The newly discovered cytokine IL-34 is expressed in gingival fibroblasts, shows enhanced expression by pro-inflammatory cytokines, and stimulates osteoclast differentiation

PLoS One. 2013 Dec 10;8(12):e81665. doi: 10.1371/journal.pone.0081665. eCollection 2013.


Background: Interleukin-34 (IL-34) is a recently discovered cytokine functionally overlapping macrophage colony stimulating factor (M-CSF), a mediator of inflammation and osteoclastogenesis in bone-degenerative diseases such as rheumatoid arthritis. The objective of this study was to assess the expression of IL-34 in human gingival fibroblasts and investigate if the pro-inflammatory cytokines tumor necrosis factor alpha (TNF-α) and Interleukin-1Β (IL-1β) modulate its expression, and moreover if IL-34 could contribute to recruitment of bone-resorbing osteoclasts.

Methods: IL-34 expression was evaluated in gingival fibroblasts by real time PCR following stimulation by TNF-α, IL-1β, and treatment with inhibitors of intracellular pathways. The formation of osteoclasts was evaluated by tartrate-resistant acid phosphatase (TRAP) staining of bone marrow macrophages treated with IL-34 or M-CSF in addition to receptor activator of nuclear factor kappa-B ligand (RANKL).

Results: IL-34 was expressed in gingival fibroblasts. The expression was enhanced by TNF-α and IL-1β, regulated by the transcription factor nuclear factor kappa B (NF-κΒ) and activation of c-Jun N-terminal kinase (JNK). Further, IL-34 supports RANKL-induced osteoclastogensis of bone marrow macrophages, independently of M-CSF.

Summary: In conclusion, this study shows for the first time IL-34 expression in human gingival fibroblasts, stimulated by TNF-α and IL-1β, key mediators of periodontal inflammation. Furthermore, IL-34 can be substituted for M-CSF in RANKL-induced osteoclastogenesis. IL-34 may contribute to inflammation and osteoclastogenesis in bone-degenerative diseases such as periodontitis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Differentiation / drug effects
  • Fibroblasts / cytology*
  • Gene Expression Regulation* / drug effects
  • Gingiva / cytology*
  • Humans
  • Inflammation / metabolism
  • Interleukin-1beta / metabolism*
  • Interleukins / genetics
  • Interleukins / metabolism*
  • JNK Mitogen-Activated Protein Kinases / metabolism
  • MAP Kinase Signaling System / drug effects
  • Macrophage Colony-Stimulating Factor / pharmacology
  • Male
  • Mice
  • NF-kappa B / metabolism
  • Osteoclasts / cytology*
  • RANK Ligand / pharmacology
  • Time Factors
  • Tumor Necrosis Factor-alpha / metabolism*


  • Interleukin-1beta
  • Interleukins
  • NF-kappa B
  • RANK Ligand
  • Tumor Necrosis Factor-alpha
  • interleukin-34, human
  • Macrophage Colony-Stimulating Factor
  • JNK Mitogen-Activated Protein Kinases

Grant support

This study was supported by funds from the Swedish Patent Revenue Fund (EAB), Ollie och Elof Ericssons stiftelse (EAB), Tore Nilsson Stiftelse (EAB), Alex och Eva Wallströms Stiftelse/Karolinska Institutet (EAB), Faculty of Medicine, Umeå University (PL), County Council of Västerbotten (PL), Swedish Dental Society (PL). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.