Hachimi-jio-gan (Chinese name: Ba-Wei-Di-Huang-Wan, HMG), a traditional Japanese herbal medicine, has been used for disorders accompanying aging. Our previous studies suggested that HMG ameliorated Thl-predominant autoimmune diseases in MRL/lpr mice through inhibition of IL-12 production. In the present study, the oral administration of HMG down-regulated phosphorylated STAT4 and up-regulated phosphorylated STAT6 in CD4 T cells. In the T cells, IL-12Rbeta1 and IL-12Rbeta2 mRNA expression levels were suppressed. In antigen-presenting cells (CD45R- MHC class II+ cells) which control Th1 and Th2 immune responses, the total cell number and the percentage of cells expressing co-stimulatory molecules decreased in the HMG-treated group. In addition, the levels of IL-12 and 18 mRNA expression increased and conversely, IL-10 mRNA expression decreased. Further, the production of IL-10 was up-regulated and that of IL-12 was down-regulated by HMG in the presence of anti-CD40 antibody. These results suggest that the opposite effects on IL-10 production and, IL-12 or IL-18 production in antigen-presenting cells of oral administration of HMG are due a decline in IL-12R expression, and consequently, amelioration of MRL/lpr autoimmune diseases occurs through the suppression of Th1 predominance via STAT4/STAT6 signaling.