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 (M phi s). 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 M phi s significantly enhanced the KRM-mediated killing of MAC bacteria residing in M phi s, although MBST alone did not potentiate the M phi anti-MAC activity. MBST-treated M phi s 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 M phi populations. MBST partially blocked the interleukin-10 (IL-10) production of MAC-infected M phi s without affecting their transforming growth factor beta (TGF-beta)-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-gamma), IL-10, and TGF-beta mRNAs. KRM treatment of infected mice tended to decrease the levels of the test cytokine mRNAs, except that it increased TGF-beta 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-gamma mRNAs, although 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 combined therapeutic effects of KRM and MBST against MAC infection.
Shimizu
T
T
Department of Microbiology and Immunology, Shimane Medical University, Japan.
Tomioka
H
H
Sato
K
K
Sano
C
C
Akaki
T
T
Dekio
S
S
Yamada
Y
Y
Kamei
T
T
Shibata
H
H
Higashi
N
N
D000818:Animals; D000900:Anti-Bacterial Agents / Q000627:therapeutic use*; D016207:Cytokines / Q000096:biosynthesis; D004195:Disease Models, Animal; D004357:Drug Synergism; D004365:Drugs, Chinese Herbal / Q000627:therapeutic use*; D005260:Female; D005609:Free Radicals / Q000378:metabolism; D016753:Interleukin-10 / Q000096:biosynthesis; D008168:Lung / Q000187:drug effects / Q000378:metabolism / Q000382:microbiology; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism / Q000382:microbiology; D051379:Mice; D008807:Mice, Inbred BALB C; D015270:Mycobacterium avium-intracellulare Infection / Q000188:drug therapy* / Q000382:microbiology; D009584:Nitrogen / Q000378:metabolism; D012333:RNA, Messenger / Q000096:biosynthesis; D012294:Rifamycins / Q000627:therapeutic use*; D016212:Transforming Growth Factor beta / Q000096:biosynthesis
D000900:Anti-Bacterial Agents; D016207:Cytokines; D004365:Drugs, Chinese Herbal; D005609:Free Radicals; D012333:RNA, Messenger; D012294:Rifamycins; D016212:Transforming Growth Factor beta; C119422:mao-bushi-saishin-to; C068980:KRM 1648; D016753:Interleukin-10; D009584:Nitrogen