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* Department of Cancer Biology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195;
Taussig Cancer Center, Cleveland Clinic, Cleveland, OH 44195;
Immunology Program, The Wistar Institute, University of Pennsylvania, Philadelphia, PA 19104;
Department of Molecular and Cellular Biochemistry and Center for Molecular Neurobiology, Ohio State University, Columbus, OH 43210; and
¶ Monash Institute of Medical Research, Monash University, Melbourne, Australia
Activating transcription factor-3 (ATF3) is rapidly induced by LPS in mouse macrophages and regulates TLR4 responses. We show that ATF3 is rapidly induced by various TLRs in mouse macrophages and plasmacytoid dendritic cells (DCs), as well as plasmacytoid and myeloid subsets of human DCs. In primary macrophages from mice with a targeted deletion of the atf3 gene (ATF3-knockout (KO)), TLR-stimulated levels of IL-12 and IL-6 were elevated relative to responses in wild-type macrophages. Similarly, targeted deletion of atf3 correlated with enhanced responsiveness of myeloid DCs to TLR activation as measured by IL-12 secretion. Ectopic expression of ATF3 antagonized TLR-stimulated IL-12p40 activation in a reporter assay. In vivo, CpG-oligodeoxynucleotide, a TLR9 agonist, given i.p. to ATF3-KO mice resulted in enhanced cytokine production from splenocytes. Furthermore, while ATF3-KO mice challenged with a sublethal dose of PR8 influenza virus were delayed in body weight recovery in comparison to wild type, the ATF3-KO mice showed higher titers of serum neutralizing Ab against PR8 5 mo postinfection. Thus, ATF3 behaves as a negative regulatory transcription factor in TLR pathways and, accordingly, deficiency in atf3 alters responses to immunological challenges in vivo. ATF3 dysregulation merits further exploration in diseases such as type I diabetes and cancer, where altered innate immunity has been implicated in their pathogenesis.
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 in part by National Institutes of Health Grants (NIH) RO1 AI34039 and PO1 CA62220 (to B.R.G.W.) and NIH/National Cancer Institute T32 CA059366 (to M.M.W.).
2 Current address: Immunotherapy Research Group, Genzyme Corporation, 5 Mountain Road, Framingham, MA 01701.
3 Address correspondence and reprint requests to Prof. Bryan R. G. Williams, Monash Institute of Medical Research, Monash Medical Centre, 246 Clayton Road, Clayton, Victoria 3168, Australia. E-mail address: bryan.williams{at}med.monash.edu.au
4 Abbreviations used in this paper: DC, dendritic cell; pIC, poly-IC; ATF3, activating transcription factor-3; IRAK, IL-1R-associated kinase; KO, knockout; ODN, oligodeoxynucleotide; HEK, human embryonic kidney; BMM, bone marrow-derived macrophage; BMDC, bone marrow-derived DC; mDC, myeloid DC; pDC, plasmacytoid DC; IRF, IFN regulatory factor; HA, hemagglutinin.; TRIF, toll/IL-1 receptor domain-containing adapter including IFN-
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