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The inflammasome in alcoholic hepatitis: Its relationship with Mallory-Denk body formation.
- Source :
-
Experimental and molecular pathology [Exp Mol Pathol] 2014 Oct; Vol. 97 (2), pp. 305-13. Date of Electronic Publication: 2014 Aug 19. - Publication Year :
- 2014
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Abstract
- Recent studies indicate that the inflammasome activation plays important roles in the pathogenesis of alcoholic hepatitis (AH). Nod-like receptor protein 3 (NLRP3) is a key component of the macromolecular complex that is so called the inflammasome that triggers caspase 1-dependent maturation of the precursors of IL-1β and IL-18 cytokines. It is also known that the adaptor proteins including apoptosis-associated speck-like protein containing CARD (ASC) and the mitochondrial antiviral signaling protein (MAVS) are necessary for NLRP3-dependent inflammasome function. Steatohepatitis frequently includes Mallory-Denk body (MDB) formation. In the case of alcoholic steatohepatitis, MDB formation occurs in 80% of biopsies (French 1981; French 1981). While previous studies have focused on in vitro cell lines and mouse models, we are the first group to investigate inflammasome activation in AH liver biopsy specimen and correlate it with MDB formation. Expression of NOD1, NLRP3, ASC, NAIP, MAVS, caspase 1, IL-1β, IL-18, and other inflammatory components including IL-6, IL-10, TNF-α, IFN-γ, STAT3, and p65 was measured in three to eight formalin-fixed paraffin-embedded AH specimens and control normal liver specimens by immunofluorescence staining and quantified by immunofluorescence intensity. The specimens were double stained with ubiquitin to demonstrate the relationship between inflammasome activation and MDB formation. MAVS, caspase1, IL-18, and TNF-α showed increases in expression in AH compared to the controls (p<0.05), and NAIP expression markedly increased in AH compared to the controls (p<0.01). There was a trend that levels of NLRP3, ASC, caspase1, IL-18, IL-10, and p65 expression correlated with the number of MDBs found in the same field of measurement (correlation coefficients were between 0.62 and 0.93, p<0.05). Our results demonstrate the activation of the inflammasome in AH and suggest that MDB could be an indicator of the extent of inflammasome activation.<br /> (Copyright © 2014. Published by Elsevier Inc.)
- Subjects :
- Adaptor Proteins, Signal Transducing genetics
Adaptor Proteins, Signal Transducing metabolism
CARD Signaling Adaptor Proteins
Carrier Proteins genetics
Carrier Proteins metabolism
Case-Control Studies
Caspase 1 genetics
Caspase 1 metabolism
Cytoskeletal Proteins genetics
Cytoskeletal Proteins metabolism
Hepatitis, Alcoholic pathology
Humans
Interferon-gamma genetics
Interferon-gamma metabolism
Interleukins genetics
Interleukins metabolism
Mallory Bodies pathology
NLR Family, Pyrin Domain-Containing 3 Protein
Neuronal Apoptosis-Inhibitory Protein genetics
Neuronal Apoptosis-Inhibitory Protein metabolism
Nod1 Signaling Adaptor Protein genetics
Nod1 Signaling Adaptor Protein metabolism
STAT3 Transcription Factor genetics
STAT3 Transcription Factor metabolism
Tumor Necrosis Factor-alpha genetics
Tumor Necrosis Factor-alpha metabolism
eIF-2 Kinase genetics
eIF-2 Kinase metabolism
Hepatitis, Alcoholic metabolism
Inflammasomes metabolism
Mallory Bodies metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1096-0945
- Volume :
- 97
- Issue :
- 2
- Database :
- MEDLINE
- Journal :
- Experimental and molecular pathology
- Publication Type :
- Academic Journal
- Accession number :
- 25149528
- Full Text :
- https://doi.org/10.1016/j.yexmp.2014.08.006