Research output: Contribution to Journal/Magazine › Journal article › peer-review
Research output: Contribution to Journal/Magazine › Journal article › peer-review
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TY - JOUR
T1 - Overexpression of toll-like receptor 4 amplifies the host response to lipopolysaccharide and provides a survival advantage in transgenic mice
AU - Bihl, Franck
AU - Salez, Laurent
AU - Beaubier, Magali
AU - Torres, David
AU - Larivière, Line
AU - Laroche, Line
AU - Benedetto, Alexandre
AU - Martel, Dominic
AU - Lapointe, Jean-Martin
AU - Ryffel, Bernhard
AU - Malo, Danielle
PY - 2003/6/15
Y1 - 2003/6/15
N2 - Toll-like receptors are transmembrane proteins that are involved in the innate immune recognition of microbial constituents. Among them, Toll-like receptor 4 (Tlr4) is a crucial signal transducer for LPS, the major component of Gram-negative bacteria outer cell membrane. The contribution of Tlr4 to the host response to LPS and to infection with virulent Salmonella typhimurium was studied in four transgenic (Tg) strains including three overexpressing Tlr4. There was a good correlation between the level of Tlr4 mRNA expression and the sensitivity to LPS both in vitro and in vivo: Tg mice possessing the highest number of Tlr4 copies respond the most to LPS. Overexpression of Tlr4 by itself appears to have a survival advantage in Tg mice early during infection: animals possessing more than two copies of the gene survived longer and in a greater percentage to Salmonella infection. The beneficial effect of Tlr4 overexpression is greatly enhanced when the mice present a wild-type allele at natural resistance-associated macrophage protein 1, another critical innate immune gene involved in resistance to infection with Salmonella. Tlr4 and natural resistance-associated macrophage protein 1 exhibit functional epistatic interaction to improve the capacity of the host to control bacterial replication. However, this early improvement in disease resistance is not conducted later during infection, because mice overexpressing Tlr4 developed an excessive inflammatory response detrimental to the host.
AB - Toll-like receptors are transmembrane proteins that are involved in the innate immune recognition of microbial constituents. Among them, Toll-like receptor 4 (Tlr4) is a crucial signal transducer for LPS, the major component of Gram-negative bacteria outer cell membrane. The contribution of Tlr4 to the host response to LPS and to infection with virulent Salmonella typhimurium was studied in four transgenic (Tg) strains including three overexpressing Tlr4. There was a good correlation between the level of Tlr4 mRNA expression and the sensitivity to LPS both in vitro and in vivo: Tg mice possessing the highest number of Tlr4 copies respond the most to LPS. Overexpression of Tlr4 by itself appears to have a survival advantage in Tg mice early during infection: animals possessing more than two copies of the gene survived longer and in a greater percentage to Salmonella infection. The beneficial effect of Tlr4 overexpression is greatly enhanced when the mice present a wild-type allele at natural resistance-associated macrophage protein 1, another critical innate immune gene involved in resistance to infection with Salmonella. Tlr4 and natural resistance-associated macrophage protein 1 exhibit functional epistatic interaction to improve the capacity of the host to control bacterial replication. However, this early improvement in disease resistance is not conducted later during infection, because mice overexpressing Tlr4 developed an excessive inflammatory response detrimental to the host.
KW - Adjuvants, Immunologic
KW - Animals
KW - Cell Membrane
KW - Cells, Cultured
KW - Crosses, Genetic
KW - Flow Cytometry
KW - Gene Dosage
KW - Gene Expression Regulation
KW - Injections, Intraperitoneal
KW - Lipopolysaccharides
KW - Lymphocyte Activation
KW - Membrane Glycoproteins
KW - Mice
KW - Mice, Inbred C3H
KW - Mice, Inbred C57BL
KW - Mice, Transgenic
KW - Receptors, Cell Surface
KW - Reverse Transcriptase Polymerase Chain Reaction
KW - Salmonella Infections, Animal
KW - Shock, Septic
KW - Survival Rate
KW - Toll-Like Receptor 4
KW - Toll-Like Receptors
KW - Transgenes
KW - Journal Article
KW - Research Support, Non-U.S. Gov't
U2 - 10.4049/jimmunol.170.12.6141
DO - 10.4049/jimmunol.170.12.6141
M3 - Journal article
C2 - 12794144
VL - 170
SP - 6141
EP - 6150
JO - Journal of Immunology
JF - Journal of Immunology
SN - 0022-1767
IS - 12
ER -