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Critical Role of IRF-8 in Negative Regulation of TLR3 Expression by Src Homology 2 Domain-Containing Protein Tyrosine Phosphatase-2 Activity in Human Myeloid Dendritic Cells

Fragale, Alessandra, Stellacci, Emilia, Ilari, Ramona, Remoli, Anna Lisa, Lanciotti, Angela, Perrotti, Edvige, Shytaj, Iart, Orsatti, Roberto, Lawrence, Harshani R, Lawrence, Nicholas J, Wu, Jerry, Rehli, Michael, Ozato, Keiko, Battistini, Angela·2011·The Journal of Immunology
DOI 10.4049/jimmunol.1000918PMC PMC4053178
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Abstract

Despite extensive studies that unraveled ligands and signal transduction pathways triggered by TLRs, little is known about the regulation of TLR gene expression. TLR3 plays a crucial role in the recognition of viral pathogens and induction of immune responses by myeloid DCs. IFN regulatory factor (IRF)-8, a member of the IRF family, is a transcriptional regulator that plays essential roles in the development and function of myeloid lineage, affecting different subsets of myeloid DCs. In this study, we show that IRF-8 negatively controls TLR3 gene expression by suppressing IRF-1– and/or polyinosinic-polycytidylic acid-stimulated TLR3 expression in primary human monocyte-derived DCs (MDDCs). MDDCs expressed TLR3 increasingly during their differentiation from monocytes to DCs with a peak at day 5, when TLR3 expression was further enhanced upon stimulation with polyinosinic-polycytidylic acid and then was promptly downregulated. We found that both IRF-1 and IRF-8 bind the human TLR3 promoter during MDDC differentiation in vitro and in vivo but with different kinetic and functional effects. We demonstrate that IRF-8–induced repression of TLR3 is specifically mediated by ligand-activated Src homology 2 domain-containing protein tyrosine phosphatase association. Indeed, Src homology 2 domain-containing protein tyrosine phosphatase–dephosphorylated IRF-8 bound to the human TLR3 promoter competing with IRF-1 and quashing its activity by recruitment of histone deacetylase 3. Our findings identify IRF-8 as a key player in the control of intracellular viral dsRNA-induced responses and highlight a new mechanism for negative regulation of TLR3 expression that can be exploited to block excessive TLR activation.

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Metadata

Authors
Fragale, A., Stellacci, E., Ilari, R., Remoli, A. L., Lanciotti, A., Perrotti, E., Shytaj, I., Orsatti, R., Lawrence, H. R., Lawrence, N. J., Wu, J., Rehli, M., Ozato, K., & Battistini, A.
Affiliations
  • Dipartimento di Malattie Infettive, Parassitarie ed Immunomediate, Istituto Superiore di Sanità , Rome ,
  • H. Lee Moffitt Cancer Center and Research Institute , Tampa, FL 33612
  • Department of Hematology and Oncology, University Hospital , Regensburg ,
  • Laboratory of Molecular Growth Regulation, National Institute of Child Health and Human Development, National Institutes of Health , Bethesda, MD 20814
Venue
The Journal of Immunology
Publisher
Oxford University Press (OUP)
Published
2011-02
Volume
186
Issue
4
Pages
1951-1962
ISSN
  • 0022-1767
  • 1550-6606
DOI
10.4049/jimmunol.1000918
PMC
PMC4053178
Cited by
27
References
7
Language
en
Licence
academic.oup.com/pages/standard-publication-reuse-rights (vor)

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