Anti-tumor mechanism of Z-100, an immunomodulatory Arabinomannan extracted from Mycobacterium tuberculosis strain Aoyama B, on pulmonary metastases of B16F10 melanoma: restoration of helper T cell responses via suppression of glucocorticoid-genesis.
In the present study, the anti-tumor mechanism of Z-100 was investigated with the use of pulmonary metastasis of B16F10 melanoma. In B16F10 mice, Th1 cytokine production (IL-2, IFN-gamma) was suppressed in comparison with normal mice. On the other hand, Th2 cytokine production (IL-4, IL-10) was increased in the B16F10 mice. The administration of Z-100 to B16F10 mice restored the balance of Th1/Th2 cell responses from the Th2 dominant state to the normal state. Z-100 significantly suppressed the pulmonary metastasis of B16F10 melanoma in a dose-dependent manner. These results suggest that Z-100 restored the breakdown of Th1 cell responses, resulting in the suppression of pulmonary metastasis of B16F10 melanoma. Moreover, Z-100 decreased the corticosterone levels, which is known to suppress the Th1 cell responses, in both serum specimens and splenic tissue, and the steroidogenic CYP11A1 mRNA expression in CD4+ T cells. These results suggest that a suppression of pulmonary metastasis and restoration of Thl/Th2 cell responses by Z-100 may be due to the decrease in the corticosterone levels and the steroidogenic CYP11A1 mRNA expression of CD4+ T cells in B16F10 mice. Further, the role of Th1 cytokine, IFN-gamma, on these activities of Z-100 was examined. The suppressive effects of Z-100 on pulmonary metastasis and restoration of Th1/Th2 cell responses were eliminated by the administration of anti-IFN-gamma mAb. Moreover, the suppressive effects of Z-100 on glucocorticoid-genesis were eliminated by the administration of anti-IFN-gamma-mAb. These results suggest that Z-100 restores the balance of Th1/Th2 cell responses via the suppression of glucocorticoid-genesis by Z-100-induced IFN-gamma. IFN-gamma acts as a key cytokine in anti-tumor activities of Z-100.
Oka
Hideki
H
Central Research Laboratories, Zeria Pharmaceutical Co., Ltd, Saitama, Japan. hideki-oka@zeria.co.jp
Emori
Yutaka
Y
Sasaki
Hidetaka
H
Shiraishi
Yumiko
Y
Yoshinaga
Koji
K
Kurimoto
Tadashi
T
D000276:Adjuvants, Immunologic / Q000494:pharmacology*; D000818:Animals; D000970:Antineoplastic Agents / Q000276:immunology* / Q000494:pharmacology; D002786:Cholesterol Side-Chain Cleavage Enzyme / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology; D003345:Corticosterone / Q000097:blood; D004797:Enzyme-Linked Immunosorbent Assay; D005938:Glucocorticoids / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D007371:Interferon-gamma / Q000276:immunology / Q000378:metabolism; D008055:Lipids / Q000276:immunology* / Q000494:pharmacology; D008175:Lung Neoplasms / Q000276:immunology / Q000556:secondary / Q000628:therapy*; D008297:Male; D008351:Mannans / Q000276:immunology* / Q000494:pharmacology; D008546:Melanoma, Experimental / Q000276:immunology / Q000556:secondary / Q000628:therapy*; D051379:Mice; D008810:Mice, Inbred C57BL; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D018417:Th1 Cells / Q000276:immunology* / Q000378:metabolism; D018418:Th2 Cells / Q000276:immunology* / Q000378:metabolism
D000276:Adjuvants, Immunologic; D000970:Antineoplastic Agents; D005938:Glucocorticoids; D008055:Lipids; D008351:Mannans; D012333:RNA, Messenger; C031208:specific substance maruyama; D007371:Interferon-gamma; D002786:Cholesterol Side-Chain Cleavage Enzyme; D003345:Corticosterone