Deprecated: Implicit conversion from float 229.6 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534
Deprecated: Implicit conversion from float 229.6 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534
Deprecated: Implicit conversion from float 229.6 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534
Deprecated: Implicit conversion from float 229.6 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534
Deprecated: Implicit conversion from float 229.6 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534
Deprecated: Implicit conversion from float 229.6 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534
Deprecated: Implicit conversion from float 263.2 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534
Deprecated: Implicit conversion from float 263.2 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534
Deprecated: Implicit conversion from float 263.2 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534
Deprecated: Implicit conversion from float 263.2 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534
Deprecated: Implicit conversion from float 263.2 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534
Warning: imagejpeg(C:\Inetpub\vhosts\kidney.de\httpdocs\phplern\26632633
.jpg): Failed to open stream: No such file or directory in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 117 J+Hepatol
2016 ; 64
(3
): 651-60
Nephropedia Template TP
gab.com Text
Twit Text FOAVip
Twit Text #
English Wikipedia
Alcohol stimulates macrophage activation through caspase-dependent hepatocyte
derived release of CD40L containing extracellular vesicles
#MMPMID26632633
Verma VK
; Li H
; Wang R
; Hirsova P
; Mushref M
; Liu Y
; Cao S
; Contreras PC
; Malhi H
; Kamath PS
; Gores GJ
; Shah VH
J Hepatol
2016[Mar]; 64
(3
): 651-60
PMID26632633
show ga
BACKGROUND & AIMS: The mechanisms by which hepatocyte exposure to alcohol
activates inflammatory cells such as macrophages in alcoholic liver disease (ALD)
are unclear. The role of released nano-sized membrane vesicles, termed
extracellular vesicles (EV), in cell-to-cell communication has become
increasingly recognized. We tested the hypothesis that hepatocytes exposed to
alcohol may increase EV release to elicit macrophage activation. METHODS: Primary
hepatocytes or HepG2 hepatocyte cell lines overexpressing ethanol-metabolizing
enzymes alcohol dehydrogenase (HepG2(ADH)) or cytochrome P450 2E1 (HepG2(Cyp2E1))
were treated with ethanol and EV release was quantified with nanoparticle
tracking analysis. EV mediated macrophage activation was monitored by analysing
inflammatory cytokines and macrophage associated mRNA expression,
immunohistochemistry, biochemical serum alanine aminotransferase and
triglycerides analysis in our in vitro macrophage activation and in vivo murine
ethanol feeding studies. RESULTS: Ethanol significantly increased EV release by
3.3-fold from HepG2(Cyp2E1) cells and was associated with activation of
caspase-3. Blockade of caspase activation with pharmacological or genetic
approaches abrogated alcohol-induced EV release. EV stimulated macrophage
activation and inflammatory cytokine induction. An unbiased microarray-based
approach and antibody neutralization experiments demonstrated a critical role of
CD40 ligand (CD40L) in EV mediated macrophage activation. In vivo, wild-type mice
receiving a pan-caspase, Rho kinase inhibitor or with genetic deletion of CD40
(CD40(-/-)) or the caspase-activating TRAIL receptor (TR(-/-)), were protected
from alcohol-induced injury and associated macrophage infiltration. Moreover,
serum from patients with alcoholic hepatitis showed increased levels of CD40L
enriched EV. CONCLUSION: In conclusion, hepatocytes release CD40L containing EV
in a caspase-dependent manner in response to alcohol exposure which promotes
macrophage activation, contributing to inflammation in ALD.