Red nucleus IL-6 mediates the maintenance of neuropathic pain by inducing the productions of TNF-α and IL-1β through the JAK2/STAT3 and ERK signaling pathways.
Animals
Hyperalgesia
/ metabolism
Interleukin-1beta
/ metabolism
Interleukin-6
/ metabolism
Janus Kinase 2
/ metabolism
MAP Kinase Signaling System
/ physiology
Male
Neuralgia
/ etiology
Peripheral Nerve Injuries
/ complications
Rats
Rats, Sprague-Dawley
Red Nucleus
/ metabolism
STAT3 Transcription Factor
/ metabolism
Tumor Necrosis Factor-alpha
/ metabolism
interleukin-1β
interleukin-6
neuropathic pain
red nucleus
tumor necrosis factor-α
Journal
Neuropathology : official journal of the Japanese Society of Neuropathology
ISSN: 1440-1789
Titre abrégé: Neuropathology
Pays: Australia
ID NLM: 9606526
Informations de publication
Date de publication:
Aug 2020
Aug 2020
Historique:
received:
17
12
2019
revised:
14
02
2020
accepted:
21
02
2020
pubmed:
8
5
2020
medline:
28
8
2021
entrez:
8
5
2020
Statut:
ppublish
Résumé
We previously reported that interleukin (IL)-6 in the red nucleus (RN) is involved in the maintenance of neuropathic pain induced by spared nerve injury (SNI), and exerts a facilitatory effect via Janus-activated kinase 2/signal transducer and activator of transcription 3 (JAK2/STAT3) and extracellular signal-regulated kinase (ERK) signal transduction pathways. The present study aimed at investigating the roles of tumor necrosis factor-α (TNF-α) and IL-1β in RN IL-6-mediated maintenance of neuropathic pain and related signal transduction pathways. Being similar to the elevation of RN IL-6 three weeks after SNI, increased protein levels of both TNF-α and IL-1β were also observed in the contralateral RN three weeks after the nerve injury. The upregulations of TNF-α and IL-1β were closely correlative with IL-6 and suppressed by intrarubral injection of a neutralizing antibody against IL-6. Administration of either the JAK2 antagonist AG490 or the ERK antagonist PD98059 to the RN of rats with SNI remarkably increased the paw withdrawal threshold (PWT) and inhibited the up-regulations of local TNF-α and IL-1β. Further experiments indicated that intrarubral injection of exogenous IL-6 in naive rats apparently lowered the PWT of the contralateral hindpaw and boosted the local expressions of TNF-α and IL-1β. Pretreatment with AG490 could block IL-6-induced tactile hypersensitivity and suppress the up-regulations of both TNF-α and IL-1β. However, injection of PD98059 in advance only inhibited the upregulation of IL-1β, but not TNF-α. These findings indicate that RN IL-6 mediates the maintenance of neuropathic pain by inducing the productions of TNF-α and IL-1β. IL-6 induces the expression of TNF-α through the JAK2/STAT3 pathway, and the production of IL-1β through the JAK2/STAT3 and ERK pathways.
Substances chimiques
Interleukin-1beta
0
Interleukin-6
0
STAT3 Transcription Factor
0
Tumor Necrosis Factor-alpha
0
Janus Kinase 2
EC 2.7.10.2
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
347-357Subventions
Organisme : National Natural Science Foundation of China
ID : 31640032
Organisme : Natural Science Foundation of Shaanxi Province
ID : 2016JM3028
Informations de copyright
© 2020 Japanese Society of Neuropathology.
Références
Paxinos G, Watson C. The Rat Brain in Stereotaxic Coordinates, 6th edn. San Diego, CA: Academic Press, 2007.
Milardi D, Cacciola A, Cutroneo G et al. Red nucleus connectivity as revealed by constrained spherical deconvolution tractography. Neurosci Lett 2016; 626: 68-73.
Basso DM, Beattie MS, Bresnahan JC. Descending systems contributing to locomotor recovery after mild or moderate spinal cord injury in rats: experimental evidence and a review of literature. Restor Neurol Neurosci 2002; 20: 189-218.
Küchler M, Fouad K, Weinmann O, Schwab ME, Raineteau O. Red nucleus projections to distinct motor neuron pools in the rat spinal cord. J Comp Neurol 2002; 448: 349-359.
Lavoie S, Drew T. Discharge characteristics of neurons in the red nucleus during voluntary gait modifications: A comparison with the motor cortex. J Neurophysiol 2002; 88: 1791-1814.
Muir GD, Whishaw IQ. Red nucleus lesions impair overground locomotion in rats: A kinetic analysis. Eur J Neurosci 2000; 12: 1113-1122.
Zelenin PV, Beloozerova IN, Sirota MG, Orlovsky GN, Deliagina TG. Activity of red nucleus neurons in the cat during postural corrections. J Neurosci 2010; 30: 14533-14542.
Porras-Garcia E, Sanchez-Campusano R, Martinez-Vargas D et al. Behavioral characteristics, associative learning capabilities, and dynamic association mapping in an animal model of cerebellar degeneration. J Neurophysiol 2010; 104: 346-365.
Liu Y, Pu Y, Gao JH et al. The human red nucleus and lateral cerebellum in supporting roles for sensory information processing. Hum Brain Mapp 2000; 10: 147-159.
Huang M, Liu M, Li X. The analgesic effect of red nucleus and preliminary research on its mechanism. Zhen Ci Yan Jiu 1992; 17: 166-170.
Matsumoto RR, Walker JM. Inhibition of rubral neurons by noxious and non-noxious pressure. Brain Res 1991; 556: 78-84.
Steffens H, Rathelot JA, Padel Y. Effects of noxious skin heating on spontaneous cell activity in the magnocellular red nucleus of the cat. Exp Brain Res 2000; 131: 215-224.
Ding CP, Xue YS, Yu J, Guo YJ, Zeng XY, Wang JY. The red nucleus interleukin-6 participates in the maintenance of neuropathic pain induced by spared nerve injury. Neurochem Res 2016; 41: 3042-3051.
Ding CP, Guo YJ, Li HN, Wang JY, Zeng XY. Red nucleus interleukin-6 participates in the maintenance of neuropathic pain through JAK/STAT3 and ERK signaling pathways. Exp Neurol 2018; 300: 212-221.
Cunha FQ, Poole S, Lorenzetti BB, Ferreira SH. The pivotal role of tumour necrosis factor alpha in the development of inflammatory hyperalgesia. Br J Pharmacol 1992; 107: 660-664.
Manjavachi MN, Motta EM, Marotta DM, Leite DF, Calixto JB. Mechanisms involved in IL-6-induced muscular mechanical hyperalgesia in mice. Pain 2010; 151: 345-355.
Zimmermann M. Ethical guidelines for investigations of experimental pain in conscious animals. Pain 1983; 16: 109-110.
Wang J, Yu J, Ding CP, Han SP, Zeng XY, Wang JY. Transforming growth factor-beta in the red nucleus plays antinociceptive effect under physiological and pathological pain conditions. Neuroscience 2015; 291: 37-45.
Brázda V, Klusáková I, Hradilová Svíženská I, Dubový P. 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. Mol Pain 2013; 9: 42.
Erta M, Quintana A, Hidalgo J. Interleukin-6, a major cytokine in the central nervous system. Int J Biol Sci 2012; 8: 1254-1266.
Gadient RA, Otten UH. Interleukin-6 (IL-6)-a molecule with both beneficial and destructive potentials. Prog Neurobiol 1997; 52: 379-390.
Asiedu MN, Tillu DV, Melemedjian OK et al. Spinal protein kinase M ζ underlies the maintenance mechanism of persistent nociceptive sensitization. J Neurosci 2011; 31: 6646-6653.
DeLeo JA, Colburn RW, Nichols M, Malhotra A. Interleukin-6-mediated hyperalgesia/allodynia and increased spinal IL-6 expression in a rat mononeuropathy model. J Interferon Cytokine Res 1996; 16: 695-700.
Dina OA, Green PG, Levine JD. Role of interleukin-6 in chronic muscle hyperalgesic priming. Neuroscience 2008; 152: 521-525.
Oka T, Oka K, Hosoi M, Hori T. Intracerebroventricular injection of interleukin-6 induces thermal hyperalgesia in rats. Brain Res 1995; 692: 123-128.
Xu XJ, Hao JX, Andell-Jonsson S, Poli V, Bartfai T, Wiesenfeld-Hallin Z. Nociceptive responses in interleukin-6-deficient mice to peripheral inflammation and peripheral nerve section. Cytokine 1997; 9: 1028-1033.
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: 4305-4313.
Al-Amin H, Sarkis R, Atweh S, Jabbur S, Saadé N. Chronic dizocilpine or apomorphine and development of neuropathy in two animal models II: Effects on brain cytokines and neurotrophins. Exp Neurol 2011; 228: 30-40.
Brázda V, Klusáková I, Svízenská I, Veselková Z, Dubový P. Bilateral changes in IL-6 protein, but not in its receptor gp130, in rat dorsal root ganglia following sciatic nerve ligature. Cell Mol Neurobiol 2009; 29: 1053-1062.
Chu H, Sun J, Xu H, Niu Z, Xu M. Effect of periaqueductal gray melanocortin 4 receptor in pain facilitation and glial activation in rat model of chronic constriction injury. Neurol Res 2012; 34: 871-888.
Dubový P, Klusáková I, Svízenská I, Brázda V. Satellite glial cells express IL-6 and corresponding signal-transducing receptors in the dorsal root ganglia of rat neuropathic pain model. Neuron Glia Biol 2010; 6: 73-83.
Dubový P, Brázda V, Klusáková I, Hradilová-Svíženská I. 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. J Neuroinflammation 2013; 10: 55.
Sacerdote P, Franchi S, Moretti S et al. Cytokine modulation is necessary for efficacious treatment of experimental neuropathic pain. J Neuroimmune Pharmacol 2013; 8: 202-211.
Wei XH, Na XD, Liao GJ et al. The up-regulation of IL-6 in DRG and spinal dorsal horn contributes to neuropathic pain following L5 ventral root transection. Exp Neurol 2013; 241: 159-168.
Arruda JL, Sweitzer S, Rutkowski MD, DeLeo JA. Intrathecal anti-IL-6 antibody and IgG attenuates peripheral nerve injury-induced mechanical allodynia in the rat: Possible immune modulation in neuropathic pain. Brain Res 2000; 879: 216-225.
Twining CM, Sloane EM, Milligan ED et al. Peri-sciatic proinflammatory cytokines, reactive oxygen species, and complement induce mirror-image neuropathic pain in rats. Pain 2004; 110: 299-309.
Ma W, Quirion R. Increased calcitonin gene-related peptide in neuroma and invading macrophages is involved in the up-regulation of interleukin-6 and thermal hyperalgesia in a rat model of mononeuropathy. J Neurochem 2006; 98: 180-192.
Lee KM, Jeon SM, Cho HJ. Tumor necrosis factor receptor 1 induces interleukin-6 upregulation through NF-kappaB in a rat neuropathic pain model. Eur J Pain 2009; 13: 794-806.
Ohtori S, Miyagi M, Eguchi Y et al. Efficacy of epidural administration of anti-interleukin-6 receptor antibody onto spinal nerve for treatment of sciatica. Eur Spine J 2012; 21: 2079-2084.
Rothaug M, Becker PC, Rose JS. The role of interleukin-6 signaling in nervous tissue. Biochim Biophys Acta 1863; 2016: 1218-1227.
Dominguez E, Rivat C, Pommier B, Mauborgne A, Pohl M. JAK/STAT3 pathway is activated in spinal cord microglia after peripheral nerve injury and contributes to neuropathic pain development in rat. J Neurochem 2008; 107: 50-60.
Dominguez E, Mauborgne A, Mallet J, Desclaux M, Pohl M. SOCS3-mediated blockade of JAK/STAT3 signaling pathway reveals its major contribution to spinal cord neuroinflammation and mechanical allodynia after peripheral nerve injury. J Neurosci 2010; 30: 5754-5766.
Eulenfeld R, Dittrich A, Khouri C et al. Interleukin-6 signalling: More than Jaks and STATs. Eur J Cell Biol 2012; 91: 486-495.
Schaper F, Rose-John S. Interleukin-6: Biology, signaling and strategies of blockade. Cytokine Growth Factor Rev 2015; 26: 475-487.
Lee KM, Jeon SM, Cho HJ. Interleukin-6 induces microglial CX3CR1 expression in the spinal cord after peripheral nerve injury through the activation of p38 MAPK. Eur J Pain 2010; 14: 682.e1-682.e12.
Fang D, Kong LY, Cai J et al. Interleukin-6-mediated functional upregulation of TRPV1 receptors in dorsal root ganglion neurons through the activation of JAK/PI3K signaling pathway: Roles in the development of bone cancer pain in a rat model. Pain 2015; 156: 1124-1144.
Clark AK, Old EA, Malcangio M. Neuropathic pain and cytokines: Current perspectives. J Pain Res 2013; 6: 803-814.
Zhuang YT, Xu DY, Wang GY, Sun JL, Huang Y, Wang SZ. IL-6 induced lncRNA MALAT1 enhances TNF-α expression in LPS-induced septic cardiomyocytes via activation of SAA3. Eur Rev Med Pharmacol Sci 2017; 21: 302-309.
Song J, Ying Y, Wang W et al. The role of P2X7R/ERK signaling in dorsal root ganglia satellite glial cells in the development of chronic postsurgical pain induced by skin/muscle incision and retraction (SMIR). Brain Behav Immun 2018; 69: 180-189.
Zhang Q, Cao DL, Zhang ZJ, Jiang BC, Gao YJ. Chemokine CXCL13 mediates orofacial neuropathic pain via CXCR5/ERK pathway in the trigeminal ganglion of mice. J Neuroinflammation 2016; 13: 183.
Huang SJ, Yan JQ, Luo H, Zhou LY, Luo JG. IL-33/ST2 signaling contributes to radicular pain by modulating MAPK and NF-κB activation and inflammatory mediator expression in the spinal cord in rat models of noncompressive lumber disk herniation. J Neuroinflammation 2018; 15: 12.
Austin PJ, Moalem-Taylor G. The neuro-immune balance in neuropathic pain: Involvement of inflammatory immune cells, immune-like glial cells and cytokines. J Neuroimmunol 2010; 229: 26-50.
Busch-Dienstfertig M, Gonzalez-Rodriguez S. IL-4, JAK-STAT signaling, and pain. JAKSTAT 2013; 2: e27638.