Identification of the Molecular Mechanism by which TLR Ligation and IFN-γ Synergize to Induce Mig

Research output: Contribution to journalArticle

Abstract

Monokine Induced by Interferon-γ (MIG), a CXC chemokine, is a potent inducer of T-cell chemotaxis and activation and has been implicated in the host response to viral infections and tumor immunity as well as in the pathogenesis of autoimmunity and transplant rejection. Although it is known that the Toll-Like Receptor-4 (TLR-4) ligand LPS synergizes with IFN-γ to induce MIG expression in macrophages, the molecular mechanisms responsible for the synergy have yet to be elucidated. We determined that the marked synergy between LPS and IFN-γ on MIG mRNA expression in mouse macrophages is a result of LPS-induced NF-κB and IFN-γ-induced STAT. The synergy was not dependent on new protein synthesis, was independent of TNF-α, and occurred at the level of gene transcription. We identified 2 NF-κB sites located at - 154 and - 129 of the MIG promoter proximal to the γ-responsive element that mediated this effect. Finally, we demonstrated that other TLR ligands (zymosan, double stranded RNA and CpG) synergized with IFN-γ to induce MIG in an NF-κB dependent fashion. These data emphasize the ability of bacterial and viral products to activate/modify immune responses and promote adaptive T cell immunity through the NF-κB pathway.

Original languageEnglish (US)
Pages (from-to)77-85
Number of pages9
JournalClinical and Developmental Immunology
Volume11
Issue number1
DOIs
StatePublished - Mar 2004

Fingerprint

Ligation
Immunity
Macrophages
Monokines
Ligands
T-Lymphocytes
CXC Chemokines
Toll-Like Receptor 4
Aptitude
Zymosan
Double-Stranded RNA
Graft Rejection
Adaptive Immunity
Virus Diseases
Chemotaxis
Helper-Inducer T-Lymphocytes
Autoimmunity
Interferons
Messenger RNA
Genes

Keywords

  • Adaptive immunity
  • Innate immunity
  • Interferon-γ
  • MIG
  • NF-κB
  • TLR

ASJC Scopus subject areas

  • Immunology
  • Cell Biology
  • Developmental Biology

Cite this

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abstract = "Monokine Induced by Interferon-γ (MIG), a CXC chemokine, is a potent inducer of T-cell chemotaxis and activation and has been implicated in the host response to viral infections and tumor immunity as well as in the pathogenesis of autoimmunity and transplant rejection. Although it is known that the Toll-Like Receptor-4 (TLR-4) ligand LPS synergizes with IFN-γ to induce MIG expression in macrophages, the molecular mechanisms responsible for the synergy have yet to be elucidated. We determined that the marked synergy between LPS and IFN-γ on MIG mRNA expression in mouse macrophages is a result of LPS-induced NF-κB and IFN-γ-induced STAT. The synergy was not dependent on new protein synthesis, was independent of TNF-α, and occurred at the level of gene transcription. We identified 2 NF-κB sites located at - 154 and - 129 of the MIG promoter proximal to the γ-responsive element that mediated this effect. Finally, we demonstrated that other TLR ligands (zymosan, double stranded RNA and CpG) synergized with IFN-γ to induce MIG in an NF-κB dependent fashion. These data emphasize the ability of bacterial and viral products to activate/modify immune responses and promote adaptive T cell immunity through the NF-κB pathway.",
keywords = "Adaptive immunity, Innate immunity, Interferon-γ, MIG, NF-κB, TLR",
author = "Jonathan Powell and Sada Boodoo and Maureen Horton",
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T1 - Identification of the Molecular Mechanism by which TLR Ligation and IFN-γ Synergize to Induce Mig

AU - Powell, Jonathan

AU - Boodoo, Sada

AU - Horton, Maureen

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N2 - Monokine Induced by Interferon-γ (MIG), a CXC chemokine, is a potent inducer of T-cell chemotaxis and activation and has been implicated in the host response to viral infections and tumor immunity as well as in the pathogenesis of autoimmunity and transplant rejection. Although it is known that the Toll-Like Receptor-4 (TLR-4) ligand LPS synergizes with IFN-γ to induce MIG expression in macrophages, the molecular mechanisms responsible for the synergy have yet to be elucidated. We determined that the marked synergy between LPS and IFN-γ on MIG mRNA expression in mouse macrophages is a result of LPS-induced NF-κB and IFN-γ-induced STAT. The synergy was not dependent on new protein synthesis, was independent of TNF-α, and occurred at the level of gene transcription. We identified 2 NF-κB sites located at - 154 and - 129 of the MIG promoter proximal to the γ-responsive element that mediated this effect. Finally, we demonstrated that other TLR ligands (zymosan, double stranded RNA and CpG) synergized with IFN-γ to induce MIG in an NF-κB dependent fashion. These data emphasize the ability of bacterial and viral products to activate/modify immune responses and promote adaptive T cell immunity through the NF-κB pathway.

AB - Monokine Induced by Interferon-γ (MIG), a CXC chemokine, is a potent inducer of T-cell chemotaxis and activation and has been implicated in the host response to viral infections and tumor immunity as well as in the pathogenesis of autoimmunity and transplant rejection. Although it is known that the Toll-Like Receptor-4 (TLR-4) ligand LPS synergizes with IFN-γ to induce MIG expression in macrophages, the molecular mechanisms responsible for the synergy have yet to be elucidated. We determined that the marked synergy between LPS and IFN-γ on MIG mRNA expression in mouse macrophages is a result of LPS-induced NF-κB and IFN-γ-induced STAT. The synergy was not dependent on new protein synthesis, was independent of TNF-α, and occurred at the level of gene transcription. We identified 2 NF-κB sites located at - 154 and - 129 of the MIG promoter proximal to the γ-responsive element that mediated this effect. Finally, we demonstrated that other TLR ligands (zymosan, double stranded RNA and CpG) synergized with IFN-γ to induce MIG in an NF-κB dependent fashion. These data emphasize the ability of bacterial and viral products to activate/modify immune responses and promote adaptive T cell immunity through the NF-κB pathway.

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