title: IL-8 signaling is up-regulated in alcoholic hepatitis and DDC fed mice with Mallory Denk Bodies (MDBs) present.
abstract: Chemokines and their receptors are involved in oncogenesis and in tumor progression, invasion, and metastasis. Various chemokines also promote cell proliferation and resistance to apoptosis of stressed cells. The chemokine CXCL8, also known as interleukin-8 (IL-8), is a proinflammatory molecule that has functions within the tumor microenvironment. Deregulation of IL-8 signaling is shown to play pivotal roles in tumorigenesis and progression. Mallory-Denk Bodies (MDBs) are prevalent in various liver diseases including alcoholic hepatitis (AH) and are formed in mice livers by feeding DDC. By comparing AH livers where MDBs had formed with normal livers, there were significant changes of IL-8 signaling by RNA sequencing (RNA-Seq) analyses. Real-time PCR analysis of CXCR2 further shows a 6-fold up-regulation in AH livers and a 26-fold up-regulation in the livers of DDC re-fed mice. IL-8 mRNA was also significantly up-regulated in AH livers and DDC re-fed mice livers. This indicates that CXCR2 and IL-8 may be crucial for liver MDB formation. MDB containing balloon hepatocytes in AH livers had increased intensity of staining of the cytoplasm for both CXCR2 and IL-8. Overexpression of IL-8 leads to an increase of the mitogen activated protein kinase (MAPK) cascade and exacerbates the inflammatory cycle. These observations constitute a demonstration of the altered regulation of IL-8 signaling in the livers of AH and mice fed DDC where MDBs formed, providing further insight into the mechanism of MDB formation mediated by IL-8 signaling in AH.
authors.affiliation: Department of Pathology, LABioMed at Harbor UCLA Medical Center, 1000 West Carson Street, Torrance, CA 90509, USA.
authors.forename: Hui
authors.initials: H
authors.lastname: Liu
authors.affiliation: Department of Pathology, LABioMed at Harbor UCLA Medical Center, 1000 West Carson Street, Torrance, CA 90509, USA.
authors.forename: Barbara A
authors.initials: BA
authors.lastname: French
authors.affiliation: Department of Pathology, LABioMed at Harbor UCLA Medical Center, 1000 West Carson Street, Torrance, CA 90509, USA.
authors.forename: Tyler J
authors.initials: TJ
authors.lastname: Nelson
authors.affiliation: Department of Pathology, LABioMed at Harbor UCLA Medical Center, 1000 West Carson Street, Torrance, CA 90509, USA.
authors.forename: Jun
authors.initials: J
authors.lastname: Li
authors.affiliation: Department of Pathology, LABioMed at Harbor UCLA Medical Center, 1000 West Carson Street, Torrance, CA 90509, USA.
authors.forename: Brittany
authors.initials: B
authors.lastname: Tillman
authors.affiliation: Department of Pathology, LABioMed at Harbor UCLA Medical Center, 1000 West Carson Street, Torrance, CA 90509, USA. Electronic address: sfrench@labiomed.org.
authors.forename: Samuel W
authors.initials: SW
authors.lastname: French
mesh_terms: D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D015153:Blotting, Western; D002478:Cells, Cultured; D020869:Gene Expression Profiling; D006519:Hepatitis, Alcoholic / Q000209:etiology / Q000378:metabolism* / Q000473:pathology; D022781:Hepatocytes / Q000166:cytology / Q000378:metabolism*; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D007124:Immunoenzyme Techniques; D016209:Interleukin-8 / Q000235:genetics / Q000378:metabolism*; D008099:Liver / Q000166:cytology / Q000378:metabolism*; D008297:Male; D059609:Mallory Bodies / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008809:Mice, Inbred C3H; D011725:Pyridines / Q000633:toxicity*; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: C530773:3,5-diethoxycarbonyl-1,4-dihydrocollidine; D015415:Biomarkers; D016209:Interleukin-8; D011725:Pyridines; D012333:RNA, Messenger
keywords: Alcoholic hepatitis; CXCR2; IL-8 signaling; Mallory–Denk Bodies