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TLR3/4 signaling is mediated via the NFκB-CXCR4/7 pathway in human alcoholic hepatitis and non-alcoholic steatohepatitis which formed Mallory-Denk bodies.
- Source :
-
Experimental and molecular pathology [Exp Mol Pathol] 2014 Oct; Vol. 97 (2), pp. 234-40. Date of Electronic Publication: 2014 Jul 02. - Publication Year :
- 2014
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Abstract
- Activation of Toll-like receptor (TLR) signaling which stimulates inflammatory and proliferative pathways is the key element in the pathogenesis of Mallory-Denk bodies (MDBs) in mice fed DDC. However, little is known as to how TLR signaling is regulated in MDB formation during chronic liver disease development. The first systematic study of TLR signaling pathway transcript regulation in human archived formalin-fixed, paraffin-embedded (FFPE) liver biopsies with MDB formation is presented here. When compared to the activation of Toll-like signaling in alcoholic hepatitis (AH) and non-alcoholic steatohepatitis (NASH) patients, striking similarities and obvious differences were observed. Similar TLRs (TLR3 and TLR4, etc.), TLR downstream adaptors (MyD88 and TRIF, etc.) and transcript factors (NFκB and IRF7, etc.) were all upregulated in the patients' livers. MyD88, TLR3 and TLR4 were significantly induced in the livers of AH and NASH compared to normal subjects, while TRIF and IRF7 mRNA were only slightly upregulated in AH patients. This is a different pathway from the induction of the TLR4-MyD88-independent pathway in the AH and NASH patients with MDBs present. Importantly, chemokine receptor 4 and 7 (CXCR4/7) mRNAs were found to be induced in the patients livers in FAT10 positive hepatocytes. The CXCR7 pathway was significantly upregulated in patients with AH and the CXCR4 was markedly upregulated in patients with NASH, indicating that CXCR4/7 is crucial in liver MDB formation. This data constitutes the first demonstration of the upregulation of the MyD88-dependent TLR4/NFκB pathway in AH and NASH where MDBs formed, via the NFκB-CXCR4/7 pathway, and provides further insight into the mechanism of MDB formation in human liver diseases.<br /> (Copyright © 2014 Elsevier Inc. All rights reserved.)
- Subjects :
- Case-Control Studies
Fatty Liver pathology
Hepatitis, Alcoholic pathology
Hepatocytes metabolism
Hepatocytes pathology
Humans
Interferon Regulatory Factor-7 genetics
Interferon Regulatory Factor-7 metabolism
Mallory Bodies metabolism
Myeloid Differentiation Factor 88 genetics
Myeloid Differentiation Factor 88 metabolism
NF-kappa B genetics
NF-kappa B metabolism
RNA, Messenger genetics
RNA, Messenger metabolism
Receptors, CXCR genetics
Receptors, CXCR metabolism
Receptors, CXCR4 genetics
Receptors, CXCR4 metabolism
Signal Transduction
Toll-Like Receptor 3 genetics
Toll-Like Receptor 4 genetics
Up-Regulation
Fatty Liver metabolism
Hepatitis, Alcoholic metabolism
Mallory Bodies pathology
Toll-Like Receptor 3 metabolism
Toll-Like Receptor 4 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 :
- 24997224
- Full Text :
- https://doi.org/10.1016/j.yexmp.2014.07.001