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Small anti-viral compounds activate immune cells via the TLR7 MyD88–dependent signaling pathway

Abstract

The imidazoquinoline compounds imiquimod and R-848 are low-molecular-weight immune response modifiers that can induce the synthesis of interferon-α and other cytokines in a variety of cell types. These compounds have potent anti-viral and anti-tumor properties; however, the mechanisms by which they exert their anti-viral activities remain unclear. Here we show that the imidazoquinolines activate immune cells via the Toll-like receptor 7 (TLR7)-MyD88–dependent signaling pathway. In response to the imidazoquinolines, neither MyD88- nor TLR7-deficient mice showed any inflammatory cytokine production by macrophages, proliferation of splenocytes or maturation of dendritic cells. Imidazoquinoline-induced signaling events were also abolished in both MyD88- and TLR7-deficient mice.

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Acknowledgements

We thank Sumitomo Pharmaceuticals for valuable discussions of this work; E. Horita for secretarial assistance; N. Tsuji and N. Iwami for technical assistance; and Hayashibara Biochemical Laboratories for the antibody to IRAK. Supported in part by grants from Special Coordination Founds for Promoting Science and Technology; the Ministry of Education, Culture, Sports, Science and Technology of Japan; and the Japan Society for the Promotion of Science for Young Scientists.

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Correspondence to Shizuo Akira.

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Figure 1: The imidazoquinolines activate macrophages in a MyD88-dependent manner.
Figure 2: TLR7-deficient cells respond normally to various immunostimulatory CpG DNAs.
Figure 3: Immune cell activation by the imidazoquinolines is dependent on TLR7.
Figure 4: Activation of intracellular molecules induced by R-848 depends on TLR7.
Figure 5: R-848 induces NF-κB activation through TLR7.
Figure 6: In vivo cytokine responses to R-848 are dependent on TLR7 and MyD88.