Altered Toll-like Receptor 2-mediated Endotoxin Tolerance Is Related to Diminished Interferon β Production

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 organism...

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Bibliographic Details
Published in:	The Journal of biological chemistry 2011-08, Vol.286 (34), p.29492-29500
Main Authors:	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.
Format:	Article
Language:	eng
Subjects:	Animals Cell Line Chemokines Chronic Inflammation Cytokine Cytokines - biosynthesis Cytokines - genetics Drug Resistance - drug effects Drug Resistance - genetics Endotoxin Endotoxin Tolerance Fibroblasts - metabolism Humans Immunology Interferon Interferon Regulatory Factor-3 - genetics Interferon Regulatory Factor-3 - metabolism Interferon-beta - biosynthesis Interferon-beta - genetics Lipopolysaccharides - pharmacology Macrophages - metabolism Mice Mice, Knockout NF-kappa B - genetics NF-kappa B - metabolism Signal Transduction - drug effects Signal Transduction - genetics Toll-Like Receptor 2 - genetics Toll-Like Receptor 2 - metabolism Toll-like receptors (TLR)
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Summary:	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-α and, in mice, keratinocyte-derived cytokine (KC), macrophage inflammatory protein-2 (MIP-2), and TNF-α after repeated challenge with Escherichia coli LPS, cells repeatedly exposed to P. gingivalis LPS responded by producing less TNF-α 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-κB activation, whereas TNF-α expression is blocked at the gene transcription level. Interferon β 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 β. 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 β and may partly explain the involvement of these LPS isoforms in the pathogenesis of chronic inflammatory diseases.
ISSN:	0021-9258 1083-351X