The Role of Cytokines in the Degenerative Spine

  • Björn Rydevik
  • Helena Brisby


The intervertebral disc has traditionally been regarded as a biomechanically important structure in the spine, with characteristic biomechanical properties related to both the annulus fibrosus and the nucleus pulposus. However, research performed mainly during the last 15 years has revealed that the intervertebral disc is also biologically active and that, for example, the pathophysiology of disc degeneration and herniation is related to the production by disc cells of substances such as pro-inflammatory cytokines, for example, TNF and various interleukins. It has been shown that herniated cervical and lumbar disc specimens spontaneously produce increased amounts of various substances, such as nitrix oxide, interleukin-6, prostaglandin E2 and certain matrix metalloproteinases. Furthermore, the cells of intervertebral discs are biologically responsive and increase their production in vitro of these substances even more when stimulated by interleukin-1 beta. Increased levels of interleukin-6 and interleukin-8 have been found in disc specimens from patients with discogenic low back pain, indicating a possible role of such substances in the pathogenesis of low back pain. Increased levels of pro-inflammatory cytokines such as interleukin-1 beta have been found in facet joint tissues in patients undergoing surgery for lumbar spinal stenosis and disc herniation. These observations suggest the involvement of pro-inflammatory cytokines as a factor in the genesis of pain production in degenerated lumbar facet joints. The pathophysiology of sciatic pain, in association with disc herniation, has been shown to be related to a combination of biochemical nerve root irritation via pro-inflammatory cytokines such as TNF, produced by nucleus pulposus cells and mechanical nerve root compression. The cytokine mediated nerve root inflammation induces a sensitization of the nerve root so that the mechanical nerve root compression leads to radiating sciatic pain. Animal experimental studies have shown that anti-TNF substances, e.g. infliximab and etanercept, can reduce or prevent TNF induced nerve root changes, as well as pain behavioural reactions. Initial clinical studies have indicated a possible role of anti-TNF treatment in patients with sciatica and lumbar disc herniation, but recent studies have provided contradictory results. Further clinical studies in this field are in progress. In conclusion, there is a large body of evidence indicating that pro-inflammatory cytokines and other related substances play important roles in the pathophysiology of various spinal pain conditions.


Nerve Root Intervertebral Disc Nucleus Pulposus Disc Herniation Lumbar Spinal Stenosis 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.



This review is partly based on research supported by the Swedish Research Council, Project number K2008-53X-20627-01-3, and Marianne and Marcus Wallenberg’s Foundation.


  1. 1.
    Ahn SH, Cho YW, Ahn MW et al (2002) mRNA expression of cytokines and chemokines in herniated lumbar intervertebral discs. Spine 27:911–917CrossRefPubMedGoogle Scholar
  2. 2.
    Anzai H, Hamba M, Onda A et al (2002) Epidural application of nucleus pulposus enhances nociresponses of rat dorsal horn neurons. Spine 27:E50–E55CrossRefPubMedGoogle Scholar
  3. 3.
    Brisby H (2000) Nerve tissue injury markers, inflammatory mechanisms and immunologic factors in lumbar disc herniation. Clinical and experimental studies: Thesis, Gothenburg University; ISBN 91-628-4380-XGoogle Scholar
  4. 4.
    Brisby H, Ashley H, Diwan AD (2007) In vivo measurement of facet joint nitric oxide in patients with chronic low back pain. Spine 32:1488–1492CrossRefPubMedGoogle Scholar
  5. 5.
    Brisby H, Hammar I (2007) Thalamic activation in a disc herniation model. Spine 32:2846–2852CrossRefPubMedGoogle Scholar
  6. 6.
    Brisby H, Olmarker K, Larsson K et al (2002) Proinflammatory cytokines in cerebrospinal fluid and serum in patients with disc herniation and sciatica. Eur Spine J 11:62–66CrossRefPubMedGoogle Scholar
  7. 7.
    Burke JG, GW RW, Conhyea D et al (2003) Human nucleus pulposus can respond to a pro-inflammatory stimulus. Spine 28:2685–2693CrossRefPubMedGoogle Scholar
  8. 8.
    Chao Z, Yue Z, Tong-wei C et al (2007) Microendoscopic discectomy, a less traumatic procedure for lumbar disk herniation. Chin J Traumatol 10:311–314PubMedGoogle Scholar
  9. 9.
    Cohen SP, Bogduk N, Dragovic A et al (2009) Randomized, double-blind, placebo-controlled dose-response, and pre-clinical safety study of transforaminal etanercept for the treatment of sciatica. Anaesthesiology 110(5):1116–1126CrossRefGoogle Scholar
  10. 10.
    Cuellar JM, Montesano PX, Antognini JF et al (2005) Application of nucleus pulposus to L5 dorsal root ganglion in rats enhances nociceptive dorsal horn neuronal windup. J Neurophysiol 94:35–48CrossRefPubMedGoogle Scholar
  11. 11.
    Genevay S, Guerne PA, Gabay C (2004) Efficacy of tumor necrosis factor-alpha blockade for severe sciatica? Rev Med Suisse Romande 124:543–545PubMedGoogle Scholar
  12. 12.
    Goldring SR (2002) Bone and joint destruction in rheumatoid arthritis: what is really happening? J Rheumatol Suppl 65:44–48PubMedGoogle Scholar
  13. 13.
    Hehlgans T, Pfeffer K (2005) The intriguing biology of the tumour necrosis factor/tumour necrosis factor receptor superfamily: players, rules and the games. Immunology 115:1–20CrossRefPubMedGoogle Scholar
  14. 14.
    Hotchkiss RS, Karl IE (2003) The pathophysiology and treatment of sepsis. N Engl J Med 348:138–150CrossRefPubMedGoogle Scholar
  15. 15.
    Huang TJ, Hsu RW, Li YY et al (2005) Less systemic cytokine response in patients following microendoscopic versus open lumbar discectomy. J Orthop Res 23:406–411CrossRefPubMedGoogle Scholar
  16. 16.
    Igarashi A, Kikuchi S, Konno S (2007) Correlation between inflammatory cytokines released from the lumbar facet joint tissue and symptoms in degenerative lumbar spinal disorders. J Orthop Sci 12:154–160CrossRefPubMedGoogle Scholar
  17. 17.
    Igarashi T, Kikuchi S, Shubayev V et al (2000) 2000 Volvo Award winner in basic science studies: Exogenous tumor necrosis factor-alpha mimics nucleus pulposus-induced neuropathology. Molecular, histologic, and behavioral comparisons in rats. Spine 25:2975–2980CrossRefPubMedGoogle Scholar
  18. 18.
    Kang JD, Georgescu HI, McIntyre-Larkin L et al (1996) Herniated lumbar intervertebral discs spontaneously produce matrix metalloproteinases, nitric oxide, interleukin-6, and prostaglandin E2. Spine 21:271–277CrossRefPubMedGoogle Scholar
  19. 19.
    Karppinen J, Korhonen T, Malmivaara A et al (2003) Tumor necrosis factor-alpha monoclonal antibody, infliximab, used to manage severe sciatica. Spine 28:750–753; discussion 753–754CrossRefPubMedGoogle Scholar
  20. 20.
    Kayama S, Olmarker K, Larsson K et al (1998) Cultured, autologous nucleus pulposus cells induce functional changes in spinal nerve roots. Spine 23:2155–2158CrossRefPubMedGoogle Scholar
  21. 21.
    Korhonen T, Karppinen J, Paimela L et al (2005) The treatment of disc herniation-induced sciatica with infliximab: results of a randomized, controlled, 3-month follow-up study. Spine 30:2724–2728CrossRefPubMedGoogle Scholar
  22. 22.
    Le Maitre CL, Hoyland JA, Freemont AJ (2007) 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:R83CrossRefPubMedGoogle Scholar
  23. 23.
    BJ MWJ (1934) Rupture of the intervertebral disc with involvement of the spinal canal. New Engl J Med 211:210–215CrossRefGoogle Scholar
  24. 24.
    Murata Y, Nannmark U, Rydevik B et al (2006) Nucleus pulposus-induced apoptosis in dorsal root ganglion following experimental disc herniation in rats. Spine 31:382–390CrossRefPubMedGoogle Scholar
  25. 25.
    Okamoto H, Hoshi D, Kiire A et al (2008) Molecular targets of rheumatoid arthritis. Inflamm Allergy Drug Targets 7:53–66CrossRefPubMedGoogle Scholar
  26. 26.
    Olmarker K, Larsson K (1998) Tumor necrosis factor alpha and nucleus-pulposus-induced nerve root injury. Spine 23:2538–2544CrossRefPubMedGoogle Scholar
  27. 27.
    Olmarker K, Myers R, Rydevik B et al (2004) Pathophysiology of nerve root pain in disc herniation and spinal stenosis. In: Wiesel SW et al (eds) The lumbar spine. Lippincott William and Wilkins, Philadelphia, pp 25-39Google Scholar
  28. 28.
    Olmarker K, Nutu M, Storkson R (2003) Changes in spontaneous behavior in rats exposed to experimental disc herniation are blocked by selective TNF-alpha inhibition. Spine 28:1635–1641; discussion 1642CrossRefPubMedGoogle Scholar
  29. 29.
    Olmarker K, Rydevik B (2001) Selective inhibition of tumor necrosis factor-alpha prevents nucleus pulposus-induced thrombus formation, intraneural edema, and reduction of nerve conduction velocity: possible implications for future pharmacologic treatment strategies of sciatica. Spine 26: 863–869CrossRefPubMedGoogle Scholar
  30. 30.
    Olmarker K, Rydevik B, Nordborg C (1993) Autologous nucleus pulposus induces neurophysiologic and histologic changes in porcine cauda equina nerve roots. Spine 18:1425–1432PubMedGoogle Scholar
  31. 31.
    Park MS, Lee HM, Hahn SB et al (2007) The association of the activation-inducible tumor necrosis factor receptor and ligand with lumbar disc herniation. Yonsei Med J 48:839–846CrossRefPubMedGoogle Scholar
  32. 32.
    Sommer C, Schafers M, Marziniak M et al (2001) Etanercept reduces hyperalgesia in experimental painful neuropathy. J Peripher Nerv Syst 6:67–72CrossRefPubMedGoogle Scholar
  33. 33.
    Tachihara H, Kikuchi S, Konno S et al (2007) Does facet joint inflammation induce radiculopathy?: an investigation using a rat model of lumbar facet joint inflammation. Spine 32:406–412CrossRefPubMedGoogle Scholar
  34. 34.
    Takebayashi T, Cavanaugh JM, Cuneyt Ozaktay A et al (2001) Effect of nucleus pulposus on the neural activity of dorsal root ganglion. Spine 26:940–945CrossRefPubMedGoogle Scholar
  35. 35.
    Wang H, Schiltenwolf M, Buchner M (2008) The role of TNF-alpha in patients with chronic low back pain-a prospective comparative longitudinal study. Clin J Pain 24:273–278CrossRefPubMedGoogle Scholar
  36. 36.
    Weiler C, Nerlich AG, Bachmeier BE et al (2005) Expression and distribution of tumor necrosis factor alpha in human lumbar intervertebral discs: a study in surgical specimen and autopsy controls. Spine 30:44–53; discussion 54CrossRefPubMedGoogle Scholar
  37. 37.
    Vilcek J (1998) The cytokines: an overview. In: Thomson A (ed) The cytokine handbook, 3rd edn, Chapter 1. Academic Press, San Deigo, pp 1–20Google Scholar
  38. 38.
    Yoshida M, Nakamura T, Sei A et al (2005) Intervertebral disc cells produce tumor necrosis factor alpha, interleukin-1beta, and monocyte chemoattractant protein-1 immediately after herniation: an experimental study using a new hernia model. Spine 30:55–61PubMedGoogle Scholar
  39. 39.
    Zanella JM, Burright EN, Hildebrand K et al (2008) Effect of etanercept, a tumor necrosis factor-alpha inhibitor, on neuropathic pain in the rat chronic constriction injury model. Spine 33:227–234CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2010

Authors and Affiliations

  1. 1.Department of OrthopaedicsSahlgrenska University HospitalGothenburgSweden

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