title: Microarray analysis on germfree mice elucidates the primary target of a traditional Japanese medicine juzentaihoto: acceleration of IFN-α response via affecting the ISGF3-IRF7 signaling cascade.
abstract: BACKGROUND
  The traditional Japanese medicine juzentaihoto (JTX) is a pharmaceutical grade multi-herbal medicine widely used for the prevention of cancer metastasis and infection in immuno-compromized patients in Japan. The effect of JTX has been supposed to be intimately affected by the immunological properties of host and enteric microflora. The influence of JTX on the gene expression profile in the large and small intestines was investigated by microarray analyses using mice of different strains with or without enteric microflora.
  
  
  RESULTS
  In all types of mice, including germfree (GF) animals, the genes most affected by two-week oral JTX treatment were the type 1 interferon (IFN)-related genes including Stat1, Isgf3g and Irf7, which play a critical role in the feedback loop of IFN-α production cascade. In IQI specific pathogen free (SPF) mice JTX increased the steady state level of the expression of IFN-related genes, but had the opposite effect in IQI GF and BALB/c SPF mice. Promoter analysis suggests that tandem repeated $IRFF (the promoter sequences for interferon regulatory factors) may be a primary target for JTX action. Pre-treatment of JTX accelerated the effects of an oral IFN "inducer" 2-amino-5-bromo-6-methyl-4-pyrimidinol (ABMP) (up-regulation of IFN-α production in IQI strain and down-regulation in BALB/c mice), which is in good accordance with the effect of JTX on gene expression of type 1 IFN-related genes.
  
  
  CONCLUSIONS
  Microarray analysis revealed that the target of JTX might be the transcription machinery regulating the steady-state level of genes involved in the ISGF3-IRF7 cascade, whose effect is bi-directional in a strain- and microbiota-dependent manner.
authors.affiliation: Center for Kampo Medicine, Keio University School of Medicine, Tokyo, Japan.
authors.forename: Kaori
authors.initials: K
authors.lastname: Munakata
authors.forename: Kiyoe
authors.initials: K
authors.lastname: Takashima
authors.forename: Mitsue
authors.initials: M
authors.lastname: Nishiyama
authors.forename: Naoko
authors.initials: N
authors.lastname: Asano
authors.forename: Akihito
authors.initials: A
authors.lastname: Mase
authors.forename: Kyoji
authors.initials: K
authors.lastname: Hioki
authors.forename: Yasuyuki
authors.initials: Y
authors.lastname: Ohnishi
authors.forename: Masahiro
authors.initials: M
authors.lastname: Yamamoto
authors.forename: Kenji
authors.initials: K
authors.lastname: Watanabe
mesh_terms: D000818:Animals; D016000:Cluster Analysis; D004365:Drugs, Chinese Herbal / Q000494:pharmacology*; D005786:Gene Expression Regulation / Q000187:drug effects*; D050839:Interferon Regulatory Factor-7 / Q000235:genetics / Q000378:metabolism*; D050832:Interferon-Stimulated Gene Factor 3 / Q000378:metabolism*; D016898:Interferon-alpha / Q000235:genetics / Q000378:metabolism*; D008297:Male; D008519:Medicine, Traditional; D051379:Mice; D008807:Mice, Inbred BALB C; D020411:Oligonucleotide Array Sequence Analysis; D011401:Promoter Regions, Genetic; D015398:Signal Transduction / Q000187:drug effects*
chemical_list: D004365:Drugs, Chinese Herbal; D050839:Interferon Regulatory Factor-7; D050832:Interferon-Stimulated Gene Factor 3; D016898:Interferon-alpha; C063587:juzentaihoto