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* Advanced Medical Discovery Institute, University Health Network and Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada;
Laboratory for Cell Signaling, RIKEN Research Center for Allergy and Immunology, Yokohama City, Kanagawa, Japan;
University Health Network and Departments of Medical Biophysics and Immunology, University of Toronto, Toronto, Ontario, Canada;
Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada;
¶ Department of Tumor Cell Biology, Tokyo Metropolitan Institute of Medical Science, Tokyo, Japan;
|| Department of Molecular Genetics, Chiba University Graduate School of Medicine, Chiba, Japan; and
# Department of Host Defense, Research Institute for Microbial Diseases, Osaka University, Osaka, Japan
The bacterial product LPS is a critical stimulus for the host immune system in the response against the corresponding bacterial infection. LPS provides an activation stimulus for macrophages and a maturation signal for dendritic cells to set up innate and adaptive immune responses, respectively. The signaling cascade of myeloid differentiation factor 88
IL-1R-associated kinase (IRAK)TNFR-associated factor 6 has been implicated in mediating LPS signaling. In this report, we studied the function of IRAK-4 in various LPS-induced signals. We found that IRAK-4-deficient cells were severely impaired in producing some IFN-regulated genes as well as inflammatory cytokines in response to LPS. Among the critical downstream signaling pathways induced by LPS, NF-
B activation but not IFN regulatory factor 3 or STAT1 activation was defective in cells lacking IRAK-4. IRAK-4 was also required for the proper maturation of dendritic cells by LPS stimulation, particularly in terms of cytokine production and the ability to stimulate Th cell differentiation. Our results demonstrate that IRAK-4 is critical for the LPS-induced activations of APCs.
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