title: Intervertebral disc and macrophage interaction induces mechanical hyperalgesia and cytokine production in a herniated disc model in rats.
abstract: OBJECTIVE
  The expression of proinflammatory factors such as tumor necrosis factor α (TNFα), interleukin-6 (IL-6), IL-8, and prostaglandin E(2) (PGE(2) ) 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 TNFα, IL-6, IL-8, and PGE(2) .
  
  
  METHODS
  We developed 2 animal models to assess the interactions of IVDs with macrophages in terms of TNFα, IL-6, IL-8, and PGE(2) production and pain-related behavior. We also cocultured IVDs and macrophages to assess the role of TNFα in IL-6, IL-8, and PGE(2) production.
  
  
  RESULTS
  IVD autografts induced TNFα, 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 TNFα, IL-6, IL-8, and COX-2 mRNA. Only IVD and macrophage cocultures resulted in IL-8 and PGE(2) up-regulation. TNFα up-regulation was maximized before that of IL-6 and IL-8. TNFα neutralization attenuated production of IL-6 and PGE(2) , but not that of IL-8. Neutralization of TNFα and IL-8 significantly increased the paw withdrawal mechanical threshold in the IVD autograft and spinal nerve ligation model.
  
  
  CONCLUSIONS
  IVD-macrophage interaction plays a major role in sciatica and in the production of TNFα, IL-6, IL-8, and PGE(2) . TNFα is required for IL-6 and PGE(2) production, but not for IL-8 production, during IVD-macrophage interaction. Neutralization of TNFα and IL-8 can be a valuable therapy for herniated disc disease.
authors.affiliation: Kobe University Graduate School of Medicine, Kobe, Japan. takadat2003@ybb.ne.jp
authors.forename: Toru
authors.initials: T
authors.lastname: Takada
authors.forename: Kotaro
authors.initials: K
authors.lastname: Nishida
authors.forename: Koichiro
authors.initials: K
authors.lastname: Maeno
authors.forename: Kenichiro
authors.initials: K
authors.lastname: Kakutani
authors.forename: Takashi
authors.initials: T
authors.lastname: Yurube
authors.forename: Minoru
authors.initials: M
authors.lastname: Doita
authors.forename: Masahiro
authors.initials: M
authors.lastname: Kurosaka
mesh_terms: D000818:Animals; D002450:Cell Communication / Q000502:physiology*; D018920:Coculture Techniques; D051546:Cyclooxygenase 2 / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism*; D015232:Dinoprostone / Q000378:metabolism; D006930:Hyperalgesia / Q000209:etiology* / Q000378:metabolism / Q000473:pathology; D015850:Interleukin-6 / Q000378:metabolism; D016209:Interleukin-8 / Q000378:metabolism; D007403:Intervertebral Disc / Q000473:pathology*; D007405:Intervertebral Disc Displacement / Q000378:metabolism* / Q000473:pathology*; D008264:Macrophages / Q000473:pathology*; D008297:Male; D023421:Models, Animal; D051381:Rats; D017207:Rats, Sprague-Dawley; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D015854:Up-Regulation
chemical_list: D016207:Cytokines; D015850:Interleukin-6; D016209:Interleukin-8; D014409:Tumor Necrosis Factor-alpha; D051546:Cyclooxygenase 2; D015232:Dinoprostone