Intervertebral disc and macrophage interaction induces mechanical hyperalgesia and cytokine production in a herniated disc model in rats

Objective The expression of proinflammatory factors such as tumor necrosis factor a (TNFa), interleukin-6 (IL-6), IL-8, and prostaglandin E2 (PGE2) is significantly correlated with the symptoms of herniated disc disease. Among the different types of immune cells, macrophages are frequently noted in the herniated disc tissue. We undertook this study to clarify the interaction of the intervertebral disc (IVD) and macrophages with regard to the production of TNFa, IL-6, IL-8, and PGE2. Methods We developed 2 animal models to assess the interactions of IVDs with macrophages in terms of TNFa, IL-6, IL-8, and PGE2 production and pain-related behavior. We also cocultured IVDs and macrophages to assess the role of TNFa in IL-6, IL-8, and PGE2 production. Results IVD autografts induced TNFa, IL-6, IL-8, and cyclooxygenase 2 (COX-2) messenger RNA (mRNA) up-regulation; macrophage infiltration was seen shortly after the autograft was implanted. A significant decrease was noted in the mechanical threshold of the ipsilateral paw following the up-regulation of TNFa, IL-6, IL-8, and COX-2 mRNA. Only IVD and macrophage cocultures resulted in IL-8 and PGE2 up-regulation. TNFa up-regulation was maximized before that of IL-6 and IL-8. TNFa neutralization attenuated production of IL-6 and PGE2, but not that of IL-8. Neutralization of TNFa and IL-8 significantly increased the paw withdrawal mechanical threshold in the IVD autograft and spinal nerve ligation model. Conclusion IVDmacrophage interaction plays a major role in sciatica and in the production of TNFa, IL-6, IL-8, and PGE2. TNFa is required for IL-6 and PGE2 production, but not for IL-8 production, during IVDmacrophage interaction. Neutralization of TNFa and IL-8 can be a valuable therapy for herniated disc disease.