| 研究概要 |
Infection with certain pathogens induces a shift of the Th subset balance to a Th1 dominant state. This, in turn, results in the suppression of Th2 responses. We focused on the role of IRF-1 during pathogen infection, especially the involvement of IRF-1 in the suppression of Th2 cells during Listeria infection. We found that the inhibition of IL-4 production by Th2 cells is mediated by a soluble factor (LmSN) produced by Listeria-infected APCs. The inhibition is not observed with T cells from Irf1 gene targeted mice. We also found that IRF-1 directly suppresses transcription of the Il4 gene in Th2 cells. Under the influence of the LmSN, IRF-1 binds to the 3’UTR region of the Il4 gene and down-regulates Il4 gene transcription. Finally, we identified IL-1 as the mediator of the LmSN activity. IL-1β treatment induces the stabilization and/or nuclear translocation of IRF-1. Based on these results, we propose that IRF-1 functions to induce the Th1 shift via two distinct mechanisms, the previously known mechanism and a novel function described here. IRF-1 activates the Il12p40 gene promoter and induces its transcription, resulting in the shift to the Th1 subset. In addition, under the influence of IL-1, IRF-1 translocates into the nucleus and acts on the 3’UTR region of the Il4 gene, thus inhibiting its transcription in Th2 cells. As a result of these two activities, the immune system shifts predominantly to a Th1 response during Listeria-infection, resulting in effective protection of the host.
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