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CUTTING EDGE |
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,§

*
Department of Host Defense, Research Institute for Microbial Diseases, Osaka University, Osaka, Japan;
Department of Immunology and Medical Zoology, Hyogo College of Medicine, Hyogo, Japan;
Department of Immunology, Saga Medical School, Saga, Japan; and
§
Core Research for Evolutional Science and Technology, Japan Science and Technology Corporation, Tokyo, Japan
Monocytes/macrophages exposed to LPS show reduced responses to
second stimulation with LPS, which is termed LPS tolerance. In this
study, we investigated molecular mechanism of LPS tolerance in
macrophages. Mouse peritoneal macrophages pre-exposed to LPS exhibited
reduced production of inflammatory cytokines in a time- and
dose-dependent manner. Activation of neither IL-1 receptor-associated
kinase nor NF-
B was observed in macrophages that became tolerant by
LPS pretreatment, indicating that the proximal event in Toll-like
receptor 4 (TLR4)-MyD88-dependent signaling is affected in tolerant
macrophages. Although TLR4 mRNA expression significantly decreased
within a few hours of LPS pretreatment and returned to the original
level at 24 h, the surface TLR4 expression began to decrease
within 1 h, with a gradual decrease after that, and remained
suppressed over 24 h. A decrease in inflammatory cytokine
production in tolerant macrophages well correlates with down-regulation
of the surface TLR4 expression, which may explain one of the mechanisms
for LPS tolerance.
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