Antimetastatic effect of an immunomodulatory arabinomannan extracted from Mycobacterium tuberculosis strain Aoyama B, Z-100, through the production of interleukin-12.
In this study, the role of interleukin (IL)-12 on the antimetastatic effect of Z-100 was investigated using wild-type C57BL/6 mice or IL-12p40 knockout (IL-12p40 KO) mice inoculated with highly metastatic B16F10 melanoma. When C57BL/6 mice were inoculated with B16F10 melanoma (2x10(5) cells/mouse i.v.), Z-100 (10 mg/kg i.p.) significantly suppressed the pulmonary metastasis of B16F10 melanoma 14 d after tumor inoculation. On the other hand, the antimetastatic effect of Z-100 was not observed in IL-12p40 KO mice inoculated with B16F10 melanoma. These results indicate that IL-12 is essentially required for the appearance of the antimetastatic effect of Z-100. Since helper T (Th) 2 cell responses have been reported to have a role in tumor metastasis, the regulatory effect of Z-100 on the immune balance of Th1/Th2 cell responses was investigated. In both C57BL/6 mice and IL-12p40 KO mice bearing B16F10 melanoma, Th1 cytokine production (IL-2, interferon-gamma) was significantly suppressed as compared with those in normal mice. On the other hand, Th2 cytokine production (IL-4, IL-10) in these mice was increased. The administration of Z-100 (10 mg/kg i.p.) in C57BL/6 mice bearing B16F10 melanoma improved the balance of Th1/Th2 cell responses from the Th2-dominant state to the normal state. However, the improvement of Th1/Th2 cell responses by Z-100 was not observed in IL-12p40 KO mice bearing the same tumors. In addition, Z-100 significantly increased IL-12 production by macrophages in a concentration-dependent manner, while Z-100 significantly decreased IL-10 production by these cells in vitro. These results suggested that up-regulation of IL-12 production and down-regulation of IL-10 production by Z-100 are related to the improvement of Th1/Th2 cell responses from the Th2-dominant state to the normal state, which resulted in suppression of tumor metastasis.
Oka
Hideki
H
Central Research Laboratories, Zeria Pharmaceutical Co., Ltd., Ohsato-gun, Saitama, Japan. hideki-oka@zeria.co.jp
Shiraishi
Yumiko
Y
Sasaki
Hidetaka
H
Yoshinaga
Koji
K
Emori
Yutaka
Y
Takei
Mineo
M
D000276:Adjuvants, Immunologic / Q000737:chemistry / Q000494:pharmacology*; D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D007202:Indicators and Reagents; D018664:Interleukin-12 / Q000096:biosynthesis* / Q000235:genetics*; D008055:Lipids / Q000737:chemistry / Q000494:pharmacology*; D008351:Mannans / Q000737:chemistry / Q000494:pharmacology*; D008546:Melanoma, Experimental / Q000188:drug therapy / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009163:Mycobacterium bovis / Q000737:chemistry; D009169:Mycobacterium tuberculosis / Q000737:chemistry*; D009362:Neoplasm Metastasis / Q000188:drug therapy*; D009368:Neoplasm Transplantation; D018417:Th1 Cells / Q000187:drug effects / Q000378:metabolism; D018418:Th2 Cells / Q000187:drug effects / Q000378:metabolism
D000276:Adjuvants, Immunologic; D000970:Antineoplastic Agents; D007202:Indicators and Reagents; D008055:Lipids; D008351:Mannans; C031208:specific substance maruyama; D018664:Interleukin-12; C012189:arabinomannan