IL-15 promotes osteoclastogenesis via the PLD pathway in rheumatoid arthritis

Mi Kyung Park, Yang Mi Her, Mi La Cho, Hye Joa Oh, Eun Mi Park, Seung Ki Kwok, Ji Hyeon Ju, Kyung Su Park, Do Sik Min, Ho Youn Kim, Sung Hwan Park

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39 Citations (Scopus)


Osteoclastogenesis plays an important role in joint destruction in rheumatoid arthritis (RA). IL-15 is a pleiotropic proinflammatory cytokine that appears to help mediate the pathological bone loss. This study was undertaken to explore the signaling molecules essential for osteoclastogenesis mediated by IL-15 in rheumatoid synovial fibroblasts. Expression of phospholipase D1 (PLD1) and osteoclast-related gene expression in synovial tissues and their modulation by treatment with IL-15 and different inhibitors in synovial fibroblasts of RA patients were evaluated using immunohistochemistry and quantitative polymerase chain reaction. The levels of IL-15 in serum and synovial fluid were measured by ELISA. The effects of IL-15 and phosphatidic acid (PA) on osteoclast formation were evaluated in cocultures of rheumatoid synovial fibroblasts and peripheral blood monocytes or monocytes alone in the presence of M-CSF and RANKL. The levels of RANKL and PLD1 but not PLD2 were upregulated significantly by IL-15, and the RANKL level was significantly upregulated by PA in rheumatoid synovial fibroblasts. Blocking PA production with 1-butanol and siRNA against PLD1 significantly inhibited the IL-15-stimulated expression of RANKL and PLD1. IL-15 levels were significantly higher in serum and synovial fluid from patients with RA than in osteoarthritis patients and healthy controls. IL-15 and PA induced osteoclast formation through the mitogen-activated protein kinases (MAPKs) and NF-κB signaling pathways. Activation of PLD1 contributes to IL-15-mediated osteoclastogenesis via the MAPKs and NF-κB signaling pathways in rheumatoid synovial fibroblasts. Our data suggest that PLD1 might be an efficient therapeutic strategy for preventing bone destruction in rheumatoid arthritis.

Original languageEnglish
Pages (from-to)42-51
Number of pages10
JournalImmunology Letters
Issue number1-2
Publication statusPublished - 2011 Sept 30

Bibliographical note

Funding Information:
This research was supported by a grant of the Korea Health Technology R&D Project, Ministry for Health, Welfare & Family Affairs, Republic of Korea (grant number A09225 8).

All Science Journal Classification (ASJC) codes

  • Immunology and Allergy
  • Immunology


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