title: The inflammasome in alcoholic hepatitis: Its relationship with Mallory-Denk body formation.
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.
authors.affiliation: LABioMed at Harbor UCLA Medical Center, Department of Pathology, Torrance, CA 90509, USA.
authors.forename: Yue
authors.initials: Y
authors.lastname: Peng
authors.affiliation: LABioMed at Harbor UCLA Medical Center, Department of Pathology, Torrance, CA 90509, USA.
authors.forename: Barbara A
authors.initials: BA
authors.lastname: French
authors.affiliation: LABioMed at Harbor UCLA Medical Center, Department of Pathology, Torrance, CA 90509, USA.
authors.forename: Brittany
authors.initials: B
authors.lastname: Tillman
authors.affiliation: VA Medical Center, Department of Medicine, Long Beach, CA, USA.
authors.forename: Timothy R
authors.initials: TR
authors.lastname: Morgan
authors.affiliation: LABioMed at Harbor UCLA Medical Center, Department of Pathology, Torrance, CA 90509, USA. Electronic address: sfrench@labiomed.org.
authors.forename: Samuel W
authors.initials: SW
authors.lastname: French
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism; D053468:CARD Signaling Adaptor Proteins; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism; D016022:Case-Control Studies; D020170:Caspase 1 / Q000235:genetics / Q000378:metabolism; D003598:Cytoskeletal Proteins / Q000235:genetics / Q000378:metabolism; D006519:Hepatitis, Alcoholic / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D058847:Inflammasomes / Q000378:metabolism*; D007371:Interferon-gamma / Q000235:genetics / Q000378:metabolism; D007378:Interleukins / Q000235:genetics / Q000378:metabolism; D059609:Mallory Bodies / Q000378:metabolism* / Q000473:pathology; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D051616:Neuronal Apoptosis-Inhibitory Protein / Q000235:genetics / Q000378:metabolism; D053474:Nod1 Signaling Adaptor Protein / Q000235:genetics / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000235:genetics / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism; D019892:eIF-2 Kinase / Q000235:genetics / Q000378:metabolism
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D053468:CARD Signaling Adaptor Proteins; D002352:Carrier Proteins; D003598:Cytoskeletal Proteins; D058847:Inflammasomes; D007378:Interleukins; C505371:MAVS protein, human; C496800:NAIP protein, human; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C453881:NLRP3 protein, human; C119067:NOD1 protein, human; D051616:Neuronal Apoptosis-Inhibitory Protein; D053474:Nod1 Signaling Adaptor Protein; C402202:PYCARD protein, human; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D014409:Tumor Necrosis Factor-alpha; D007371:Interferon-gamma; D019892:eIF-2 Kinase; D020170:Caspase 1
keywords: Alcoholic steatohepatitis; Inflammasome; Liver disease development; Mallory–Denk bodies (MDBs)