Celecoxib alleviates nociceptor sensitization mediated by interleukin-1beta-primed annulus fibrosus cells

Junxuan Ma, Surya Häne, Janick Eglauf, Judith Pfannkuche, Astrid Soubrier, Zhen Li, Marianna Peroglio, Sven Hoppe, Lorin Benneker, Gernot Lang, Sebastian Wangler, Mauro Alini, Laura B Creemers, Sibylle Grad, Sonja Häckel

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Abstract

PURPOSE: This study aims to analyze the effect of pro-inflammatory cytokine-stimulated human annulus fibrosus cells (hAFCs) on the sensitization of dorsal root ganglion (DRG) cells. We further hypothesized that celecoxib (cxb) could inhibit hAFCs-induced DRG sensitization.

METHODS: hAFCs from spinal trauma patients were stimulated with TNF-α or IL-1β. Cxb was added on day 2. On day 4, the expression of pro-inflammatory and neurotrophic genes was evaluated using RT-qPCR. Levels of prostaglandin E2 (PGE-2), IL-8, and IL-6 were measured in the conditioned medium (CM) using ELISA. hAFCs CM was then applied to stimulate the DRG cell line (ND7/23) for 6 days. Then, calcium imaging (Fluo4) was performed to evaluate DRG cell sensitization. Both spontaneous and bradykinin-stimulated (0.5 μM) calcium responses were analyzed. The effects on primary bovine DRG cell culture were performed in parallel to the DRG cell line model.

RESULTS: IL-1ß stimulation significantly enhanced the release of PGE-2 in hAFCs CM, while this increase was completely suppressed by 10 µM cxb. hAFCs revealed elevated IL-6 and IL-8 release following TNF-α and IL-1β treatment, though cxb did not alter this. The effect of hAFCs CM on DRG cell sensitization was influenced by adding cxb to hAFCs; both the DRG cell line and primary bovine DRG nociceptors showed a lower sensitivity to bradykinin stimulation.

CONCLUSION: Cxb can inhibit PGE-2 production in hAFCs in an IL-1β-induced pro-inflammatory in vitro environment. The cxb applied to the hAFCs also reduces the sensitization of DRG nociceptors that are stimulated by the hAFCs CM.

Keywords

  • Animals
  • Annulus Fibrosus
  • Bradykinin/pharmacology
  • Calcium/pharmacology
  • Cattle
  • Celecoxib/pharmacology
  • Cells, Cultured
  • Ganglia, Spinal
  • Humans
  • Interleukin-1beta/pharmacology
  • Interleukin-6
  • Interleukin-8/pharmacology
  • Nociceptors
  • Tumor Necrosis Factor-alpha

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