Altered Toll-like receptor 2-mediated endotoxin tolerance is related to diminished interferon beta production

Svetislav S Zaric, Wilson A Coulter, Charles E Shelburne, Catherine R Fulton, Marija S Zaric, Aaron Scott, Mark J Lappin, Denise C Fitzgerald, Christopher R Irwin, Clifford C Taggart

Research output: Contribution to journalArticle

13 Citations (Scopus)

Abstract

Induction of endotoxin tolerance leads to a reduced inflammatory response after repeated challenge by LPS and is important for resolution of inflammation and prevention of tissue damage. Enterobacterial LPS is recognized by the TLR4 signaling complex, whereas LPS of some non-enterobacterial organisms is capable of signaling independently of TLR4 utilizing TLR2-mediated signal transduction instead. In this study we report that Porphyromonas gingivalis LPS, a TLR2 agonist, fails to induce a fully endotoxin tolerant state in a human monocytic cell line (THP-1) and mouse bone marrow-derived macrophages. In contrast to significantly decreased production of human IL-8 and TNF-a and, in mice, keratinocyte-derived cytokine (KC), macrophage inflammatory protein-2 (MIP-2), and TNF-a after repeated challenge with Escherichia coli LPS, cells repeatedly exposed to P. gingivalis LPS responded by producing less TNF-a but sustained elevated secretion of IL-8, KC, and MIP-2. Furthermore, in endotoxin-tolerant cells, production of IL-8 is controlled at the signaling level and correlates well with NF-¿B activation, whereas TNF-a expression is blocked at the gene transcription level. Interferon ß plays an important role in attenuation of chemokine expression in endotoxin-tolerized cells as shown in interferon regulatory factor-3 knock-out mice. In addition, human gingival fibroblasts, commonly known not to display LPS tolerance, were found to be tolerant to repeated challenge by LPS if pretreated with interferon ß. The data suggest that the inability of the LPS-TLR2 complex to induce full endotoxin tolerance in monocytes/macrophages is related to diminished production of interferon ß and may partly explain the involvement of these LPS isoforms in the pathogenesis of chronic inflammatory diseases.
Original languageEnglish
Pages (from-to)29492-29500
Number of pages9
JournalThe Journal of Biological Chemistry
Volume286
Issue number34
DOIs
Publication statusPublished - 2011

Fingerprint

Toll-Like Receptor 2
Interferon-beta
Endotoxins
Interleukin-8
Chemokine CXCL2
Interferons
Porphyromonas gingivalis
Macrophages
Keratinocytes
Interferon Regulatory Factor-3
Cytokines
Signal transduction
Transcription
Fibroblasts
Chemokines
Knockout Mice
Escherichia coli
Monocytes
Signal Transduction
Protein Isoforms

Keywords

  • Animals
  • Cell Line
  • Cytokines
  • Drug Resistance
  • Fibroblasts
  • Humans
  • Interferon Regulatory Factor-3
  • Interferon-beta
  • Lipopolysaccharides
  • Macrophages
  • Mice
  • Mice, Knockout
  • NF-kappa B
  • Signal Transduction
  • Toll-Like Receptor 2

Cite this

Zaric, S. S., Coulter, W. A., Shelburne, C. E., Fulton, C. R., Zaric, M. S., Scott, A., ... Taggart, C. C. (2011). Altered Toll-like receptor 2-mediated endotoxin tolerance is related to diminished interferon beta production. The Journal of Biological Chemistry, 286(34), 29492-29500. https://doi.org/10.1074/jbc.M111.252791

Altered Toll-like receptor 2-mediated endotoxin tolerance is related to diminished interferon beta production. / Zaric, Svetislav S; Coulter, Wilson A; Shelburne, Charles E; Fulton, Catherine R; Zaric, Marija S; Scott, Aaron; Lappin, Mark J; Fitzgerald, Denise C; Irwin, Christopher R; Taggart, Clifford C.

In: The Journal of Biological Chemistry, Vol. 286, No. 34, 2011, p. 29492-29500.

Research output: Contribution to journalArticle

Zaric, SS, Coulter, WA, Shelburne, CE, Fulton, CR, Zaric, MS, Scott, A, Lappin, MJ, Fitzgerald, DC, Irwin, CR & Taggart, CC 2011, 'Altered Toll-like receptor 2-mediated endotoxin tolerance is related to diminished interferon beta production', The Journal of Biological Chemistry, vol. 286, no. 34, pp. 29492-29500. https://doi.org/10.1074/jbc.M111.252791
Zaric, Svetislav S ; Coulter, Wilson A ; Shelburne, Charles E ; Fulton, Catherine R ; Zaric, Marija S ; Scott, Aaron ; Lappin, Mark J ; Fitzgerald, Denise C ; Irwin, Christopher R ; Taggart, Clifford C. / Altered Toll-like receptor 2-mediated endotoxin tolerance is related to diminished interferon beta production. In: The Journal of Biological Chemistry. 2011 ; Vol. 286, No. 34. pp. 29492-29500.
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AU - Fulton, Catherine R

AU - Zaric, Marija S

AU - Scott, Aaron

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AB - Induction of endotoxin tolerance leads to a reduced inflammatory response after repeated challenge by LPS and is important for resolution of inflammation and prevention of tissue damage. Enterobacterial LPS is recognized by the TLR4 signaling complex, whereas LPS of some non-enterobacterial organisms is capable of signaling independently of TLR4 utilizing TLR2-mediated signal transduction instead. In this study we report that Porphyromonas gingivalis LPS, a TLR2 agonist, fails to induce a fully endotoxin tolerant state in a human monocytic cell line (THP-1) and mouse bone marrow-derived macrophages. In contrast to significantly decreased production of human IL-8 and TNF-a and, in mice, keratinocyte-derived cytokine (KC), macrophage inflammatory protein-2 (MIP-2), and TNF-a after repeated challenge with Escherichia coli LPS, cells repeatedly exposed to P. gingivalis LPS responded by producing less TNF-a but sustained elevated secretion of IL-8, KC, and MIP-2. Furthermore, in endotoxin-tolerant cells, production of IL-8 is controlled at the signaling level and correlates well with NF-¿B activation, whereas TNF-a expression is blocked at the gene transcription level. Interferon ß plays an important role in attenuation of chemokine expression in endotoxin-tolerized cells as shown in interferon regulatory factor-3 knock-out mice. In addition, human gingival fibroblasts, commonly known not to display LPS tolerance, were found to be tolerant to repeated challenge by LPS if pretreated with interferon ß. The data suggest that the inability of the LPS-TLR2 complex to induce full endotoxin tolerance in monocytes/macrophages is related to diminished production of interferon ß and may partly explain the involvement of these LPS isoforms in the pathogenesis of chronic inflammatory diseases.

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