title: Interleukin-18 inhibits osteolytic bone metastasis by human lung cancer cells possibly through suppression of osteoclastic bone-resorption in nude mice.
abstract: Interleukin (IL)-18 exhibits antitumor as well as antiosteoclastogenic activities. These findings suggest that IL-18 is a potential tool for the treatment of cancers with associated osteolytic bone metastasis. We have previously shown that systemic daily administration of recombinant (r) IL-18 inhibits the development of osteolytic bone metastasis by human breast cancer cells. Here we demonstrate that systemic daily administration of rIL-18 (1 microg/mouse/d) for 21 days significantly inhibited the number and the total area of osteolytic bone metastasis by RWGT2 human lung cancer cells in nude mice. No severe adverse effects were observed. Natural killer (NK) cells did not increase in splenocytes from rIL-18-treated mice, and the in vitro NK activity of splenocytes against RWGT2 cells was only weakly enhanced in the presence of IL-18. The administration of rIL-18 made no difference in the growth of subcutaneous tumors, histologic indices (mitotic index, apoptotic index, and Ki-67-labeling index) of subcutaneous tumors or metastatic bone foci, or in the number of osteoclasts along the bone surface adjacent to tumors. Moreover, serum levels of cytokines including interferon-gamma, IL-1alpha, IL-6, tumor necrosis factor-alpha, and granulocyte/macrophage colony-stimulating factor, which regulate bone-resorbing activity of osteoclasts, were evaluated. Among them, IL-6 was remarkably downregulated in rIL-18-treated mice. These findings suggest that IL-18 inhibits osteolytic bone metastasis possibly through suppression of osteoclastic bone-resorption mediated in part by IL-6.
authors.affiliation: First Department of Pathology, Hyogo College of Medicine, Nishinomiya, Japan.
authors.forename: Teruo
authors.initials: T
authors.lastname: Iwasaki
authors.forename: Kunihiro
authors.initials: K
authors.lastname: Yamashita
authors.forename: Tohru
authors.initials: T
authors.lastname: Tsujimura
authors.forename: Shin-ichiro
authors.initials: S
authors.lastname: Kashiwamura
authors.forename: Hiroko
authors.initials: H
authors.lastname: Tsutsui
authors.forename: Tsuneyasu
authors.initials: T
authors.lastname: Kaisho
authors.forename: Ayako
authors.initials: A
authors.lastname: Sugihara
authors.forename: Naoko
authors.initials: N
authors.lastname: Yamada
authors.forename: Mutsuko
authors.initials: M
authors.lastname: Mukai
authors.forename: Toshiyuki
authors.initials: T
authors.lastname: Yoneda
authors.forename: Haruki
authors.initials: H
authors.lastname: Okamura
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Akedo
authors.forename: Nobuyuki
authors.initials: N
authors.lastname: Terada
mesh_terms: D000818:Animals; D001859:Bone Neoplasms / Q000473:pathology / Q000517:prevention & control* / Q000556:secondary*; D001862:Bone Resorption / Q000517:prevention & control; D016207:Cytokines / Q000032:analysis / Q000187:drug effects; D004195:Disease Models, Animal; D006801:Humans; D007371:Interferon-gamma / Q000032:analysis / Q000187:drug effects; D020382:Interleukin-18 / Q000494:pharmacology*; D008175:Lung Neoplasms / Q000473:pathology*; D008297:Male; D051379:Mice; D008805:Mice, Inbred A; D009368:Neoplasm Transplantation; D010014:Osteolysis / Q000517:prevention & control; D011336:Probability; D012680:Sensitivity and Specificity; D018709:Statistics, Nonparametric; D014407:Tumor Cells, Cultured
chemical_list: D016207:Cytokines; D020382:Interleukin-18; D007371:Interferon-gamma