PMID- 19181857
OWN - NLM
STAT- MEDLINE
DCOM- 20090327
LR  - 20211020
IS  - 1091-6490 (Electronic)
IS  - 0027-8424 (Print)
IS  - 0027-8424 (Linking)
VI  - 106
IP  - 7
DP  - 2009 Feb 17
TI  - Protection from lethal gram-negative bacterial sepsis by targeting Toll-like 
      receptor 4.
PG  - 2348-52
LID - 10.1073/pnas.0808146106 [doi]
AB  - Toll-like receptor 4 (TLR4), the signal-transducing molecule of the LPS receptor 
      complex, plays a fundamental role in the sensing of LPS from gram-negative 
      bacteria. Activation of TLR4 signaling pathways by LPS is a critical upstream 
      event in the pathogenesis of gram-negative sepsis, making TLR4 an attractive 
      target for novel antisepsis therapy. To validate the concept of TLR4-targeted 
      treatment strategies in gram-negative sepsis, we first showed that TLR4(-/-) and 
      myeloid differentiation primary response gene 88 (MyD88)(-/-) mice were fully 
      resistant to Escherichia coli-induced septic shock, whereas TLR2(-/-) and 
      wild-type mice rapidly died of fulminant sepsis. Neutralizing anti-TLR4 
      antibodies were then generated using a soluble chimeric fusion protein composed 
      of the N-terminal domain of mouse TLR4 (amino acids 1-334) and the Fc portion of 
      human IgG1. Anti-TLR4 antibodies inhibited intracellular signaling, markedly 
      reduced cytokine production, and protected mice from lethal endotoxic shock and 
      E. coli sepsis when administered in a prophylactic and therapeutic manner up to 
      13 h after the onset of bacterial sepsis. These experimental data provide strong 
      support for the concept of TLR4-targeted therapy for gram-negative sepsis.
FAU - Roger, Thierry
AU  - Roger T
AD  - Infectious Diseases Service, Department of Medicine, Centre Hospitalier 
      Universitaire Vaudois and University of Lausanne, CH-1011 Lausanne, Switzerland.
FAU - Froidevaux, Celine
AU  - Froidevaux C
FAU - Le Roy, Didier
AU  - Le Roy D
FAU - Reymond, Marlies Knaup
AU  - Reymond MK
FAU - Chanson, Anne-Laure
AU  - Chanson AL
FAU - Mauri, Davide
AU  - Mauri D
FAU - Burns, Kim
AU  - Burns K
FAU - Riederer, Beat Michel
AU  - Riederer BM
FAU - Akira, Shizuo
AU  - Akira S
FAU - Calandra, Thierry
AU  - Calandra T
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20090130
PL  - United States
TA  - Proc Natl Acad Sci U S A
JT  - Proceedings of the National Academy of Sciences of the United States of America
JID - 7505876
RN  - 0 (Immunoglobulin G)
RN  - 0 (Lipopolysaccharides)
RN  - 0 (Myd88 protein, mouse)
RN  - 0 (Myeloid Differentiation Factor 88)
RN  - 0 (Recombinant Fusion Proteins)
RN  - 0 (Toll-Like Receptor 4)
SB  - IM
MH  - Animals
MH  - Escherichia coli/metabolism
MH  - *Gene Expression Regulation, Bacterial
MH  - Gram-Negative Bacteria/*metabolism
MH  - Humans
MH  - Immunoglobulin G/chemistry
MH  - Lipopolysaccharides/metabolism
MH  - Mice
MH  - Mice, Inbred C57BL
MH  - Models, Genetic
MH  - Myeloid Differentiation Factor 88/genetics
MH  - Recombinant Fusion Proteins/metabolism
MH  - Sepsis/genetics/*microbiology/pathology
MH  - Time Factors
MH  - Toll-Like Receptor 4/*physiology
PMC - PMC2650125
COIS- The authors declare no conflict of interest.
EDAT- 2009/02/03 09:00
MHDA- 2009/03/28 09:00
PMCR- 2009/08/17
CRDT- 2009/02/03 09:00
PHST- 2009/02/03 09:00 [entrez]
PHST- 2009/02/03 09:00 [pubmed]
PHST- 2009/03/28 09:00 [medline]
PHST- 2009/08/17 00:00 [pmc-release]
AID - 0808146106 [pii]
AID - 6654 [pii]
AID - 10.1073/pnas.0808146106 [doi]
PST - ppublish
SO  - Proc Natl Acad Sci U S A. 2009 Feb 17;106(7):2348-52. doi: 
      10.1073/pnas.0808146106. Epub 2009 Jan 30.