatic nerve. Neuroscience (2008) 152(3):601–8.10.1016/j.neuroscience.2008.01.014
    1. Tofaris GK, Patterson PH, Jessen KR, Mirsky R. Denervated Schwann cells attract macrophages by secretion of leukemia inhibitory factor (LIF) and monocyte chemoattractant protein-1 in a process regulated by interleukin-6 and LIF. J Neurosci (2002) 22(15):6696–703.
    1. Terada M, Yasuda H, Kikkawa R. Delayed Wallerian degeneration and increased neurofilament phosphorylation in sciatic nerves of rats with streptozocin-induced diabetes. J Neurol Sci (1998) 155(1):23–30.10.1016/S0022-510X(97)00269-4
    1. Kamijo M, Merry AC, Akdas G, Cherian PV, Sima AA. Nerve fiber regeneration following axotomy in the diabetic biobreeding Worcester rat: the effect of ARI treatment. J Diabetes Complications (1996) 10(4):183–91.10.1016/1056-8727(95)00008-9
    1. Haggiag S, Chebath J, Revel M. Induction of myelin gene expression in Schwann cell cultures by an interleukin-6 receptor-interleukin-6 chimera. FEBS Lett (1999) 457(2):200–4.10.1016/S0014-5793(99)01040-6
    1. Haggiag S, Zhang PL, Slutzky G, Shinder V, Kumar A, Chebath J, et al. Stimulation of myelin gene expression in vitro and of sciatic nerve remyelination by interleukin-6 receptor-interleukin-6 chimera. J Neurosci Res (2001) 64(6):564–74.10.1002/jnr.1108
    1. Ito T, Ikeda K, Tomita K, Yokoyama S. Interleukin-6 upregulates the expression of PMP22 in cultured rat Schwann cells via a JAK2-dependent pathway. Neurosci Lett (2010) 472(2):104–8.10.1016/j.neulet.2010.01.061
    1. Lin G, Zhang H, Sun F, Lu Z, Reed-Maldonado A, Lee YC, et al. Brain-derived neurotrophic factor promotes nerve regeneration by activating the JAK/STAT pathway in Schwann cells. Transl Androl Urol (2016) 5(2):167–75.10.21037/tau.2016.02.03
    1. Skundric DS, Dai R, Mataverde P. IL-6 modulates hyperglycemia-induced changes of Na+ channel beta-3 subunit expression by Schwann cells. Ann N Y Acad Sci (2003) 1005:233–6.10.1196/annals.1288.034
    1. Lehmann HC, Hoke A. Schwann cells as a therapeutic target for peripheral neuropathies. CNS Neurol Disord Drug Targets (2010) 9(6):801–6.10.2174/187152710793237412
    1. Kalichman MW, Powell HC, Mizisin AP. Reactive, degenerative, and proliferative Schwann cell responses in experimental galactose and human diabetic neuropathy. Acta Neuropathol (1998) 95(1):47–56.10.1007/s004010050764
    1. Erta M, Quintana A, Hidalgo J. Interleukin-6, a major cytokine in the central nervous system. Int J Biol Sci (2012) 8(9):1254–66.10.7150/ijbs.4679
    1. Zigmond RE. gp130 cytokines are positive signals triggering changes in gene expression and axon outgrowth in peripheral neurons following injury. Front Mol Neurosci (2011) 4:62.10.3389/fnmol.2011.00062
    1. Pieraut S, Lucas O, Sangari S, Sar C, Boudes M, Bouffi C, et al. An autocrine neuronal interleukin-6 loop mediates chloride accumulation and NKCC1 phosphorylation in axotomized sensory neurons. J Neurosci (2011) 31(38):13516–26.10.1523/JNEUROSCI.3382-11.2011
    1. Carmel JB, Young W, Hart RP. Flipping the transcriptional switch from myelin inhibition to axon growth in the CNS. Front Mol Neurosci (2015) 8:34.10.3389/fnmol.2015.00034
    1. Leibinger M, Müller A, Gobrecht P, Diekmann H, Andreadaki A, Fischer D. Interleukin-6 contributes to CNS axon regeneration upon inflammatory stimulation. Cell Death Dis (2013) 4:e609.10.1038/cddis.2013.126
    1. Ito Y, Yamamoto M, Li M, Doyu M, Tanaka F, Mutch T, et al. Differential temporal expression of mRNAs for ciliary neurotrophic factor (CNTF), leukemia inhibitory factor (LIF), interleukin-6 (IL-6), and their receptors (CNTFR alpha, LIFR beta, IL-6R alpha and gp130) in injured peripheral nerves. Brain Res (1998) 793(1–2):321–7.10.1016/S0006-8993(98)00242-X
    1. Gaudet AD, Popovich PG, Ramer MS. Wallerian degeneration: gaining perspective on inflammatory events after peripheral nerve injury. J Neuroinflammation (2011) 8:110.10.1186/1742-2094-8-110
    1. Shuto T, Horie H, Hikawa N, Sango K, Tokashiki A, Murata H, et al. IL-6 up-regulates CNTF mRNA expression and enhances neurite regeneration. Neuroreport (2001) 12(5):1081–5.10.1097/00001756-200104170-00043
    1. März P, Herget T, Lang E, Otten U, Rose-John S. Activation of gp130 by IL-6/soluble IL-6 receptor induces neuronal differentiation. Eur J Neurosci (1997) 9(12):2765–73.10.1111/j.1460-9568.1997.tb01705.x
    1. Cafferty WB, Gardiner NJ, Das P, Qiu J, McMahon SB, Thompson SW. Conditioning injury-induced spinal axon regeneration fails in interleukin-6 knock-out mice. J Neurosci (2004) 24(18):4432–43.10.1523/JNEUROSCI.2245-02.2004
    1. Yang P, Qin Y, Bian C, Zhao Y, Zhang W. Intrathecal delivery of IL-6 reactivates the intrinsic growth capacity of pyramidal cells in the sensorimotor cortex after spinal cord injury. PLoS One (2015) 10(5):e0127772.10.1371/journal.pone.0127772
    1. Knezevic-Cuca J, Stansberry KB, Johnston G, Zhang J, Keller ET, Vinik AI, et al. Neurotrophic role of interleukin-6 and soluble interleukin-6 receptors in N1E-115 neuroblastoma cells. J Neuroimmunol (2000) 102(1):8–16.10.1016/S0165-5728(99)00151-4
    1. Kunz D, Walker G, Bedoucha M, Certa U, März-Weiss P, Dimitriades-Schmutz B, et al. Expression profiling and ingenuity biological function analyses of interleukin-6- versus nerve growth factor-stimulated PC12 cells. BMC Genomics (2009) 10:90.10.1186/1471-2164-10-90
    1. Siddiq MM, Hannila SS. Looking downstream: the role of cyclic AMP-regulated genes in axonal regeneration. Front Mol Neurosci (2015) 8:26.10.3389/fnmol.2015.00026
    1. White CA, Nicola NA. SOCS3: an essential physiological inhibitor of signaling by interleukin-6 and G-CSF family cytokines. JAKSTAT (2013) 2(4):e25045.10.4161/jkst.25045
    1. Hirota H, Kiyama H, Kishimoto T, Taga T. Accelerated nerve regeneration in mice by upregulated expression of interleukin (IL) 6 and IL-6 receptor after trauma. J Exp Med (1996) 183(6):2627–34.10.1084/jem.183.6.2627
    1. Zhong J, Dietzel ID, Wahle P, Kopf M, Heumann R. Sensory impairments and delayed regeneration of sensory axons in interleukin-6-deficient mice. J Neurosci (1999) 19(11):4305–13.
    1. Skundric DS, Lisak RP. Role of neuropoietic cytokines in development and progression of diabetic polyneuropathy: from glucose metabolism to neurodegeneration. Exp Diabesity Res (2003) 4(4):303–12.10.1155/EDR.2003.303

Source: PubMed

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