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 ant i-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 M BST on the anti-MAC activity of murine peritoneal macrophages (M phi s). Fi rst, MBST significantly increased the anti-MAC therapeutic activity of KRM when given to mice in combination with KRM, although MBST alone did not exh ibit such effects. Second, MBST treatment of M phi s significantly enhanced the KRM-mediated killing of MAC bacteria residing in M phi s, although MBS T alone did mt potentiate the M phi anti-MAC activity. MBST-treated M phi s showed decreased levels of reactive nitrogen intermediate (RNI) release, s uggesting that RNIs are not decisive in the expression of the anti-MAC acti vity of such M phi populations, MBST partially blocked the interleukin-10 ( IL-10) production of MAC-infected M phi s without affecting their transform ing growth factor beta (TGF-beta)-producing activity. Reverse transcription -PCR analysis of the lung tissues of MAC-infected mice at weeks 4 and 8 aft er infection revealed a marked increase in the levels of tumor necrosis fac tor alpha, gamma interferon (IFN-gamma), IL-10, and TGF-beta mRNAs. KRM tre atment of infected mice tended to decrease the levels of the test cytokine mRNAs, except that it increased TGF-beta mRNA expression at meek 4. MBST tr eatment 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 le vels of the test cytokines mRNAs, especially IL-10 and IFN-gamma mRNAs, alt hough such effects were obscure at week 4. These findings suggest that down -regulation of the expression of IL-10 and TGF-beta is related to the combi ned therapeutic effects of KRM and MBST against MAC infection.