Antimetastatic effect of an immunomodulatory arabinomannan extracted from Mycobacterium tuberculosis strain Aoyama B, Z-100, through the production of interleukin-12.

Abstract

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.

• Authors: Hideki Oka, Yumiko Shiraishi, Hidetaka Sasaki, Koji Yoshinaga, Yutaka Emori, Mineo Takei
• Journal: Biological & pharmaceutical bulletin (Biol Pharm Bull) Vol. 26 Issue 9 Pg. 1336-41 (Sep 2003) ISSN: 0918-6158 [Print] Japan
• PMID: 12951482 (Publication Type: Journal Article)

Chemical References

• Adjuvants, Immunologic
• Antineoplastic Agents
• Indicators and Reagents
• Lipids
• Mannans
• specific substance maruyama
• Interleukin-12
• arabinomannan

Topics

• Adjuvants, Immunologic (chemistry, pharmacology)
• Animals
• Antineoplastic Agents (chemistry, pharmacology)
• Indicators and Reagents
• Interleukin-12 (biosynthesis, genetics)
• Lipids (chemistry, pharmacology)
• Mannans (chemistry, pharmacology)
• Melanoma, Experimental (drug therapy, metabolism)
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• Mycobacterium bovis (chemistry)
• Mycobacterium tuberculosis (chemistry)
• Neoplasm Metastasis (drug therapy)
• Neoplasm Transplantation
• Th1 Cells (drug effects, metabolism)
• Th2 Cells (drug effects, metabolism)