IL-15 and RANKL Play a Synergistically Important Role in Osteoclastogenesis.
Interleukin-15 (IL-15), a cytokine secreted by several cell types, has important physiological roles in the activity, proliferation, and viability of immune cells. It has both chemoattractant and proinflammatory properties, and may promote bone destruction. A previous study has shown that IL-15 alone exerts no effect on osteoclastogenesis. Therefore, the current study addressed the synergistic effect of IL-15 on osteoclast formation using RAW264.7 (RAW) cells by co-stimulation with receptor activator of nuclear factor (NF)-κB ligand (RANKL) that has a major role in osteoclastogenesis involving the pathogenesis of rheumatoid arthritis and periodontal disease. Co-stimulation of RAW cells by IL-15 and RANKL significantly increased the gene expression of osteoclast differentiation and osteoclastogenesis markers compared with stimulation by RANKL or IL-15 independently as evaluated by tartrate-resistant acid phosphate-positive cell numbers, the fusion index, a pit formation assay with Alizarin red staining (calcification estimation), and quantitative polymerase chain reaction. Phosphorylation of extracellular signal-regulated kinase (ERK), c-jun N-terminal kinase, p38 mitogen-activated protein kinase, and NF-κB was significantly increased by RANKL and IL-15 (P < 0.05) compared with RANKL alone. In addition, these differentiation activities induced by RANKL and IL-15 were comparatively suppressed by inhibition of ERK, suggesting that this synergistic effect on osteoclastogenesis is mainly mediated by ERK. Taken together, our results demonstrate that IL-15 and RANKL induce osteoclastogenesis synergistically, and IL-15 might play a novel and major role in destructive inflammatory bone diseases. J. Cell. Biochem. 118: 739-747, 2017. © 2016 Wiley Periodicals, Inc.
Department of Periodontology, School of Dentistry, Aichi Gakuin University, 2-11 Suemoridori, Chikusa-ku, Nagoya, Aichi, 464-8651, Japan.
Iichiro
I
Okabe
Department of Periodontology, School of Dentistry, Aichi Gakuin University, 2-11 Suemoridori, Chikusa-ku, Nagoya, Aichi, 464-8651, Japan.
Takeshi
T
Kikuchi
Department of Integrative Education of Pharmacy, School of Pharmacy, Aichi Gakuin University, 1-100 Kusumoto-cho, Chikusa-ku, Nagoya, Aichi, 464-8651, Japan.
Makio
M
Mogi
Department of Periodontology, School of Dentistry, Aichi Gakuin University, 2-11 Suemoridori, Chikusa-ku, Nagoya, Aichi, 464-8651, Japan.
Hiroaki
H
Takeda
Department of Periodontology, School of Dentistry, Aichi Gakuin University, 2-11 Suemoridori, Chikusa-ku, Nagoya, Aichi, 464-8651, Japan.
Makoto
M
Aino
Department of Periodontology, School of Dentistry, Aichi Gakuin University, 2-11 Suemoridori, Chikusa-ku, Nagoya, Aichi, 464-8651, Japan.
Yosuke
Y
Kamiya
Department of Periodontology, School of Dentistry, Aichi Gakuin University, 2-11 Suemoridori, Chikusa-ku, Nagoya, Aichi, 464-8651, Japan.
Takeki
T
Fujimura
Department of Periodontology, School of Dentistry, Aichi Gakuin University, 2-11 Suemoridori, Chikusa-ku, Nagoya, Aichi, 464-8651, Japan.
Hisashi
H
Goto
Department of Periodontology, School of Dentistry, Aichi Gakuin University, 2-11 Suemoridori, Chikusa-ku, Nagoya, Aichi, 464-8651, Japan.
Kosuke
K
Okada
Department of Microbiology, School of Dentistry, Aichi Gakuin University, 1-100 Kusumoto-cho, Chikusa-ku, Nagoya, Aichi, 464-8651, Japan.
Yoshiaki
Y
Hasegawa
Department of Periodontology, School of Dentistry, Aichi Gakuin University, 2-11 Suemoridori, Chikusa-ku, Nagoya, Aichi, 464-8651, Japan.
Toshihide
T
Noguchi
Department of Periodontology, School of Dentistry, Aichi Gakuin University, 2-11 Suemoridori, Chikusa-ku, Nagoya, Aichi, 464-8651, Japan.
Akio
A
Mitani
D000818:Animals; D002454:Cell Differentiation / Q000187:drug effects / Q000235:genetics / Q000502:physiology; D004357:Drug Synergism; D015870:Gene Expression / Q000187:drug effects; D019409:Interleukin-15 / Q000008:administration & dosage / Q000502:physiology*; D020935:MAP Kinase Signaling System / Q000187:drug effects; D051379:Mice; D016328:NF-kappa B / Q000037:antagonists & inhibitors; D010012:Osteogenesis / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D053245:RANK Ligand / Q000008:administration & dosage / Q000502:physiology*; D000067996:RAW 264.7 Cells
D019409:Interleukin-15; D016328:NF-kappa B; D053245:RANK Ligand; C505689:Tnfsf11 protein, mouse
INFLAMMATORY BONE DESTRUCTION; INTERLEUKIN-15; OSTEOIMMUNOLOGY