PMID- 18419766
OWN - NLM
STAT- MEDLINE
DCOM- 20080916
LR  - 20131121
IS  - 1471-4159 (Electronic)
IS  - 0022-3042 (Linking)
VI  - 106
IP  - 2
DP  - 2008 Jul
TI  - Ethanol mimics ligand-mediated activation and endocytosis of IL-1RI/TLR4 
      receptors via lipid rafts caveolae in astroglial cells.
PG  - 625-39
LID - 10.1111/j.1471-4159.2008.05425.x [doi]
AB  - We have recently reported that ethanol-induced inflammatory processes in the 
      brain and glial cells are mediated via the activation of interleukin-1 beta 
      receptor type I (IL-1RI)/toll-like receptor type 4 (TLR4) signalling. The 
      mechanism(s) by which ethanol activates these receptors in astroglial cells 
      remains unknown. Recently, plasma membrane microdomains, lipid rafts, have been 
      identified as platforms for receptor signalling and, in astrocytes, 
      rafts/caveolae constitute an important integrators of signal events and 
      trafficking. Here we show that stimulation of astrocytes with IL-1beta, 
      lipopolysaccharide or ethanol (10 and 50 mM), triggers the translocation of 
      IL-1RI and/or TLR4 into lipid rafts caveolae-enriched fractions, promoting the 
      recruitment of signalling molecules (phospho-IL-1R-associated kinase and 
      phospho-extracellular regulated-kinase) into these microdomains. With confocal 
      microscopy, we further demonstrate that IL-1RI is internalized by caveolar 
      endocytosis via enlarged caveosomes organelles upon IL-1beta or ethanol 
      treatment, which sorted their IL-1RI cargo into the endoplasmic reticulum-Golgi 
      compartment and into the nucleus of astrocytes. In short, our findings 
      demonstrate that rafts/caveolae are critical for IL-1RI and TLR4 signalling in 
      astrocytes, and reveal a novel mechanism by which ethanol, by interacting with 
      lipid rafts caveolae, promotes IL-1RI and TLR4 receptors recruitment, triggering 
      their endocytosis via caveosomes and downstream signalling stimulation. These 
      results suggest that TLRs receptors are important targets of ethanol-induced 
      inflammatory damage in the brain.
FAU - Blanco, Ana M
AU  - Blanco AM
AD  - Department of Cellular Pathology, Centro de Investigacion Principe Felipe, 
      Valencia, Spain.
FAU - Perez-Arago, Amparo
AU  - Perez-Arago A
FAU - Fernandez-Lizarbe, Sara
AU  - Fernandez-Lizarbe S
FAU - Guerri, Consuelo
AU  - Guerri C
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20080414
PL  - England
TA  - J Neurochem
JT  - Journal of neurochemistry
JID - 2985190R
RN  - 0 (Central Nervous System Depressants)
RN  - 0 (Interleukin-1beta)
RN  - 0 (Lipopolysaccharides)
RN  - 0 (Tlr4 protein, rat)
RN  - 0 (Toll-Like Receptor 4)
RN  - 3K9958V90M (Ethanol)
SB  - IM
MH  - Analysis of Variance
MH  - Animals
MH  - Animals, Newborn
MH  - Astrocytes/*cytology
MH  - Caveolae/*metabolism
MH  - Cells, Cultured
MH  - Central Nervous System Depressants/*pharmacology
MH  - Cerebral Cortex/cytology
MH  - Dose-Response Relationship, Drug
MH  - Endocytosis/*drug effects/physiology
MH  - Ethanol/*pharmacology
MH  - Interleukin-1beta/pharmacology
MH  - Lipopolysaccharides/pharmacology
MH  - Microscopy, Confocal
MH  - Protein Transport/drug effects
MH  - Rats
MH  - Signal Transduction/drug effects/physiology
MH  - Time Factors
MH  - Toll-Like Receptor 4/*metabolism
EDAT- 2008/04/19 09:00
MHDA- 2008/09/17 09:00
CRDT- 2008/04/19 09:00
PHST- 2008/04/19 09:00 [pubmed]
PHST- 2008/09/17 09:00 [medline]
PHST- 2008/04/19 09:00 [entrez]
AID - JNC5425 [pii]
AID - 10.1111/j.1471-4159.2008.05425.x [doi]
PST - ppublish
SO  - J Neurochem. 2008 Jul;106(2):625-39. doi: 10.1111/j.1471-4159.2008.05425.x. Epub 
      2008 Apr 14.