PMID- 12391239
OWN - NLM
STAT- MEDLINE
DCOM- 20021210
LR  - 20190515
IS  - 0022-1767 (Print)
IS  - 0022-1767 (Linking)
VI  - 169
IP  - 9
DP  - 2002 Nov 1
TI  - Dysregulation of LPS-induced Toll-like receptor 4-MyD88 complex formation and 
      IL-1 receptor-associated kinase 1 activation in endotoxin-tolerant cells.
PG  - 5209-16
AB  - Prior exposure to LPS induces a transient state of cell refractoriness to 
      subsequent LPS restimulation, known as endotoxin tolerance. Induction of LPS 
      tolerance has been reported to correlate with decreased cell surface expression 
      of the LPS receptor complex, Toll-like receptor 4 (TLR4)/MD-2. However, other 
      results have underscored the existence of mechanisms of LPS tolerance that 
      operate downstream of TLR4/MD-2. In the present study we sought to delineate 
      further the molecular basis of LPS tolerance by examining the TLR4 signaling 
      pathway in endotoxin-tolerant cells. Pretreatment of human monocytes with LPS 
      decreased LPS-mediated NF-kappaB activation, p38 mitogen-activated protein kinase 
      phosphorylation, and TNF-alpha gene expression, documenting the induction of 
      endotoxin tolerance. FACS and Western blot analyses of LPS-tolerant monocytes 
      showed increased TLR2 expression, whereas TLR4 expression levels were not 
      affected. Comparable levels of mRNA and protein for myeloid differentiation 
      factor 88 (MyD88), IL-1R-associated kinase 1 (IRAK-1), and TNFR-associated 
      factor-6 were found in normal and LPS-tolerant monocytes, while MD-2 mRNA 
      expression was slightly increased in LPS-tolerant cells. LPS induced the 
      association of MyD88 with TLR4 and increased IRAK-1 activity in medium-pretreated 
      cells. In LPS-tolerant monocytes, however, MyD88 failed to be recruited to TLR4, 
      and IRAK-1 was not activated in response to LPS stimulation. Moreover, 
      endotoxin-tolerant CHO cells that overexpress human TLR4 and MD-2 also showed 
      decreased IRAK-1 kinase activity in response to LPS despite the failure of LPS to 
      inhibit cell surface expression of transfected TLR4 and MD-2 proteins. Thus, 
      decreased TLR4-MyD88 complex formation with subsequent impairment of IRAK-1 
      activity may underlie the LPS-tolerant phenotype.
FAU - Medvedev, Andrei E
AU  - Medvedev AE
AD  - Department of Microbiology and Immunology, University of Maryland, Baltimore 
      21201, USA.
FAU - Lentschat, Arnd
AU  - Lentschat A
FAU - Wahl, Larry M
AU  - Wahl LM
FAU - Golenbock, Douglas T
AU  - Golenbock DT
FAU - Vogel, Stefanie N
AU  - Vogel SN
LA  - eng
GR  - AI18797/AI/NIAID NIH HHS/United States
GR  - AI44936/AI/NIAID NIH HHS/United States
GR  - AIP0150305/AI/NIAID NIH HHS/United States
GR  - R01GM54060/GM/NIGMS NIH HHS/United States
PT  - Journal Article
PT  - Research Support, U.S. Gov't, P.H.S.
PL  - United States
TA  - J Immunol
JT  - Journal of immunology (Baltimore, Md. : 1950)
JID - 2985117R
RN  - 0 (Adaptor Proteins, Signal Transducing)
RN  - 0 (Antigens, Differentiation)
RN  - 0 (Drosophila Proteins)
RN  - 0 (Enzyme Inhibitors)
RN  - 0 (Lipopolysaccharides)
RN  - 0 (MYD88 protein, human)
RN  - 0 (Macromolecular Substances)
RN  - 0 (Membrane Glycoproteins)
RN  - 0 (Myeloid Differentiation Factor 88)
RN  - 0 (Protein Kinase Inhibitors)
RN  - 0 (RNA, Messenger)
RN  - 0 (Receptors, Cell Surface)
RN  - 0 (Receptors, Immunologic)
RN  - 0 (Receptors, Interleukin-1)
RN  - 0 (TLR2 protein, human)
RN  - 0 (TLR4 protein, human)
RN  - 0 (Toll-Like Receptor 2)
RN  - 0 (Toll-Like Receptor 4)
RN  - 0 (Toll-Like Receptors)
RN  - EC 2.7.- (Protein Kinases)
RN  - EC 2.7.11.1 (Interleukin-1 Receptor-Associated Kinases)
SB  - IM
MH  - Adaptor Proteins, Signal Transducing
MH  - Animals
MH  - Antigens, Differentiation/metabolism
MH  - CHO Cells
MH  - Cricetinae
MH  - Down-Regulation/*immunology
MH  - *Drosophila Proteins
MH  - Enzyme Activation/immunology
MH  - Enzyme Inhibitors/pharmacology
MH  - Humans
MH  - *Immune Tolerance
MH  - Interleukin-1 Receptor-Associated Kinases
MH  - Intracellular Fluid/immunology/metabolism
MH  - Lipopolysaccharides/*pharmacology
MH  - Macromolecular Substances
MH  - Membrane Glycoproteins/*antagonists & 
      inhibitors/biosynthesis/metabolism/physiology
MH  - Monocytes/enzymology/immunology/metabolism
MH  - Myeloid Differentiation Factor 88
MH  - Phosphorylation
MH  - *Protein Kinase Inhibitors
MH  - Protein Kinases/metabolism
MH  - RNA, Messenger/biosynthesis
MH  - Receptors, Cell Surface/*antagonists & 
      inhibitors/biosynthesis/metabolism/physiology
MH  - Receptors, Immunologic/*antagonists & inhibitors/metabolism
MH  - Receptors, Interleukin-1/*metabolism
MH  - Signal Transduction/immunology
MH  - Toll-Like Receptor 2
MH  - Toll-Like Receptor 4
MH  - Toll-Like Receptors
EDAT- 2002/10/23 04:00
MHDA- 2002/12/11 04:00
CRDT- 2002/10/23 04:00
PHST- 2002/10/23 04:00 [pubmed]
PHST- 2002/12/11 04:00 [medline]
PHST- 2002/10/23 04:00 [entrez]
AID - 10.4049/jimmunol.169.9.5209 [doi]
PST - ppublish
SO  - J Immunol. 2002 Nov 1;169(9):5209-16. doi: 10.4049/jimmunol.169.9.5209.