Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 103, Issue 7, Pages 2292-2297Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.0510874103
Keywords
endotoxin; interferon; Toll; receptor; infection
Categories
Ask authors/readers for more resources
Although activation of Toll-like receptor 4 (TLR4)-positive cells is essential for eliminating Gram-negative bacteria, overactivation of these cells by the TLR4 ligand LPS initiates a systemic inflammatory reaction and shock. Here we demonstrate that SPRET/Ei mice, derived from Mus spretus, exhibit a dominant resistance against LPS-induced lethality. This resistance is mediated by bone marrow-derived cells. Macrophages from these mice exhibit normal signaling and gene expression responses that depend on the myeloid differentiation factor 88 adaptor protein, but they are impaired in IFN-beta production. The defect appears to be specific for IFN-beta although the SPRET/Ei IFN-beta promoter is normal. In vivo IFN-beta induction by LPS or influenza virus is very low in SPRET/Ei mice, but IFN-beta-treatment restores the sensitivity to LIPS, and IFN type 1 receptor-deficient mice are also resistant to LIPS. Because of the defective induction of IFN-beta, these mice are completely resistant to Listeria monocytogenes and highly sensitive to Leishmania major infection. Stimulation of SPRET/Ei macrophages leads to rapid down-regulation of IFN type 1 receptor mRNA expression, which is reflected in poor induction of IFN-beta-dependent genes. This finding indicates that the resistance of SPRET/Ei mice to LIPS is due to disruption of a positive-feed back loop that amplifies IFN-beta production. In contrast to TLR4-deficient mice, SPRET/Ei mice resist both LPS and sepsis induced with Klebsiella pneumoniae.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available