Differential effects of CpG DNA on IFN-β induction and STAT1 activation in murine macrophages versus dendritic cells: Alternatively activated STAT1 negatively regulates TLR signaling in macrophages

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, Matthew J. Sweet

Research output: Contribution to journalArticlepeer-review

41 Scopus citations

Abstract

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-β 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-β in mouse bone marrow-derived macrophages (BMM) and a CpG-B oligonucleotide did not induce IFn-β 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 STAT1S727A 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-β mRNA and consequently triggered STAT1 phosphorylation on S727, but not Y701, in human monocyte-derived macrophages. The differential activation of Ifn-β 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.

Original languageEnglish (US)
Pages (from-to)3495-3503
Number of pages9
JournalJournal of Immunology
Volume179
Issue number6
DOIs
StatePublished - Sep 15 2007

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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