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Novel signaling interactions between proteinase-activated receptor 2 and Toll-like receptors in vitro and in vivo

Academic Article
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Overview

authors

  • Nhu, Q. M.
  • Shirey, K.
  • Teijaro, John R.
  • Farber, D. L.
  • Netzel-Arnett, S.
  • Antalis, T. M.
  • Fasano, A.
  • Vogel, S. N.

publication date

  • January 2010

journal

  • Mucosal Immunol  Journal

abstract

  • Toll-like receptors (TLRs) and proteinase-activated receptors (PARs) function as innate immune biosensors in mucosal epithelial cells (ECs). We previously reported the functional and physical interactions between TLR4 and PAR(2). We have extended these findings herein by showing the cooperation between PAR(2) and TLR2, TLR3, or TLR4 for activation of nuclear factor-kappaB-dependent signaling in mucosal EC lines. In contrast, activation of PAR(2) negatively regulated TLR3-dependent antiviral pathway, blunting the expression of TLR3/interferon regulatory factor-3 (IRF-3)-driven genes, as well as activation of IRF-3 and STAT1. Consistent with these in vitro observations, PAR(2)(-/-) and TLR4(-/-) mice, which were refractory to footpad edema induced by PAR(2) agonist peptide, were protected from mouse-adapted H1N1 influenza A virus-induced lethality when compared to wild-type (WT) mice. These data support and extend our recently described, novel model of PAR(2)-TLR4 "receptor cooperativity" and highlight the complexity of signaling integration between heterologous innate immune biosensors.

subject areas

  • Animals
  • Cell Line
  • Edema
  • Epithelial Cells
  • Humans
  • Influenza A Virus, H1N1 Subtype
  • Interferon Regulatory Factor-3
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mucous Membrane
  • NF-kappa B
  • Orthomyxoviridae Infections
  • Receptor, PAR-2
  • STAT1 Transcription Factor
  • Signal Transduction
  • Toll-Like Receptors
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Identity

PubMed Central ID

  • PMC2851245

International Standard Serial Number (ISSN)

  • 1933-0219

Digital Object Identifier (DOI)

  • 10.1038/mi.2009.120

PubMed ID

  • 19865078
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Additional Document Info

start page

  • 29

end page

  • 39

volume

  • 3

issue

  • 1

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