Skip to main content
SpringerLink
Log in

The Role of Cytokines in the Degenerative Spine

  • Chapter
  • First Online:
Surgery for Low Back Pain

Abstract

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.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 119.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 159.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 159.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  1. Ahn SH, Cho YW, Ahn MW et al (2002) mRNA expression of cytokines and chemokines in herniated lumbar intervertebral discs. Spine 27:911–917

    Article  PubMed  Google Scholar 

  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–E55

    Article  PubMed  Google Scholar 

  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-X

    Google Scholar 

  4. Brisby H, Ashley H, Diwan AD (2007) In vivo measurement of facet joint nitric oxide in patients with chronic low back pain. Spine 32:1488–1492

    Article  PubMed  Google Scholar 

  5. Brisby H, Hammar I (2007) Thalamic activation in a disc herniation model. Spine 32:2846–2852

    Article  PubMed  Google Scholar 

  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 11:62–66

    Article  CAS  PubMed  Google Scholar 

  7. Burke JG, GW RW, Conhyea D et al (2003) Human nucleus pulposus can respond to a pro-inflammatory stimulus. Spine 28:2685–2693

    Article  CAS  PubMed  Google Scholar 

  8. Chao Z, Yue Z, Tong-wei C et al (2007) Microendoscopic discectomy, a less traumatic procedure for lumbar disk herniation. Chin J Traumatol 10:311–314

    PubMed  Google Scholar 

  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):1116–1126

    Article  CAS  Google Scholar 

  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 94:35–48

    Article  CAS  PubMed  Google Scholar 

  11. Genevay S, Guerne PA, Gabay C (2004) Efficacy of tumor necrosis factor-alpha blockade for severe sciatica? Rev Med Suisse Romande 124:543–545

    PubMed  Google Scholar 

  12. Goldring SR (2002) Bone and joint destruction in rheumatoid arthritis: what is really happening? J Rheumatol Suppl 65:44–48

    CAS  PubMed  Google Scholar 

  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 115:1–20

    Article  CAS  PubMed  Google Scholar 

  14. Hotchkiss RS, Karl IE (2003) The pathophysiology and treatment of sepsis. N Engl J Med 348:138–150

    Article  CAS  PubMed  Google Scholar 

  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 23:406–411

    Article  CAS  PubMed  Google Scholar 

  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 12:154–160

    Article  CAS  PubMed  Google Scholar 

  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 25:2975–2980

    Article  CAS  PubMed  Google Scholar 

  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 21:271–277

    Article  CAS  PubMed  Google Scholar 

  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 753–754

    Article  PubMed  Google Scholar 

  20. Kayama S, Olmarker K, Larsson K et al (1998) Cultured, autologous nucleus pulposus cells induce functional changes in spinal nerve roots. Spine 23:2155–2158

    Article  CAS  PubMed  Google Scholar 

  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 30:2724–2728

    Article  PubMed  Google Scholar 

  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:R83

    Article  PubMed  Google Scholar 

  23. BJ MWJ (1934) Rupture of the intervertebral disc with involvement of the spinal canal. New Engl J Med 211:210–215

    Article  Google Scholar 

  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 31:382–390

    Article  PubMed  Google Scholar 

  25. Okamoto H, Hoshi D, Kiire A et al (2008) Molecular targets of rheumatoid arthritis. Inflamm Allergy Drug Targets 7:53–66

    Article  CAS  PubMed  Google Scholar 

  26. Olmarker K, Larsson K (1998) Tumor necrosis factor alpha and nucleus-pulposus-induced nerve root injury. Spine 23:2538–2544

    Article  CAS  PubMed  Google Scholar 

  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 25-39

    Google Scholar 

  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 1642

    Article  PubMed  Google Scholar 

  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: 863–869

    Article  CAS  PubMed  Google Scholar 

  30. Olmarker K, Rydevik B, Nordborg C (1993) Autologous nucleus pulposus induces neurophysiologic and histologic changes in porcine cauda equina nerve roots. Spine 18:1425–1432

    CAS  PubMed  Google Scholar 

  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 48:839–846

    Article  CAS  PubMed  Google Scholar 

  32. Sommer C, Schafers M, Marziniak M et al (2001) Etanercept reduces hyperalgesia in experimental painful neuropathy. J Peripher Nerv Syst 6:67–72

    Article  CAS  PubMed  Google Scholar 

  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 32:406–412

    Article  PubMed  Google Scholar 

  34. Takebayashi T, Cavanaugh JM, Cuneyt Ozaktay A et al (2001) Effect of nucleus pulposus on the neural activity of dorsal root ganglion. Spine 26:940–945

    Article  CAS  PubMed  Google Scholar 

  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 24:273–278

    Article  PubMed  Google Scholar 

  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 54

    Article  PubMed  Google Scholar 

  37. Vilcek J (1998) The cytokines: an overview. In: Thomson A (ed) The cytokine handbook, 3rd edn, Chapter 1. Academic Press, San Deigo, pp 1–20

    Google Scholar 

  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 30:55–61

    PubMed  Google Scholar 

  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 33:227–234

    Article  PubMed  Google Scholar 

Download references

Acknowledgements

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.

Author information

Authors and Affiliations

  1. Department of Orthopaedics, Sahlgrenska University Hospital, 413 45, Gothenburg, Sweden

    Björn Rydevik

Authors
  1. Björn Rydevik
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Helena Brisby
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Björn Rydevik .

Editor information

Editors and Affiliations

  1. Avenue Coghen 21, Bruxelles, 1180, Belgium

    Marek Szpalski

  2. Algemeen Ziekenhuis Monica, Eeuwfeestkliniek, Harmoniestraat 68, Antwerpen, 2018, Belgium

    Robert Gunzburg

  3. Dept. Orthopaedic Surgery, Sahlgrenska Univ.Hospital/Sahlgrenska, Göteborg, 413 45, Sweden

    Björn L. Rydevik

  4. Hopital Pellegrin, CHU Bordeaux, place Amalie Raba Leon, Bordeaux CX, 33076, France

    Jean-Charles Le Huec

  5. München-Harlaching, Orthopädische Klinik, Harlachinger Str. 51, München, 81243, Germany

    H. Michael Mayer

Rights and permissions

Reprints and permissions

Copyright information

© 2010 Springer-Verlag Berlin Heidelberg

About this chapter

Cite this chapter

Rydevik, B., Brisby, H. (2010). The Role of Cytokines in the Degenerative Spine. In: Szpalski, M., Gunzburg, R., Rydevik, B., Le Huec, JC., Mayer, H. (eds) Surgery for Low Back Pain. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-642-04547-9_3

Download citation

  • DOI: https://doi.org/10.1007/978-3-642-04547-9_3

  • Published:

  • Publisher Name: Springer, Berlin, Heidelberg

  • Print ISBN: 978-3-642-04546-2

  • Online ISBN: 978-3-642-04547-9

  • eBook Packages: MedicineMedicine (R0)

Publish with us

Policies and ethics

Search

Navigation