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Abstract
Mallory-Denk Bodies (MDBs) are prevalent in various liver diseases including alcoholic hepatitis (AH) and are formed in mice livers by feeding diethyl 1,4-dehydro-2,4,6-trimethyl-3,5-pyridine-dicarboxylate (DDC). The chemokine CXCL8, also known as interleukin-8 (IL-8) and its receptors are involved in oncogenesis and in tumor progression, invasion, and metastasis. We reported previously the marked upregulation of IL-8 signaling in AH and DDC fed mice with MDBs present by RNA sequencing (RNA-Seq) analyses. Central molecules including IL-8 and the chemokine (C-X-C motif) receptor 2 (CXCR2) of this pathway were significantly upregulated in the livers of DDC refed mice and human liver biopsies from AH livers. MDB containing balloon hepatocytes in AH livers have increased intensity of staining of the cytoplasm for both IL-8 and CXCR2. Taken conjointly, these data indicates a crucial role of IL-8 signaling during MDB formation, and IL-8 and CXCR2 may be targeted as biomarkers for personalized treatment of AH.
Highlights
Mallory-Denk Bodies (MDBs) are prevalent in various liver diseases including alcoholic hepatitis (AH) and are formed in mice livers by feeding diethyl 1,4-dehydro-2,4,6trimethyl-3,5-pyridine-dicarboxylate (DDC)
MDB formation is due to the failure of the 26S proteasome protein quality control system which leads to aggresomes composed of cytokeratins (CKs) and undigested proteins such as heat shock proteins (HSPs), ubiquitin (Ub), proteasome subunits, tubulin, and the ubiquitin-binding protein p62 [10,11]
IL-8 was originally identified as a potent neutrophil activator and chemotactic factor secreted by activated monocytes and macrophages
Summary
Mallory-Denk Bodies (MDBs) are prevalent in various liver diseases including alcoholic hepatitis (AH) and are formed in mice livers by feeding diethyl 1,4-dehydro-2,4,6trimethyl-3,5-pyridine-dicarboxylate (DDC). In the DDC fed mouse model where liver cells proliferate, MDBs form and later, after DDC withdrawal (DDC primed hepatocytes), hepatocellular carcinoma (HCC) develops [12,13]. The first high-throughput RNA sequencing analysis (RNA-Seq) from Illumina was performed to explore the mechanisms (e.g., signaling pathways) that mediate the initiation and progression of liver MDB formation [14].
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