IL‑1β and TNF‑α suppress TGF‑β‑promoted NGF expression in periodontal ligament‑derived fibroblasts through inactivation of TGF‑β‑induced Smad2/3‑ and p38 MAPK‑mediated signals

Int J Mol Med. 2018 Sep;42(3):1484-1494. doi: 10.3892/ijmm.2018.3714. Epub 2018 Jun 4.


Mechanosensitive (MS) neurons in the periodontal ligament (PDL) pass information to the trigeminal ganglion when excited by mechanical stimulation of the tooth. During occlusal tooth trauma of PDL tissues, MS neurons are injured, resulting in atrophic neurites and eventual degeneration of MS neurons. Nerve growth factor (NGF), a neurotrophic factor, serves important roles in the regeneration of injured sensory neurons. In the present study, the effect of pro‑inflammatory cytokines, including interleukin 1β (IL‑1β) and tumor necrosis factor α (TNF‑α), on transforming growth factor β1 (TGF‑β1)‑induced NGF expression was evaluated in rat PDL‑derived SCDC2 cells. It was observed that TGF‑β1 promoted NGF expression via Smad2/3 and p38 mitogen‑activated protein kinase (MAPK) activation. IL‑1β and TNF‑α suppressed the TGF‑β1‑induced activation of Smad2/3 and p38 MAPK, resulting in the abrogation of NGF expression. NGF secreted by TGF‑β1‑treated SCDC2 cells promoted neurite extension and the expression of tyrosine hydroxylase, a rate‑limiting enzyme in dopamine synthesis in rat pheochromocytoma PC12 cells. These results suggested that pro‑inflammatory cytokines suppressed the TGF‑β‑mediated expression of NGF in PDL‑derived fibroblasts through the inactivation of TGF‑β‑induced Smad2/3 and p38 MAPK signaling, possibly resulting in the disturbance of the regeneration of injured PDL neurons.

MeSH terms

  • Adenosine Triphosphate / analogs & derivatives
  • Adenosine Triphosphate / pharmacology
  • Animals
  • Fibroblasts / drug effects
  • Fibroblasts / metabolism*
  • Humans
  • Interleukin-1beta / pharmacology*
  • Nerve Growth Factor / genetics
  • Nerve Growth Factor / metabolism*
  • Neurites / drug effects
  • Neurites / metabolism
  • PC12 Cells
  • Periodontal Ligament / cytology*
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • Rats
  • Receptors, Transforming Growth Factor beta / metabolism
  • Signal Transduction / drug effects
  • Smad Proteins / metabolism*
  • Transforming Growth Factor beta / pharmacology*
  • Tumor Necrosis Factor-alpha / pharmacology*
  • Tyrosine 3-Monooxygenase / metabolism
  • p38 Mitogen-Activated Protein Kinases / metabolism*


  • Interleukin-1beta
  • RNA, Messenger
  • Receptors, Transforming Growth Factor beta
  • Smad Proteins
  • Transforming Growth Factor beta
  • Tumor Necrosis Factor-alpha
  • adenosine 5'-O-(3-thiotriphosphate)
  • Adenosine Triphosphate
  • Nerve Growth Factor
  • Tyrosine 3-Monooxygenase
  • p38 Mitogen-Activated Protein Kinases