IL-33 Exacerbates Periodontal Disease through Induction of RANKL

J Dent Res. 2015 Jul;94(7):968-75. doi: 10.1177/0022034515577815. Epub 2015 Mar 25.


Cytokines mediate the balance between protective and destructive immunity in periodontitis. We sought to investigate the role of IL-33 in periodontitis. The expression of IL-33 in gingival tissue from healthy controls (n = 10) and patients with chronic periodontitis (n = 17) was investigated. Based on a murine model of periodontal disease, the function of IL-33 was determined first by administration of exogenous IL-33 and second by inhibition of IL-33 signaling using mice deficient in the IL-33 receptor ST2. Alveolar bone level, serum antibody, and lymphocyte responses were assessed in the murine model. Expression of IL-33 and ST2 was elevated in gingival tissues from patients with chronic periodontitis as compared with healthy tissues (P < 0.05). Similarly, Il33 expression was higher in periodontal tissues of Porphyromonas gingivalis-infected mice as compared with sham-infected controls (P < 0.05). IL-33 treatment of P. gingivalis-infected mice significantly exacerbated alveolar bone loss when compared with infection or IL-33 treatment alone (P < 0.001). Conversely, P. gingivalis infection-induced alveolar bone loss was attenuated in mice lacking ST2. The percentages of T and B lymphocytes expressing nuclear factor κB ligand (RANKL) in the gingival tissues and T lymphocytes expressing RANKL in the cervical draining lymph nodes were higher in IL-33-treated P. gingivalis-infected mice versus phosphate buffered saline-treated P. gingivalis-infected controls (all P < 0.001). Targeting the RANKL pathway by osteoprotegerin administration abrogated periodontal bone destruction in P. gingivalis-infected, IL-33-treated mice. These data demonstrate a previously unrecognized role for IL-33 in exacerbating bone loss in a RANKL-dependent manner in the context of bacterial infection and suggest that this pathway may be amenable to manipulation as a novel therapeutic target in periodontitis.

Keywords: OPG; Porphyromonas gingivalis; ST2; cytokines; gingiva; periodontitis.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alveolar Bone Loss / immunology
  • Alveolar Bone Loss / microbiology
  • Alveolar Bone Loss / pathology
  • Alveolar Process / pathology
  • Animals
  • Antibodies, Bacterial / blood
  • B-Lymphocytes / immunology
  • Bacteroidaceae Infections / immunology
  • Chronic Periodontitis / immunology*
  • Chronic Periodontitis / microbiology
  • Disease Models, Animal
  • Female
  • Gingiva / immunology
  • Humans
  • Immunoglobulin G / blood
  • Interleukin-1 Receptor-Like 1 Protein
  • Interleukin-33
  • Interleukins / analysis
  • Interleukins / antagonists & inhibitors
  • Interleukins / immunology*
  • Interleukins / pharmacology
  • Lymph Nodes / immunology
  • Lymphocytes / immunology
  • Maxilla / pathology
  • Mice
  • Mice, Inbred BALB C
  • Osteoprotegerin / pharmacology
  • Porphyromonas gingivalis / immunology
  • RANK Ligand / immunology*
  • Receptors, Cell Surface / analysis
  • Receptors, Interleukin / antagonists & inhibitors
  • T-Lymphocytes / immunology


  • Antibodies, Bacterial
  • IL1RL1 protein, human
  • IL33 protein, human
  • Il1rl1 protein, mouse
  • Il33 protein, mouse
  • Immunoglobulin G
  • Interleukin-1 Receptor-Like 1 Protein
  • Interleukin-33
  • Interleukins
  • Osteoprotegerin
  • RANK Ligand
  • Receptors, Cell Surface
  • Receptors, Interleukin
  • Tnfrsf11b protein, mouse
  • Tnfsf11 protein, mouse