IL-18 inhibits TNF-alpha-induced osteoclastogenesis possibly via a T cell-independent mechanism in synergy with IL-12 in vivo.
It has recently been reported that tumor necrosis factor (TNF)-alpha has the ability to accelerate osteoclastogenesis. We previously reported that the proinflammatory cytokine interleukin (IL)-18 inhibits TNF-alpha-mediated osteoclastogenesis in mouse bone marrow cultures. In the present study, the effect of IL-18 on TNF-alpha-mediated osteoclastogenesis was investigated in vivo. We administered TNF-alpha with or without IL-18 into the supracalvaria of mice. The number of osteoclasts in the suture of the calvaria was increased in mice administered TNF-alpha. The number of osteoclasts in mice administered both TNF-alpha and IL-18 was lower than that in mice administered TNF-alpha alone. We previously showed that IL-12 and IL-18 synergistically inhibit TNF-alpha-mediated osteoclastogenesis in vitro. To assess the ability of these two cytokines to synergistically inhibit TNF-alpha-induced osteoclastogenesis in vivo, mice were administered the two cytokines at doses that did not inhibit osteoclast formation. The combination of IL-12 and IL-18 markedly inhibited TNF-alpha-induced osteoclastogenesis in vivo. To evaluate how IL-12 and IL-18 synergistically affect TNF-alpha-induced osteoclastogenesis, the IL-18 receptor (IL-18R) and IL-12R expression levels were analyzed by RT-PCR in bone marrow cells cultured with IL-12 or IL-18. IL-18R mRNA was increased in cells cultured with IL-12, while IL-12R mRNA was increased in cells cultured with IL-18. In addition, IL-18 inhibited TNF-alpha-induced osteoclastogenesis in mice with T-cell depletion caused by anti-CD4 and anti-CD8 antibodies. The present results suggest that IL-18 may inhibit TNF-alpha-mediated osteoclastogenesis in vivo via a T cell-independent mechanism.
Morita
Yukiko
Y
Department of Orthodontics and Dentofacial Orthopedics, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan.
Kitaura
Hideki
H
Yoshimatsu
Masako
M
Fujimura
Yuji
Y
Kohara
Haruka
H
Eguchi
Toshiko
T
Yoshida
Noriaki
N
D000818:Animals; D016723:Bone Remodeling / Q000187:drug effects / Q000276:immunology*; D001862:Bone Resorption / Q000139:chemically induced / Q000276:immunology* / Q000503:physiopathology; D002452:Cell Count; D002454:Cell Differentiation / Q000187:drug effects / Q000276:immunology; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D018664:Interleukin-12 / Q000819:agonists / Q000378:metabolism; D020382:Interleukin-18 / Q000378:metabolism / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D010010:Osteoclasts / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D053707:Receptors, Interleukin-12 / Q000235:genetics; D053724:Receptors, Interleukin-18 / Q000235:genetics; D013234:Stem Cells / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D013601:T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects / Q000276:immunology
D020382:Interleukin-18; D012333:RNA, Messenger; D053707:Receptors, Interleukin-12; D053724:Receptors, Interleukin-18; D014409:Tumor Necrosis Factor-alpha; D018664:Interleukin-12