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

Schroder, K., Spille, M., Pilz, A., Lattin, J., Bode, K. A., Irvine, K. M., Burrows, A. D., Ravasi, T., Weighardt, H., Stacey, K. J., Decker, T., Hume, D. A., Dalpke, A. H. and Sweet, M. J. (2007) Differential effects of CpG DNA on IFN-beta induction and STAT1 activation in murine macrophages versus dendritic cells: Alternatively activated STAT1 negatively regulates TLR signaling in macrophages. Journal of Immunology, 179 6: 3495-3503.


Author Schroder, K.
Spille, M.
Pilz, A.
Lattin, J.
Bode, K. A.
Irvine, K. M.
Burrows, A. D.
Ravasi, T.
Weighardt, H.
Stacey, K. J.
Decker, T.
Hume, D. A.
Dalpke, A. H.
Sweet, M. J.
Title Differential effects of CpG DNA on IFN-beta induction and STAT1 activation in murine macrophages versus dendritic cells: Alternatively activated STAT1 negatively regulates TLR signaling in macrophages
Formatted title
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
Journal name Journal of Immunology   Check publisher's open access policy
ISSN 0022-1767
Publication date 2007-09-01
Sub-type Article (original research)
Volume 179
Issue 6
Start page 3495
End page 3503
Total pages 9
Place of publication Bethesda
Publisher Amer Assoc Immunologists
Language eng
Subject C1
780105 Biological sciences
320202 Cellular Immunology
270103 Protein Targeting and Signal Transduction
270201 Gene Expression
Abstract Classical STAT1 activation in response to TLR agonists occurs by phosphorylation of the Y701 and 5727 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-beta 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-beta in mouse bone marrow-derived macrophages (BMM) and a CpG-B oligonucleotide did not induce IFn-beta in the macrophage-like cell line, J774. In BMM, STATl 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 STATl in response to TLR agonists that activate p38 MAPK but do not elicit type I IFN production. Indeed, the TLR7 agonist, 8837, failed to induce Ifn-beta mRNA and consequently triggered STATl phosphorylation on S727, but nut Y701, in human monocyte-derived macrophages. The differential activation of Ifn-beta and STATl by CpG DNA in mouse macrophages vs dendritic cells provides a likely mechanism for their divergent roles in priming the adaptive immune response.
Keyword Immunology
Gene-expression
Mouse Macrophages
Transcription Factor
Interferon-gamma
Bacterial-dna
Serine Phosphorylation
Induced Apoptosis
Binding-protein
Growth-factor
Immune Cells
Q-Index Code C1
Q-Index Status Confirmed Code

Document type: Journal Article
Sub-type: Article (original research)
Collections: Excellence in Research Australia (ERA) - Collection
Institute for Molecular Bioscience - Publications
 
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