Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Role of cytokines in intervertebral disc degeneration: pain and disc content

Key Points

  • Intervertebral disc (IVD) degeneration is a common condition, affecting a large percentage of the adult population, with huge socio-economic costs

  • IVD disease is frequently associated with back, neck and radicular pain

  • Inflammatory cytokines play a major part in the pathogenesis of IVD degeneration by promoting extracellular matrix breakdown and recruitment of immune cells to the discal tissues

  • Infiltration and activation of immune cells in the IVD results in amplification of the inflammatory responses and the release of neurotrophins

  • Inflammatory cytokines and neurotrophins promote the generation of pain through changes in nociceptive neuron ion channel activity, as well as apoptosis of these cells in the dorsal root ganglion

  • An enhanced understanding of the contribution of cytokines and immune cells to IVD degeneration, inflammation and nociception could enable the identification of novel potential therapeutic targets in symptomatic IVD disease

Abstract

Degeneration of the intervertebral discs (IVDs) is a major contributor to back, neck and radicular pain. IVD degeneration is characterized by increases in levels of the proinflammatory cytokines TNF, IL-1α, IL-1β, IL-6 and IL-17 secreted by the IVD cells; these cytokines promote extracellular matrix degradation, chemokine production and changes in IVD cell phenotype. The resulting imbalance in catabolic and anabolic responses leads to the degeneration of IVD tissues, as well as disc herniation and radicular pain. The release of chemokines from degenerating discs promotes the infiltration and activation of immune cells, further amplifying the inflammatory cascade. Leukocyte migration into the IVD is accompanied by the appearance of microvasculature tissue and nerve fibres. Furthermore, neurogenic factors, generated by both disc and immune cells, induce expression of pain-associated cation channels in the dorsal root ganglion. Depolarization of these ion channels is likely to promote discogenic and radicular pain, and reinforce the cytokine-mediated degenerative cascade. Taken together, an enhanced understanding of the contribution of cytokines and immune cells to these catabolic, angiogenic and nociceptive processes could provide new targets for the treatment of symptomatic disc disease. In this Review, the role of key inflammatory cytokines during each of the individual phases of degenerative disc disease, as well as the outcomes of major clinical studies aimed at blocking cytokine function, are discussed.

This is a preview of subscription content, access via your institution

Relevant articles

Open Access articles citing this article.

Access options

Buy article

Get time limited or full article access on ReadCube.

$32.00

All prices are NET prices.

Figure 1: Relationship between key vertebral structures, a herniated cervical IVD and spinal nerves.
Figure 2: IL-1α and IL-1β synthesis and signal transduction pathway.
Figure 3: Roles of different classes of immune cells in amplifying the inflammatory response by disc cells during IVD degeneration.
Figure 4: Schematic of major interdependent and overlapping phases leading to IVD degeneration and pain.

References

  1. Walker, B. F. The prevalence of low back pain: a systematic review of the literature from 1966 to 1998. J. Spinal Disord. 13, 205–217 (2000).

    CAS  PubMed  Google Scholar 

  2. Martin, B. I. et al. Expenditures and health status among adults with back and neck problems. JAMA 299, 656–664 (2008).

    CAS  PubMed  Google Scholar 

  3. Côté, P., Cassidy, J. D. & Carroll, L. The Saskatchewan Health and Back Pain Survey. The prevalence of neck pain and related disability in Saskatchewan adults. Spine (Phila Pa 1976) 23, 1689–1698 (1998).

    Google Scholar 

  4. Maniadakis, N. & Gray, A. The economic burden of back pain in the UK. Pain 84, 95–103 (2000).

    CAS  PubMed  Google Scholar 

  5. Stewart, W. F., Ricci, J. A., Chee, E., Morganstein, D. & Lipton, R. Lost productive time and cost due to common pain conditions in the US workforce. JAMA 290, 2443–2454 (2003).

    CAS  PubMed  Google Scholar 

  6. Takatalo, J. et al. Does lumbar disc degeneration on MRI associate with low back symptom severity in young Finnish adults? Spine (Phila Pa 1976) 36, 2180–2189 (2011).

    Google Scholar 

  7. Livshits, G. et al. Lumbar disc degeneration and genetic factors are the main risk factors for low back pain in women: the UK Twin Spine Study. Ann. Rheum. Dis. 70, 1740–1745 (2011).

    PubMed  PubMed Central  Google Scholar 

  8. Roberts, S., Evans, H., Trivedi, J. & Menage, J. Histology and pathology of the human intervertebral disc. J. Bone Joint Surg. Am. 88, 10–14 (2006).

    PubMed  Google Scholar 

  9. Kanayama, M., Togawa, D., Takahashi, C., Terai, T. & Hashimoto, T. Cross-sectional magnetic resonance imaging study of lumbar disc degeneration in 200 healthy individuals. J. Neurosurg. Spine 11, 501–507 (2009).

    PubMed  Google Scholar 

  10. Cheung, K. M. et al. Prevalence and pattern of lumber magnetic resonance changes in a population study of one thousand forty-three individuals. Spine (Phila Pa 1976) 34, 934–940 (2009).

    Google Scholar 

  11. Battié, M. C. et al. The Twin Spine Study: contributions to a changing view of disc degeneration. Spine J. 9, 47–59 (2009).

    PubMed  Google Scholar 

  12. Adams, M. A., Freeman, B. J., Morrison, H. P., Nelson, I. W. & Dolan, P. Mechanical initiation of intervertebral disc degeneration. Spine (Phila Pa 1976) 25, 1625–1636 (2000).

    CAS  Google Scholar 

  13. Wang, D. et al. Spine degeneration in a murine model of chronic human tobacco smokers. Osteoarthritis Cartilage 20, 896–905 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  14. Stirling, A., Worthington, T., Rafiq, M., Lambert, P. A. & Elliott, T. S. Association between sciatica and Propionibacterium acnes. Lancet 357, 2024–2025 (2001).

    CAS  PubMed  Google Scholar 

  15. Yamamoto, J. et al. Fas ligand plays an important role for the production of pro-inflammatory cytokines in intervertebral disc nucleus pulposus cells. J. Orthop. Res. 31, 608–615 (2013).

    CAS  PubMed  Google Scholar 

  16. Rand, N., Reichert, F., Floman, Y. & Rotshenker, S. Murine nucleus pulposus-derived cells secrete interleukins-1-β, -6, and -10 and granulocyte-macrophage colony-stimulating factor in cell culture. Spine (Phila Pa 1976) 22, 2598–2601 (1997).

    CAS  Google Scholar 

  17. Kepler, C. K. et al. Substance P stimulates production of inflammatory cytokines in human disc cells. Spine (Phila Pa 1976) http://dx.doi.org/10.1097/BRS.0b013e3182a42bc22013.

  18. Purmessur, D. et al. A role for TNFα in intervertebral disc degeneration: a non-recoverable catabolic shift. Biochem. Biophys. Res. Commun. 433, 151–156 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  19. Shen, C., Yan, J., Jiang, L. S. & Dai, L. Y. Autophagy in rat annulus fibrosus cells: evidence and possible implications. Arthritis Res. Ther. 13, R132 (2011).

    PubMed  PubMed Central  Google Scholar 

  20. Le Maitre, C. L., Freemont, A. J. & Hoyland, J. A. The role of interleukin-1 in the pathogenesis of human intervertebral disc degeneration. Arthritis Res. Ther. 7, R732–R745 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  21. Le Maitre, C. L., Hoyland, J. A. & Freemont, A. J. Catabolic cytokine expression in degenerate and herniated human intervertebral discs: IL-1β and TNFα expression profile. Arthritis Res. Ther. 9, R77 (2007).

    PubMed  PubMed Central  Google Scholar 

  22. Séguin, C. A., Pilliar, R. M., Roughley, P. J. & Kandel, R. A. Tumor necrosis factor-α modulates matrix production and catabolism in nucleus pulposus tissue. Spine (Phila Pa 1976) 30, 1940–1948 (2005).

    Google Scholar 

  23. Shamji, M. F. et al. Proinflammatory cytokine expression profile in degenerated and herniated human intervertebral disc tissues. Arthritis Rheum. 62, 1974–1982 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  24. Cuéllar, J. M. et al. Cytokine expression in the epidural space: a model of noncompressive disc herniation-induced inflammation. Spine (Phila Pa 1976) 38, 17–23 (2013).

    Google Scholar 

  25. Hayashi, S. et al. TNF-α in nucleus pulposus induces sensory nerve growth: a study of the mechanism of discogenic low back pain using TNF-α-deficient mice. Spine (Phila Pa 1976) 33, 1542–1546 (2008).

    Google Scholar 

  26. Murata, Y. et al. Changes in pain behavior and histologic changes caused by application of tumor necrosis factor-alpha to the dorsal root ganglion in rats. Spine (Phila Pa 1976) 31, 530–535 (2006).

    Google Scholar 

  27. Wang, J. et al. TNF-α and IL-1β promote a disintegrin-like and metalloprotease with thrombospondin type I motif-5-mediated aggrecan degradation through syndecan-4 in intervertebral disc. J. Biol. Chem. 286, 39738–39749 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  28. Le Maitre, C. L., Hoyland, J. A. & Freemont, A. J. Interleukin-1 receptor antagonist delivered directly and by gene therapy inhibits matrix degradation in the intact degenerate human intervertebral disc: an in situ zymographic and gene therapy study. Arthritis Res. Ther. 9, R83 (2007).

    PubMed  PubMed Central  Google Scholar 

  29. Pockert, A. J. et al. Modified expression of the ADAMTS enzymes and tissue inhibitor of metalloproteinases 3 during human intervertebral disc degeneration. Arthritis Rheum. 60, 482–491 (2009).

    CAS  PubMed  Google Scholar 

  30. Bachmeier, B. E. et al. Matrix metalloproteinase expression levels suggest distinct enzyme roles during lumbar disc herniation and degeneration. Eur. Spine J. 18, 1573–1586 (2009).

    PubMed  PubMed Central  Google Scholar 

  31. Kokubo, Y. et al. Herniated and spondylotic intervertebral discs of the human cervical spine: histological and immunohistological findings in 500 en bloc surgical samples. Laboratory investigation. J. Neurosurg. Spine. 9, 285–295 (2008).

    PubMed  Google Scholar 

  32. Akyol, S., Eraslan. B. S., Etyemez, H., Tanriverdi, T. & Hanci, M. Catabolic cytokine expressions in patients with degenerative disc disease. Turk. Neurosurg. 20, 492–499 (2010).

    PubMed  Google Scholar 

  33. Vernon-Roberts, B., Moore, R. J. & Fraser, R. D. The natural history of age-related disc degeneration: the pathology and sequelae of tears. Spine (Phila Pa 1976) 32, 2797–2804 (2007).

    Google Scholar 

  34. Melrose, J., Roberts, S., Smith, S., Menage, J. & Ghosh, P. Increased nerve and blood vessel ingrowth associated with proteoglycan depletion in an ovine anular lesion model of experimental disc degeneration. Spine (Phila Pa 1976) 27, 1278–1285 (2002).

    Google Scholar 

  35. Freemont, A. J. et al. Nerve growth factor expression and innervation of the painful intervertebral disc. J. Pathol. 197, 286–292 (2002).

    CAS  PubMed  Google Scholar 

  36. Ohtori, S. et al. Up-regulation of acid-sensing ion channel 3 in dorsal root ganglion neurons following application of nucleus pulposus on nerve root in rats. Spine (Phila Pa 1976) 31, 2048–2052 (2006).

    Google Scholar 

  37. Mamet, J., Lazdunski, M. & Voilley, N. How nerve growth factor drives physiological and inflammatory expressions of acid-sensing ion channel 3 in sensory neurons. J. Biol. Chem. 278, 48907–48913 (2003).

    CAS  PubMed  Google Scholar 

  38. Zhang, X., Huang, J. & McNaughton, P. A. NGF rapidly increases membrane expression of TRPV1 heat-gated ion channels. EMBO J. 24, 4211–4223 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  39. Black, R. A. et al. A metalloproteinase disintegrin that releases tumour-necrosis factor-α from cells. Nature 385, 729–733 (1997).

    CAS  Google Scholar 

  40. Cabal-Hierro, L. & Lazo, P. S. Signal transduction by tumor necrosis factor receptors. Cell Signal. 24, 1297–1305 (2012).

    CAS  PubMed  Google Scholar 

  41. Silke, J. The regulation of TNF signalling: what a tangled web we weave. Curr. Opin. Immunol. 23, 620–626 (2011).

    CAS  PubMed  Google Scholar 

  42. Weber, A., Wasiliew, P. & Kracht, M. Interleukin-1 (IL-1) pathway. Sci. Signal. 3, cm1 (2010).

    PubMed  Google Scholar 

  43. Gabay, C., Lamacchia, C. & Palmer, G. IL-1 pathways in inflammation and human diseases. Nat. Rev. Rheumatol. 6, 232–241 (2010).

    CAS  PubMed  Google Scholar 

  44. Kepler, C. K. et al. Expression and relationship of proinflammatory chemokine RANTES/CCL5 and cytokine IL-1β in painful human intervertebral discs. Spine (Phila Pa 1976) 38, 873–880 (2013).

    Google Scholar 

  45. Phillips, K. L., Jordan-Mahy, N., Nicklin, M. J. & Le Maitre, C. L. Interleukin-1 receptor antagonist deficient mice provide insights into pathogenesis of human intervertebral disc degeneration. Ann. Rheum. Dis. http://dx.doi.org/10.1136/annrheumdis-2012-202266.

  46. Andrade, P. et al. Tumor necrosis factor-α levels correlate with postoperative pain severity in lumbar disc hernia patients: opposite clinical effects between tumor necrosis factor receptor 1 and 2. Pain 152, 2645–2652 (2011).

    CAS  PubMed  Google Scholar 

  47. Ponnappan, R. K. et al. An organ culture system to model early degenerative changes of the intervertebral disc. Arthritis Res. Ther. 13, R171 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  48. Oda, H. et al. Degeneration of intervertebral discs due to smoking: experimental assessment in a rat-smoking model. J. Orthop. Sci. 9, 135–141 (2004).

    CAS  PubMed  Google Scholar 

  49. Walter, B. A. et al. Complex loading affects intervertebral disc mechanics and biology. Osteoarthritis Cartilage 19, 1011–1018 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  50. Ulrich, J. A., Liebenberg, E. C., Thuillier, D. U. & Lotz, J. C. ISSLS prize winner: repeated disc injury causes persistent inflammation. Spine (Phila Pa 1976) 32, 2812–2819 (2007).

    Google Scholar 

  51. Rajan, N. et al. Toll-like receptor 4 (TLR4) expression and stimulation in a model of intervertebral disc inflammation and degeneration. Spine (Phila Pa 1976) http://dx.doi.org/10.1097/BRS.0b013e31826b71f4.

  52. Tian, Y. et al. Inflammatory cytokines associated with degenerative disc disease control aggrecanase-1 (ADAMTS-4) expression in nucleus pulposus cells through MAPK and NF-κB. Am. J. Pathol. http://dx.doi.org/10.1016/j.ajpath.2013.02.037.

  53. Séguin, C. A., Pilliar, R. M., Madri, J. A. & Kandel, R. A. TNF-α induces MMP2 gelatinase activity and MT1-MMP expression in an in vitro model of nucleus pulposus tissue degeneration. Spine (Phila Pa 1976) 33, 356–365 (2008).

    Google Scholar 

  54. Echtermeyer, F. et al. Syndecan-4 regulates ADAMTS-5 activation and cartilage breakdown in osteoarthritis. Nat. Med. 15, 1072–1076 (2009).

    CAS  Google Scholar 

  55. Séguin, C. A., Bojarski, M., Pilliar, R. M., Roughley, P. J. & Kandel, R. A. Differential regulation of matrix degrading enzymes in a TNFα-induced model of nucleus pulposus tissue degeneration. Matrix Biol. 25, 409–418 (2006).

    PubMed  Google Scholar 

  56. Patel, K. P. et al. Aggrecanases and aggrecanase-generated fragments in the human intervertebral disc at early and advanced stages of disc degeneration. Spine (Phila Pa 1976) 32, 2596–2603 (2007).

    Google Scholar 

  57. Seki, S. et al. Effect of small interference RNA (siRNA) for ADAMTS5 on intervertebral disc degeneration in the rabbit anular needle-puncture model. Arthritis Res. Ther. 11, R166 (2009).

    PubMed  PubMed Central  Google Scholar 

  58. Fujita, N. et al. Expression of prolyl hydroxylases (PHDs) is selectively controlled by HIF-1 and HIF-2 proteins in nucleus pulposus cells of the intervertebral disc: distinct roles of PHD2 and PHD3 proteins in controlling HIF-1α activity in hypoxia. J. Biol. Chem. 287, 16975–16986 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  59. Fujita, N. et al. Prolyl hydroxylase 3 (PHD3) modulates catabolic effects of tumor necrosis factor-α (TNF-α) on cells of the nucleus pulposus through co-activation of nuclear factor κB (NF-κB)/p65 signaling. J. Biol. Chem. 287, 39942–39953 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  60. Kawaguchi, S. et al. Chemokine profile of herniated intervertebral discs infiltrated with monocytes and macrophages. Spine (Phila Pa 1976) 27, 1511–1516 (2002).

    Google Scholar 

  61. Wang, J. et al. Tumor necrosis factor α- and interleukin-1β-dependent induction of CCL3 expression by nucleus pulposus cells promotes macrophage migration through CCR1. Arthritis Rheum. 65, 832–842 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  62. Ahn, S. H. et al. mRNA expression of cytokines and chemokines in herniated lumbar intervertebral discs. Spine (Phila Pa 1976) 27, 911–917 (2002).

    Google Scholar 

  63. Takada, T. et al. Intervertebral disc and macrophage interaction induces mechanical hyperalgesia and cytokine production in a herniated disc model in rats. Arthritis Rheum. 64, 2601–2610 (2012).

    CAS  PubMed  Google Scholar 

  64. Hiyama, A. et al. Hypoxia activates the notch signaling pathway in cells of the intervertebral disc: implications in degenerative disc disease. Arthritis Rheum. 63, 1355–1364 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  65. Wang, H. et al. Inflammatory cytokines induce notch signaling in nucleus pulposus cells: implications in intervertebral disc degeneration. J. Biol. Chem. 288, 16761–16774 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  66. Scheller, J., Chalaris, A., Schmidt-Arras, D. & Rose-John, S. The pro- and anti-inflammatory properties of the cytokine interleukin-6. Biochim. Biophys. Acta 1813, 878–888 (2011).

    CAS  Google Scholar 

  67. Andrade, P. et al. Elevated IL-1β and IL-6 levels in lumbar herniated discs in patients with sciatic pain. Eur. Spine J. 22, 714–720 (2013).

    PubMed  Google Scholar 

  68. Studer, R. K., Vo, N., Sowa, G., Ondeck, C. & Kang, J. Human nucleus pulposus cells react to IL-6: independent actions and amplification of response to IL-1 and TNF-α. Spine (Phila Pa 1976) 36, 593–599 (2011).

    Google Scholar 

  69. Murata, Y. et al. Local application of interleukin-6 to the dorsal root ganglion induces tumor necrosis factor-α in the dorsal root ganglion and results in apoptosis of the dorsal root ganglion cells. Spine (Phila Pa 1976) 36, 926–932 (2011).

    Google Scholar 

  70. Murata, Y., Nannmark, U., Rydevik, B., Takahashi, K. & Olmarker, K. The role of tumor necrosis factor-α in apoptosis of dorsal root ganglion cells induced by herniated nucleus pulposus in rats. Spine (Phila Pa 1976) 33, 155–162 (2008).

    Google Scholar 

  71. Wei, X. H. 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. 241, 159–168 (2013).

    CAS  PubMed  Google Scholar 

  72. Noponen-Hietala, N. et al. Genetic variations in IL6 associate with intervertebral disc disease characterized by sciatica. Pain 114, 186–194 (2005).

    CAS  PubMed  Google Scholar 

  73. Kelempisioti, A. et al. Genetic susceptibility of intervertebral disc degeneration among young Finnish adults. BMC Med. Genet. 12, 153 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  74. Gaffen, S. L. Recent advances in the IL-17 cytokine family. Curr. Opin. Immunol. 23, 613–619 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  75. Gruber, H. E, Hoelscher, G. L., Ingram, J. A., Norton, H. J. & Hanley, E. N. Jr. Increased IL-17 expression in degenerated human discs and increased production in cultured annulus cells exposed to IL-1β and TNF-α. Biotech. Histochem. http://dx.doi.org/10.3109/10520295.2013.783235.

  76. Kenna, T. J. & Brown, M. A. The role of IL-17-secreting mast cells in inflammatory joint disease. Nat. Rev. Rheumatol. http://dx.doi.org/10.1038/nrrheum.2012.205.

  77. Schroder, K., Hertzog, P. J., Ravasi, T. & Hume, D. A. Interferon-γ: an overview of signals, mechanisms and functions. J. Leukoc. Biol. 75, 163–189 (2004).

    CAS  Google Scholar 

  78. Sadir, R., Forest, E. & Lortat-Jacob, H. The heparan sulfate binding sequence of interferon-γ increased the on rate of the interferon-γ-interferon-γreceptor complex formation. J. Biol. Chem. 273, 10919–10925 (1998).

    CAS  PubMed  Google Scholar 

  79. Kim, C. F. & Moalem-Taylor, G. Interleukin-17 contributes to neuroinflammation and neuropathic pain following peripheral nerve injury in mice. J. Pain. 12, 370–383 (2011).

    CAS  PubMed  Google Scholar 

  80. Gabr, M. A. et al. Interleukin-17 synergizes with IFNγ or TNFα to promote inflammatory mediator release and intercellular adhesion molecule-1 (ICAM-1) expression in human intervertebral disc cells. J. Orthop. Res. 29, 1–7 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  81. Park, J. B., Chang, H. & Kim, Y. S. The pattern of interleukin-12 and T-helper types 1 and 2 cytokine expression in herniated lumbar disc tissue. Spine (Phila Pa 1976) 27, 2125–2128 (2002).

    Google Scholar 

  82. Cuellar, J. M. et al. Cytokine evaluation in individuals with low back pain using discographic lavage. Spine J. 10, 212–218 (2010).

    PubMed  Google Scholar 

  83. Tian, P., Ma, X. L., Wang, T., Ma, J. X. & Yang, X. Correlation between radiculalgia and counts of T lymphocyte subsets in the peripheral blood of patients with lumbar disc herniation. Orthop. Surg. 1, 317–321 (2009).

    PubMed  PubMed Central  Google Scholar 

  84. Ma, X. L., Tian, P., Wang, T. & Ma, J. X. A study of the relationship between type of lumbar disc herniation, straight leg raising test and peripheral T lymphocytes. Orthop. Surg. 2, 52–57 (2010).

    PubMed  PubMed Central  Google Scholar 

  85. Johnson, W. E. et al. Human intervertebral disc aggrecan inhibits nerve growth in vitro. Arthritis Rheum. 46, 2658–2664 (2002).

    CAS  PubMed  Google Scholar 

  86. Tolofari, S. K., Richardson, S. M., Freemont, A. J. & Hoyland, J. A. Expression of semaphorin 3A and its receptors in the human intervertebral disc: potential role in regulating neural ingrowth in the degenerate intervertebral disc. Arthritis Res. Ther. 12, R1 (2010).

    PubMed  PubMed Central  Google Scholar 

  87. Uchiyama, Y. et al. Expression of acid-sensing ion channel 3 (ASIC3) in nucleus pulposus cells of the intervertebral disc is regulated by p75NTR and ERK signaling. J. Bone Miner. Res. 22, 1996–2006 (2007).

    CAS  PubMed  Google Scholar 

  88. Purmessur, D., Freemont, A. J. & Hoyland, J. A. Expression and regulation of neurotrophins in the nondegenerate and degenerate human intervertebral disc. Arthritis Res. Ther. 10, R99 (2008).

    PubMed  PubMed Central  Google Scholar 

  89. Abe, Y. et al. Proinflammatory cytokines stimulate the expression of nerve growth factor by human intervertebral disc cells. Spine (Phila Pa 1976) 32, 635–642 (2007).

    Google Scholar 

  90. Gruber, H. E., Hoelscher, G. L., Bethea, S. & Hanley, E. N. Jr. Interleukin 1-β upregulates brain-derived neurotrophic factor, neurotrophin 3 and neuropilin 2 gene expression and NGF production in annulus cells. Biotech. Histochem. 87, 506–511 (2012).

    CAS  PubMed  Google Scholar 

  91. Ebbinghaus, M. et al. The role of interleukin-1β in arthritic pain: main involvement in thermal, but not mechanical, hyperalgesia in rat antigen-induced arthritis. Arthritis Rheum. 64, 3897–3907 (2012).

    CAS  PubMed  Google Scholar 

  92. Ohtori, S., Takahashi, K. & Moriya, H. Existence of brain-derived neurotrophic factor and vanilloid receptor subtype 1 immunoreactive sensory DRG neurons innervating L5/6 intervertebral discs in rats. J. Orthop. Sci. 8, 84–87 (2003).

    PubMed  Google Scholar 

  93. Ashton, I. K., Roberts, S., Jaffray, D. C., Polak, J. M. & Eisenstein, S. M. Neuropeptides in the human intervertebral disc. J. Orthop. Res. 12, 186–192 (1994).

    CAS  PubMed  Google Scholar 

  94. Brown, M. F. et al. Sensory and sympathetic innervation of the vertebral endplate in patients with degenerative disc disease. J. Bone Joint Surg. Br. 79, 147–153 (1997).

    CAS  PubMed  Google Scholar 

  95. Ohtori, S. et al. Substance P and calcitonin gene-related peptide immunoreactive sensory DRG neurons innervating the lumbar intervertebral discs in rats. Ann. Anat. 184, 235–240 (2002).

    CAS  PubMed  Google Scholar 

  96. García-Cosamalón, J. et al. Intervertebral disc, sensory nerves and neurotrophins: who is who in discogenic pain? J. Anat. 217, 1–15 (2010).

    PubMed  PubMed Central  Google Scholar 

  97. Ohtori, S. et al. Epidural administration of spinal nerves with the tumor necrosis factor-α inhibitor, etanercept, compared with dexamethasone for treatment of sciatica in patients with lumbar spinal stenosis: a prospective randomized study. Spine (Phila Pa 1976) 37, 439–444 (2012).

    Google Scholar 

  98. Ohtori, S. et al. Efficacy of epidural administration of anti-interleukin-6 receptor antibody onto spinal nerve for treatment of sciatica. Eur. Spine J. 21, 2079–2084 (2012).

    PubMed  PubMed Central  Google Scholar 

  99. Genevay, S. et al. Adalimumab in severe and acute sciatica: a multicenter, randomized, double-blind, placebo-controlled trial. Arthritis Rheum. 62, 2339–2346 (2010).

    PubMed  Google Scholar 

  100. Genevay, S. et al. Adalimumab in acute sciatica reduces the long-term need for surgery: a 3-year follow-up of a randomised double-blind placebo-controlled trial. Ann. Rheum. Dis. 71, 560–562 (2012).

    CAS  PubMed  Google Scholar 

  101. Genevay, S., Stingelin, S. & Gabay, C. Efficacy of etanercept in the treatment of acute, severe sciatica: a pilot study. Ann. Rheum. Dis. 63, 1120–1123 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  102. Cohen, S. P., Bogduk, N. & Dragovich, A. Randomized, double-blind, placebo-controlled, dose-response, and preclinical safety study of transforaminal epidural etanercept for the treatment of sciatica. Anesthesiology 110, 1116–1126 (2009).

    CAS  PubMed  Google Scholar 

  103. Okoro, T., Tafazal, S. I., Longworth, S. & Sell, P. J. Tumor necrosis α-blocking agent (etanercept): a triple blind randomized controlled trial of its use in treatment of sciatica. J. Spinal Disord. Tech. 23, 74–77 (2010).

    PubMed  Google Scholar 

  104. Cohen, S. P. et al. Epidural steroids, etanercept, or saline in subacute sciatica: a multicenter, randomized trial. Ann. Intern. Med. 156, 551–559 (2012).

    PubMed  Google Scholar 

  105. Korhonen, T. et al. The treatment of disc-herniation-induced sciatica with infliximab: one-year follow-up results of FIRST II, a randomized controlled trial. Spine (Phila Pa 1976) 31, 2759–2766 (2006).

    Google Scholar 

  106. Nadeau, S. et al. Functional recovery after peripheral nerve injury is dependent on the pro-inflammatory cytokines IL-1β and TNF: implications for neuropathic pain. J. Neurosci. 31, 12533–12542 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  107. Smith, L. J. et al. Nucleus pulposus cells synthesize a functional extracellular matrix and respond to inflammatory cytokine challenge following long-term agarose culture. Eur. Cell Mater. 22, 291–301 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  108. Gorth, D. J. et al. IL-1ra delivered from poly(lactic-co-glycolic acid) microspheres attenuates IL-1β-mediated degradation of nucleus pulposus in vitro. Arthritis Res. Ther. 14, R179 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  109. Rothman, S. M., Huang, Z., Lee, K. E., Weisshaar, C. L. & Winkelstein, B. A. Cytokine mRNA expression in painful radiculopathy. J. Pain. 10, 90–99 (2009).

    CAS  PubMed  Google Scholar 

  110. Rothman, S. M. & Winkelstein, B. A. Cytokine antagonism reduces pain and modulates spinal astrocytic reactivity after cervical nerve root compression. Ann. Biomed. Eng. 38, 2563–2576 (2010).

    PubMed  Google Scholar 

  111. Kim, J. S. et al. Lactoferricin mediates anti-inflammatory and anti-catabolic effects via inhibition of IL-1 and LPS activity in the intervertebral disc. J. Cell Physiol. http://dx.doi.org/10.1002/jcp.24350.

  112. Klawitter, M. et al. Triptolide exhibits anti-inflammatory, anti-catabolic as well as anabolic effects and suppresses TLR expression and MAPK activity in IL-1β treated human intervertebral disc cells. Eur. Spine J. 21, S850–S859 (2012).

    PubMed  Google Scholar 

  113. Ellman, M. B. et al. Toll-like receptor adaptor signaling molecule MyD88 on intervertebral disk homeostasis: in vitro, ex vivo studies. Gene 505, 283–290 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  114. Winkelstein, B. A., Rutkowski, M. D., Sweitzer, S. M., Pahl, J. L. & DeLeo, J. A. Nerve injury proximal or distal to the DRG induces similar spinal glial activation and selective cytokine expression but differential behavioral responses to pharmacologic treatment. J. Comp. Neurol. 439, 127–139 (2001).

    CAS  PubMed  Google Scholar 

  115. Sinclair, S. M. et al. Attenuation of inflammatory events in human intervertebral disc cells with a tumor necrosis factor antagonist. Spine (Phila Pa 1976) 36, 1190–1196 (2011).

    Google Scholar 

  116. Schafers, M., Svensson, C. I., Sommer, C. & Sorkin, L. S. Tumor necrosis factor-α induces mechanical allodynia after spinal nerve ligation by activation of p38 MAPK in primary sensory neurons. J. Neurosci. 23, 2517–2521 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  117. Allen, K. D. et al. Kinematic and dynamic gait compensations in a rat model of lumbar radiculopathy and the effects of tumor necrosis factor-α antagonism. Arthritis Res. Ther. 13, R137 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  118. Zanella, J. M. et al. Effect of etanercept, a tumor necrosis factor-α inhibitor, on neuropathic pain in the rat chronic constriction injury model. Spine (Phila Pa 1976) 33, 227–234 (2008).

    Google Scholar 

  119. Nasto, L. A. et al. Inhibition of NF-κB activity ameliorates age-associated disc degeneration in a mouse model of accelerated aging. Spine (Phila Pa 1976) 37, 1819–1825 (2012).

    Google Scholar 

  120. Suzuki, M. et al. Nuclear factor-κ B decoy suppresses nerve injury and improves mechanical allodynia and thermal hyperalgesia in a rat lumbar disc herniation model. Eur. Spine J. 18, 1001–1007 (2009).

    PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

The work of the authors is supported by US NIH National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS) awards AR050087 and AR055655. The authors wish to thank C. K. Kepler (Rothman Institute and Thomas Jefferson University, Philadelpia, PA, USA) for providing the MRI image of a herniated disc.

Author information

Authors and Affiliations

Authors

Contributions

Both authors made substantial contributions to all stages of the preparation of this manuscript for publication.

Corresponding author

Correspondence to Makarand V. Risbud.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

PowerPoint slides

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Risbud, M., Shapiro, I. Role of cytokines in intervertebral disc degeneration: pain and disc content. Nat Rev Rheumatol 10, 44–56 (2014). https://doi.org/10.1038/nrrheum.2013.160

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrrheum.2013.160

This article is cited by

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing