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Tlr2 signaling subpathways regulate tlr9 signaling for the effective induction of il-12 upon stimulation by heat-killed brucella abortus

Academic Article
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Overview

authors

  • Zhang, C. Y.
  • Bai, N.
  • Zhang, Z. H.
  • Liang, N.
  • Dong, L.
  • Xiang, Rong
  • Liu, C. H.

publication date

  • July 2012

journal

  • Cellular & Molecular Immunology  Journal

abstract

  • Brucella abortus is a Gram-negative intracellular bacterium that induces MyD88-dependent IL-12 production in dentritic cells (DCs) and a subsequent protective Th1 immune response. Previous studies have shown that the Toll-like receptor 2 (TLR2) is required for tumor-necrosis factor (TNF) production, whereas TLR9 is responsible for IL-12 induction in DCs after exposure to heat-killed Brucella abortus (HKBA). TLR2 is located on the cell surface and is required for optimal microorganism-induced phagocytosis by innate immune cells; thus, phagocytosis is an indispensable preliminary step for bacterial genomic DNA recognition by TLR9 in late-endosomal compartments. Here, we hypothesized that TLR2-triggered signals after HKBA stimulation might cross-regulate TLR9 signaling through the indirect modulation of the phagocytic function of DCs or the direct modulation of cytokine gene expression. Our results indicate that HKBA phagocytosis was TLR2-dependent and an essential step for IL-12p40 induction. In addition, HKBA exposure triggered the TLR2-mediated activation of both p38 and extracellular signal-regulated kinase 1/2 (ERK1/2). Interestingly, although p38 was required for HKBA phagocytosis and phagosome maturation, ERK1/2 did not affect these processes but negatively regulated IL-12 production. Although p38 inhibitors tempered both TNF and IL-12 responses to HKBA, pre-treatment with an ERK1/2 inhibitor significantly increased IL-12p40 and abrogated TNF production in HKBA-stimulated DCs. Further experiments showed that the signaling events that mediated ERK1/2 activation after TLR2 triggering also required HKBA-induced Ras activation. Furthermore, Ras-guanine nucleotide-releasing protein 1 (RasGRP1) mediated the TLR2-induced ERK1/2 activation and inhibition of IL-12p40 production. Taken together, our results demonstrated that HKBA-mediated TLR2-triggering activates both the p38 and ERK1/2 signaling subpathways, which divergently regulate TLR9 activation at several levels to induce an appropriate protective IL-12 response.

subject areas

  • Animals
  • Antigens, Bacterial
  • Brucella abortus
  • Cytokines
  • DNA-Binding Proteins
  • Dendritic Cells
  • Gene Expression Regulation
  • Guanine Nucleotide Exchange Factors
  • Hot Temperature
  • Immunity, Innate
  • Interleukin-12 Subunit p40
  • Mice
  • Mice, Inbred C3H
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Receptor Cross-Talk
  • Signal Transduction
  • Th1 Cells
  • Toll-Like Receptor 2
  • Toll-Like Receptor 9
  • p38 Mitogen-Activated Protein Kinases
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Research

keywords

  • ERK
  • TLR2
  • TLR9
  • TNF
  • interleukin-12
  • p38
  • phagocytosis
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Identity

PubMed Central ID

  • PMC4012865

International Standard Serial Number (ISSN)

  • 1672-7681

Digital Object Identifier (DOI)

  • 10.1038/cmi.2012.11

PubMed ID

  • 22635254
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Additional Document Info

start page

  • 324

end page

  • 333

volume

  • 9

issue

  • 4

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