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in TLR-Mediated Induction of Proinflammatory Cytokines1
,
,
* The Campbell Family Institute for Breast Cancer Research, Ontario Cancer Institute, Ontario, Canada;
Department of Medical Biophysics and
Department of Immunology, University of Toronto, Toronto, Ontario, Canada;
Department of Oral Biology, School of Dental Medicine, and Department of Microbiology and Immunology, School of Medicine and Biomedical Sciences, University at Buffalo, State University of New York, Buffalo, NY;
¶ Takeda Pharmaceutical Company Limited, Tsukuba, Ibaraki, Japan;
|| Department of Molecular and Cellular Biology, Kawanishi Pharma Research Institute, Kawanishi, Hyogo, Japan;
# Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia; and
** Department of Host Defense, Research Institute for Microbial Diseases and Exploratory Research for Advance Technology, Japan Science and Technology Corporation, Osaka University, Osaka, Japan
TLR stimulation triggers a signaling pathway via MyD88 and IL-1R-associated kinase 4 that is essential for proinflammatory cytokine induction. Although NF-
B has been shown to be one of the key transcriptional regulators of these cytokines, evidence suggests that other factors may also be important. In this study, we showed that MyD88-deficient macrophages have defective c-Rel activation, which has been linked to IL-12p40 induction, but not IL-6 or TNF-
. We also investigated other transcription factors and showed that C/EBPβ and C/EBP
expression was limited in MyD88- or IL-1R-associated kinase 4-deficient macrophages treated with LPS. Importantly, the absence of both C/EBPβ and C/EBP resulted in the impaired induction of proinflammatory cytokines stimulated by several TLR ligands. Our results identify c-Rel and C/EBPβ/ as important transcription factors in a MyD88-dependent pathway that regulate the induction of proinflammatory cytokines.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This work was supported by Canadian Institutes of Health Research Operating Grant MOP-57734. F.S. and S.L.G. were supported by National Institutes of Health Grants AR050458 and AR054389. P.S.O. holds a Canada Research Chair in Autoimmunity and Tumor Immunity.
2 Current address: Department of Molecular and Cellular Biology, Nippon Boehringer Ingelheim Company Ltd., Hygo, Japan.
3 Current address: Macfarlane Burnet Institute for Medical Research and Public Health, Prahran, Victoria 3004, Australia.
4 Current address: Laboratory of Host Defense, WPI Immunology Frontier Research Center, Osaka University, Osaka, Japan.
5 Current address: Division of Rheumatology & Clinical Immunology, University of Pittsburgh, Pittsburgh, PA 15261.
6 Address correspondence and reprint requests to Dr. Wen-Chen Yeh and Dr. Pamela S. Ohashi Ontario Cancer Institute, 620 University Avenue, Room 10-1030, Toronto, Ontario, M5G 2C1, Canada. E-mail addresses: wyeh38{at}gmail.com and pohashi{at}uhnres.utoronto.ca
7 Abbreviations used in this paper: IRAK-4, IL-1R-associated kinase 4; TRIF, Toll/IL-IR domain-containing adaptor-inducing IFN-β; bZIP, basic leucine zipper; KO, knockout; DKO, double KO; LTA, lipoteichoic acid; MEF, mouse embryonic fibroblast; WT, wild type; IRF, IFN regulatory factor.
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