Effects of the Chinese Traditional Medicine Mao-Bushi-Saishin-To on Therapeutic Efficacy of a New Benzoxazinorifamycin, KRM-1648, against Mycobacterium avium Infection in Mice

The Chinese traditional medicine mao-bushi-saishin-to (MBST), which has anti-inflammatory effects and has been used to treat the common cold and nasal allergy in Japan, was examined for its effects on the therapeutic activity of a new benzoxazinorifamycin, KRM-1648 (KRM), against Mycobacterium avium complex (MAC) infection in mice. In addition, we examined the effects of MBST on the anti-MAC activity of murine peritoneal macrophages (Mφs). First, MBST significantly increased the anti-MAC therapeutic activity of KRM when given to mice in combination with KRM, although MBST alone did not exhibit such effects. Second, MBST treatment of Mφs significantly enhanced the KRM-mediated killing of MAC bacteria residing in Mφs, although MBST alone did not potentiate the Mφ anti-MAC activity. MBST-treated Mφs showed decreased levels of reactive nitrogen intermediate (RNI) release, suggesting that RNIs are not decisive in the expression of the anti-MAC activity of such Mφ populations. MBST partially blocked the interleukin-10 (IL-10) production of MAC-infected Mφs without affecting their transforming growth factor β (TGF-β)-producing activity. Reverse transcription-PCR analysis of the lung tissues of MAC-infected mice at weeks 4 and 8 after infection revealed a marked increase in the levels of tumor necrosis factor alpha, gamma interferon (IFN-γ), IL-10, and TGF-β mRNAs. KRM treatment of infected mice tended to decrease the levels of the test cytokine mRNAs, except that it increased TGF-β mRNA expression at week 4. MBST treatment did not affect the levels of any cytokine mRNAs at week 8, while it down-regulated cytokine mRNA expression at week 4. At week 8, treatment of mice with a combination of KRM and MBST caused a marked decrease in the levels of the test cytokines mRNAs, especially IL-10 and IFN-γ mRNAs, although such effects were obscure at week 4. These findings suggest that down-regulation of the expression of IL-10 and TGF-β is related to the combined therapeutic effects of KRM and MBST against MAC infection.