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Differential Effects of CpG DNA on IFN- Induction and STAT1 Activation in Murine Macrophages versus Dendritic Cells: Alternatively Activated STAT1 Negatively Regulates TLR Signaling in Macrophages¹

Kate Schroder^*, Martina Spille, Andreas Pilz, Jane Lattin^*, Konrad A. Bode, Katharine M. Irvine^*, Allan D. Burrows^*, Timothy Ravasi, Heike Weighardt^¶, Katryn J. Stacey^*,||, Thomas Decker, David A. Hume^*, Alexander H. Dalpke and Matthew J. Sweet^2,*,||

^* Cooperative Research Centre for Chronic Inflammatory Diseases and Special Research Centre for Functional and Applied Genomics, Institute for Molecular Bioscience, University of Queensland, Brisbane, Queensland, Australia; Department of Medical Microbiology and Hygiene, University of Heidelberg, Heidelberg, Germany; Vienna Biocenter, Institute of Microbiology and Genetics, Vienna, Austria; Scripps NeuroAIDS Preclinical Studies Centre and Department of Bioengineering, Jacobs School of Engineering, University of California San Diego, La Jolla, CA 92093; ^¶ Institute for Environmental Research, Heinrich-Heine University, Düsseldorf, Germany; and ^|| School of Molecular and Microbial Sciences, University of Queensland, Brisbane, Queensland, Australia

Classical STAT1 activation in response to TLR agonists occurs by phosphorylation of the Y701 and S727 residues through autocrine type I IFN signaling and p38 MAPK signaling, respectively. In this study, we report that the TLR9 agonist CpG DNA induced Ifn- mRNA, as well as downstream type I IFN-dependent genes, in a MyD88-dependent manner in mouse myeloid dendritic cells. This pathway was required for maximal TNF and IL-6 secretion, as well as expression of cell surface costimulatory molecules. By contrast, neither A- nor B-type CpG-containing oligonucleotides induced Ifn- in mouse bone marrow-derived macrophages (BMM) and a CpG-B oligonucleotide did not induce IFn- in the macrophage-like cell line, J774. In BMM, STAT1 was alternatively activated (phosphorylated on S727, but not Y701), and was retained in the cytoplasm in response to CpG DNA. CpG DNA responses were altered in BMM from STAT1_S727A mice; Il-12p40 and Cox-2 mRNAs were more highly induced, whereas Tlr4 and Tlr9 mRNAs were more repressed. The data suggest a novel inhibitory function for cytoplasmic STAT1 in response to TLR agonists that activate p38 MAPK but do not elicit type I IFN production. Indeed, the TLR7 agonist, R837, failed to induce Ifn- mRNA and consequently triggered STAT1 phosphorylation on S727, but not Y701, in human monocyte-derived macrophages. The differential activation of Ifn- and STAT1 by CpG DNA in mouse macrophages vs dendritic cells provides a likely mechanism for their divergent roles in priming the adaptive immune response.

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 grants from the National Health and Medical Research Council of Australia (Project Grants 301211 and 301210). T.R. was supported by a research grant for the Scripps NeuroAIDS Preclinical Studies Center from the National Institute of Mental Health, Grant 2P30MH062261-07. A.H.D. was supported by Grants DFG Da592/2 and 592/3 from the German research foundation.

² Address correspondence and reprint requests to Dr. Matthew J. Sweet, Institute for Molecular Bioscience, University of Queensland, St. Lucia, Queensland, 4072, Australia. E-mail address: M.Sweet{at}imb.uq.edu.au

³ Abbreviations used in this paper: DC, dendritic cell; BMDC, bone marrow-derived DC; BMM, bone marrow-derived macrophage; HMDM, human monocyte-derived macrophage; IP-10, IFN--inducible protein-10; IRF, IFN regulatory factor; LTA, lipoteichoic acid; pDC, plasmacytoid DC; qPCR, quantitative PCR; WT, wild type.

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