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IL-18 Contributes to Bone Cancer Pain by Regulating Glia Cells and Neuron Interaction

Published:October 25, 2017DOI:https://doi.org/10.1016/j.jpain.2017.10.003

      Highlights

      • IL-18 played a critical role in bone cancer-induced pain.
      • IL-18 could induced glutamate receptor 2B (GluN2B) activation during bone cancer pain.
      • IL-18 mediated microglia/astrocyte and microglia/neuron interactions in the dorsal horn.

      Abstract

      Glial cell hyperactivity has been proposed to be responsible for chronic pain, however, the mechanisms remain unclear. Interleukin (IL)-18, released from glial cells, has been reported to be involved in neuropathic pain. In this study, we investigated the role of IL-18 in bone cancer pain. Bone cancer pain was mimicked by injecting Walker-256 mammary gland carcinoma cells into the intramedullary space of the tibia in rats. Expression and location of IL-18 and the IL-18 receptor were tested. To investigate the contribution of IL-18 signaling to bone cancer pain, IL-18 binding protein and recombinant IL-18 were used. To investigate the mechanisms of glial cells effects, MK801, N-methyl-D-aspartate (NMDA) receptor inhibitor, and Src kinase-specific inhibitor PP1 were used. Tumor cell implantation (TCI) treatment increased expression of IL-18 and IL-18 receptor in spinal cord. The time course of IL-18 upregulation was correlated with TCI-induced pain behaviors. Blocking the IL-18 signaling pathway prevented and reversed bone cancer-related pain behaviors. Meanwhile, blocking IL-18 signaling also suppressed TCI-induced glial cell hyperactivity, as well as activation of GluN2B and subsequent Ca2+-dependent signaling. Spinal administration of recombinant IL-18 in naive rat induced significant mechanical allodynia, as well as GluN2B activation. However, intrathecal injection of MK801 failed to suppress recombinant IL–18-induced GluN2B phosphorylation, whereas Src kinase inhibitor PP1 significantly inhibited IL-18-induced GluN2B activation. IL–18-mediated glial-glia and glial-neuron interaction may facilitate bone cancer pain. Blocking IL-18 signaling may effectively prevent and/or suppress bone cancer pain.

      Perspective

      IL-18 signaling may be a new target for cancer pain therapy.

      Key words

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      References

        • Alboni S.
        • Cervia D.
        • Sugama S.
        • Conti B.
        Interleukin 18 in the CNS.
        J Neuroinflammation. 2010; 7: 9
        • Badimon L.
        Interleukin-18: A potent pro-inflammatory cytokine in atherosclerosis.
        Cardiovasc Res. 2012; 96: 172-175
        • Boraschi D.
        • Dinarello C.A.
        IL-18 in autoimmunity: Review.
        Eur Cytokine Netw. 2006; 17: 224-252
        • Calvo M.
        • Zhu N.
        • Tsantoulas C.
        • Ma Z.
        • Grist J.
        • Loeb J.A.
        • Bennett D.L.
        Neuregulin-ErbB signaling promotes microglial proliferation and chemotaxis contributing to microgliosis and pain after peripheral nerve injury.
        J Neurosci. 2010; 30: 5437-5450
        • Everdingen M.V.
        • De Rijke J.M.
        • Kessels A.G.
        • Schouten H.C.
        • Van Kleef M.
        • Patijn J.
        Prevalence of pain in patients with cancer: A systematic review of the past 40 years.
        Ann Oncol. 2007; 18: 1437-1449
        • Felderhoffmueser U.
        • Schmidt O.I.
        • Oberholzer A.
        • Buhrer C.
        • Stahel P.F.
        IL-18: A key player in neuroinflammation and neurodegeneration?.
        Trends Neurosci. 2005; 28: 487-493
        • Fields R.D.
        • Stevensgraham B.
        New insights into neuron-glia communication.
        Science. 2002; 298: 556-562
        • Gao Y.
        • Ji R.
        Targeting astrocyte signaling for chronic pain.
        Neurotherapeutics. 2010; 7: 482-493
        • Gaudreault E.
        • Thompson C.
        • Stankova J.
        • Rolapleszczynski M.
        Involvement of BLT1 endocytosis and yes kinase activation in leukotriene B4-induced neutrophil degranulation.
        J Immunol. 2005; 174: 3617-3625
        • Goblirsch M.J.
        • Zwolak P.
        • Clohisy D.R.
        Advances in understanding bone cancer pain.
        J Cell Biochem. 2005; 96: 682-688
        • Gosselin R.
        • Suter M.R.
        • Ji R.
        • Decosterd I.
        Glial cells and chronic pain.
        Neuroscientist. 2010; 16: 519-531
        • Guo W.
        • Miyoshi K.
        • Dubner R.
        • Gu M.
        • Li M.
        • Liu J.
        • Yang J.
        • Zou S.
        • Ren K.
        • Noguchi K.
        Spinal 5-HT3 receptors mediate descending facilitation and contribute to behavioral hypersensitivity via a reciprocal neuron-glial signaling cascade.
        Mol Pain. 2014; 10: 35
        • Guo W.
        • Wang H.
        • Watanabe M.
        • Shimizu K.
        • Zou S.
        • Lagraize S.C.
        • Wei F.
        • Dubner R.
        • Ren K.
        Glial-cytokine-neuronal interactions underlying the mechanisms of persistent pain.
        J Neurosci. 2007; 27: 6006-6018
        • Hald A.
        • Nedergaard S.
        • Hansen R.R.
        • Ding M.
        • Heegaard A.
        Differential activation of spinal cord glial cells in murine models of neuropathic and cancer pain.
        Eur J Pain. 2009; 13: 138-145
        • Honore P.
        • Luger N.M.
        • Sabino M.A.
        • Schwei M.J.
        • Rogers S.D.
        • Mach D.B.
        • Okeefe P.F.
        • Ramnaraine M.L.
        • Clohisy D.R.
        • Mantyh P.W.
        Osteoprotegerin blocks bone cancer-induced skeletal destruction, skeletal pain and pain-related neurochemical reorganization of the spinal cord.
        Nat Med. 2000; 6: 521-528
        • Kanno T.
        • Nagata T.
        • Yamamoto S.
        • Okamura H.
        • Nishizaki T.
        Interleukin-18 stimulates synaptically released glutamate and enhances postsynaptic AMPA receptor responses in the CA1 region of mouse hippocampal slices.
        Brain Res. 2004; 1012: 190-193
        • Kato A.
        • Minami K.
        • Ito H.
        • Tomii T.
        • Matsumoto M.
        • Orita S.
        • Kihara T.
        • Narita M.
        • Suzuki T.
        Oxycodone-induced analgesic effects in a bone cancer pain model in mice.
        Oncology. 2008; 74: 55-60
        • Kwiatkowski K.
        • Piotrowska A.
        • Rojewska E.
        • Makuch W.
        • Mika J.
        The RS504393 influences the level of nociceptive factors and enhances opioid analgesic potency in neuropathic rats.
        J Neuroimmune Pharmacol. 2017; 12: 1-18
        • Liu S.
        • Liu W.T.
        • Liu Y.P.
        • Dong H.L.
        • Henkemeyer M.
        • Xiong L.Z.
        • Song X.J.
        Blocking EphB1 receptor forward signaling in spinal cord relieves bone cancer pain and rescues analgesic effect of morphine treatment in rodents.
        Cancer Res. 2011; 71: 4392-4402
        • Liu S.
        • Liu Y.
        • Song W.B.
        • Song X.
        EphrinB-EphB receptor signaling contributes to bone cancer pain via Toll-like receptor and proinflammatory cytokines in rat spinal cord.
        Pain. 2013; 154: 2823-2835
        • Medhurst S.
        • Walker K.
        • Bowes M.
        • Kidd B.L.
        • Glatt M.
        • Muller M.
        • Hattenberger M.
        • Vaxelaire J.
        • Oreilly T.
        • Wotherspoon G.
        A rat model of bone cancer pain.
        Pain. 2002; 96: 129-140
        • Milligan E.D.
        • Watkins L.R.
        Pathological and protective roles of glia in chronic pain.
        Nat Rev Neurosci. 2009; 10: 23-36
        • Miyoshi K.
        • Obata K.
        • Kondo T.
        • Okamura H.
        • Noguchi K.
        Interleukin-18-mediated microglia/astrocyte interaction in the spinal cord enhances neuropathic pain processing after nerve injury.
        J Neurosci. 2008; 28: 12775-12787
        • Nakagawa T.
        • Kaneko S.
        Spinal astrocytes as therapeutic targets for pathological pain.
        J Pharmacol Sci. 2010; 114: 347-353
        • Ojala J.O.
        • Sutinen E.M.
        The role of interleukin-18, oxidative stress and metabolic syndrome in Alzheimer's disease.
        J Clin Med. 2017; 6: 55
        • Prinz M.
        • Hanisch U.
        Murine microglial cells produce and respond to interleukin-18.
        J Neurochem. 2008; 72: 2215-2218
        • Ren B.
        • Gu X.
        • Zheng Y.
        • Liu C.
        • Wang D.
        • Sun Y.
        • Ma Z.
        Intrathecal injection of metabotropic glutamate receptor subtype 3 and 5 agonist/antagonist attenuates bone cancer pain by inhibition of spinal astrocyte activation in a mouse model.
        Anesthesiology. 2012; 116: 122-132
        • Ren K.
        • Dubner R.
        Neuron-glia crosstalk gets serious: Role in pain hypersensitivity.
        Curr Opin Anaesthesiol. 2008; 21: 570-579
        • Ren K.
        • Dubner R.
        Interactions between the immune and nervous systems in pain.
        Nat Med. 2010; 16: 1267-1276
        • Rojewska E.
        • Popiolekbarczyk K.
        • Jurga A.M.
        • Makuch W.
        • Przewlocka B.
        • Mika J.
        Involvement of pro- and antinociceptive factors in minocycline analgesia in rat neuropathic pain model.
        J Neuroimmunol. 2014; 277: 57-66
        • Romerosandoval A.
        • Chai N.
        • Nutilemcmenemy N.
        • Deleo J.A.
        A comparison of spinal Iba1 and GFAP expression in rodent models of acute and chronic pain.
        Brain Res. 2008; 1219: 116-126
        • Salter M.W.
        • Kalia V, L.
        Src kinases: A hub for NMDA receptor regulation.
        Nat Rev Neurosci. 2004; 5: 317
        • Scholz J.
        • Woolf C.J.
        The neuropathic pain triad: Neurons, immune cells and glia.
        Nat Neurosci. 2007; 10: 1361-1368
        • Schomberg D.
        • Olson J.K.
        Immune responses of microglia in the spinal cord: Contribution to pain states.
        Exp Neurol. 2012; 234: 262-270
        • Srivastava S.
        • Salim N.
        • Robertson M.J.
        Interleukin-18: Biology and role in the immunotherapy of cancer.
        Curr Med Chem. 2010; 17: 3353-3357
        • Suk K.
        • Kim S.Y.
        • Kim H.
        Regulation of IL-18 production by IFNγ and PGE2 in mouse microglial cells: Involvement of NF-kB pathway in the regulatory processes.
        Immunol Lett. 2001; 77: 79-85
        • Tanga F.Y.
        • Raghavendra V.
        • Deleo J.A.
        Quantitative real-time RT-PCR assessment of spinal microglial and astrocytic activation markers in a rat model of neuropathic pain.
        Neurochem Int. 2004; 45: 397-407
        • Verri Jr, W.A.
        • Cunha T.M.
        • Magro D.A.
        • Domingues A.C.
        • Vieira S.M.
        • Souza G.R.
        • Liew F.Y.
        • Ferreira S.H.
        • Cunha F.Q.
        Role of IL-18 in overt pain-like behaviour in mice.
        Eur J Pharmacol. 2008; 588: 207-212
        • Wang L.
        • Yang J.
        • Zhan Y.
        • Ji F.
        • Wang X.
        • Zuo J.
        • Xu Q.
        Minocycline-induced reduction of brain-derived neurotrophic factor expression in relation to cancer-induced bone pain in rats.
        J Neurosci Res. 2012; 90: 672-681
        • Woolf C.J.
        • Salter M.W.
        Neuronal plasticity: Increasing the gain in pain.
        Science. 1765–1768; 288: 2000
        • Xie W.
        • Deng H.
        • Li H.
        • Bowen T.L.
        • Strong J.A.
        • Zhang J.
        Robust increase of cutaneous sensitivity, cytokine production and sympathetic sprouting in rats with localized inflammatory irritation of the spinal ganglia.
        Neuroscience. 2006; 142: 809-822
        • Yang Y.
        • Li H.
        • Li T.
        • Luo H.
        • Gu X.
        • Lu N.
        • Ji R.
        • Zhang Y.
        Delayed activation of spinal microglia contributes to the maintenance of bone cancer pain in female Wistar rats via P2X7 receptor and IL-18.
        J Neurosci. 2015; 35: 7950-7963
        • Yao M.
        • Chang X.
        • Chu Y.
        • Yang J.
        • Wang L.
        • Cao H.
        • Liu M.
        • Xu Q.
        Antiallodynic effects of propentofylline elicited by interrupting spinal glial function in a rat model of bone cancer pain.
        J Neurosci Res. 1877–1886; 89: 2011
        • Zhang R.
        • Liu B.
        • Wang L.
        • Ren K.
        • Qiao J.
        • Berman B.M.
        • Lao L.
        Spinal glial activation in a new rat model of bone cancer pain produced by prostate cancer cell inoculation of the tibia.
        Pain. 2005; 118: 125-136
        • Zhang Y.
        • Huang Z.
        • Liu S.
        • Liu Y.
        • Song A.A.
        • Song X.
        WNT signaling underlies the pathogenesis of neuropathic pain in rodents.
        J Clin Invest. 2013; 123: 2268-2286
        • Zhao X.
        • Cheng J.
        • Yang X.
        • Qin L.
        • Liu N.
        Peripheral NMDA receptors are involved in long-term hyperalgesia and spinal microglia activation induced by formalin injection.
        FASEB J. 2006; 20: A776