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


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.

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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.


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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.

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

Correspondence to Makarand V. Risbud.

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The authors declare no competing financial interests.

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Risbud, M., Shapiro, I. Role of cytokines in intervertebral disc degeneration: pain and disc content. Nat Rev Rheumatol 10, 44–56 (2014).

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