title: Regulation of nerve growth factor by anti-inflammatory drugs, a steroid, and a selective cyclooxygenase 2 inhibitor in human intervertebral disc cells stimulated with interleukin-1.
abstract: METHODS
  Regulation of nerve growth factor (NGF) by 2 different anti-inflammatory drugs was investigated in vitro using isolated human intervertebral disc (IVD) cells stimulated with the proinflammatory cytokine interleukin-1 (IL-1).
  
  
  OBJECTIVE
  To investigate the regulation of NGF by a synthetic steroid and a selective cyclooxygenase-2 (COX-2) inhibitor and to clarify the biological role of prostaglandin E2 (PGE2) in this process.
  
  
  BACKGROUND
  NGF is known to play an important role in pain, including low back pain, and to be induced by proinflammatory cytokines in IVD cells. However, the effect of clinically used drugs for managing low back pain on the regulation of NGF is unclear.
  
  
  METHODS
  Isolated human IVD cells were stimulated with interleukin-1 (IL-1) in the presence or absence of dexamethasone or a selective COX-2 inhibitor (NS-398). NGF expression and release were determined by real-time polymerase chain reaction and enzyme-linked immuno sorbent assay, respectively. Inhibition of PGE2 release was determined by enzyme-linked immuno sorbent assay. The effects of exogenous PGE2 and its receptor (E-series prostanoid receptors [EPs] 1-4) agonists were also tested for NGF regulation.
  
  
  RESULTS
  IL-1 transiently induced, in a dose-dependent manner, the induction of NGF in human IVD cells. Pretreatment with dexamethasone strongly inhibited the NGF expression, whereas NS-398 significantly enhanced it at the concentration at which PGE2 release was substantially inhibited. Exogenous PGE2 inhibited IL-1 induction of NGF and this effect was mimicked when EP2 and EP4, but not EP1 and EP3, agonists were supplemented to the culture.
  
  
  CONCLUSIONS
  Although selective COX-2 inhibitors have been shown to be effective for acute low back pain by inhibiting PGE2 release, our findings suggest that it may have a limited efficacy because it exaggerated NGF expression, whereas dexamethasone inhibited it. On the other hand, PGE2 had an inhibitory function for NGF induction by mediating EP2/4 in human IVD cells. Further studies are needed to clarify whether these observations could take place in vivo.
  
  
  METHODS
  N/A.
authors.affiliation: Department of Orthopedic Surgery, Tokyo Medical University, Nishi-Shinjuku, Shinjuku-ku, Tokyo, Japan.
authors.forename: Wuqikun
authors.initials: W
authors.lastname: Alimasi
authors.forename: Yasunobu
authors.initials: Y
authors.lastname: Sawaji
authors.forename: Kenji
authors.initials: K
authors.lastname: Endo
authors.forename: Makiko
authors.initials: M
authors.lastname: Yorifuji
authors.forename: Hidekazu
authors.initials: H
authors.lastname: Suzuki
authors.forename: Taiichi
authors.initials: T
authors.lastname: Kosaka
authors.forename: Takaaki
authors.initials: T
authors.lastname: Shishido
authors.forename: Kengo
authors.initials: K
authors.lastname: Yamamoto
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000893:Anti-Inflammatory Agents / Q000494:pharmacology; D002478:Cells, Cultured; D052246:Cyclooxygenase 2 Inhibitors / Q000494:pharmacology*; D003907:Dexamethasone / Q000494:pharmacology*; D015232:Dinoprostone / Q000378:metabolism / Q000494:pharmacology; D004797:Enzyme-Linked Immunosorbent Assay; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D007375:Interleukin-1 / Q000494:pharmacology*; D007403:Intervertebral Disc / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D008875:Middle Aged; D020932:Nerve Growth Factor / Q000235:genetics / Q000378:metabolism*; D009578:Nitrobenzenes / Q000494:pharmacology*; D060888:Real-Time Polymerase Chain Reaction; D058307:Receptors, Prostaglandin E, EP2 Subtype / Q000819:agonists / Q000378:metabolism; D058309:Receptors, Prostaglandin E, EP4 Subtype / Q000819:agonists / Q000378:metabolism; D013449:Sulfonamides / Q000494:pharmacology*
chemical_list: D000893:Anti-Inflammatory Agents; D052246:Cyclooxygenase 2 Inhibitors; D007375:Interleukin-1; D009578:Nitrobenzenes; D058307:Receptors, Prostaglandin E, EP2 Subtype; D058309:Receptors, Prostaglandin E, EP4 Subtype; D013449:Sulfonamides; C080955:N-(2-cyclohexyloxy-4-nitrophenyl)methanesulfonamide; D003907:Dexamethasone; D020932:Nerve Growth Factor; D015232:Dinoprostone