RESUMEN
BACKGROUND AND AIM: IL-8 (C-X-L motif chemokine ligase 8) and CXCR2 (C-X-C-motif chemokine receptor 2) are up regulated in alcoholic hepatitis (AH) liver biopsies. One of the consequences is the attraction and chemotactic neutrophilic infiltrate seen at the AH stage of alcoholic liver disease. MATERIALS AND METHODS: Human formalin-fixed, paraffin-embedded (FFPE) liver biopsies from patients who have AH were studied by (2.1) RNA sequencing, (2.2) PCR and (2.3) semi quantitation of specific proteins in biopsy sections using immunohistochemical measurements of antibody fluorescent intensity with morphometric technology. RESULTS: Immunohistochemistry of IL-8 showed that the expression was increased in the cytoplasm of the hepatocytes in AH liver biopsies compared to the controls. IL-8 and ubiquitin were co-localized in the MDBs. Numerous neutrophils were found throughout and satellitosis of neutrophils around MDBs was present. This suggested that IL-8 may be involved in MDB pathogenesis. RNA seq analysis revealed activation by IL-8 which included neutrophil chemotaxis by LIM domain kinase 2 (LIMK2) (17.5 fold increase) and G protein subunit alpha 15 (GNA15) (27.8 fold increase). CONCLUSIONS: The formation of MDBs by liver cells showed colocalization of ubiquitin and IL-8 in the MDBs. This suggested that IL-8 in these hepatocytes attracted the neutrophils to form satellitosis. This correlated with up regulation of the proteins downstream from the IL-8 pathways including LIMK2, GNG2 (guanine nucleotide binding proteins) and PIK3CB (phosphatidyl isitol-4, 5-biophosphate-3-kinase, catalytic subunit beta).
Asunto(s)
Biomarcadores/metabolismo , Granulocitos/inmunología , Hepatitis Alcohólica/inmunología , Interleucina-8/metabolismo , Hígado/inmunología , Transducción de Señal , Estudios de Casos y Controles , Granulocitos/metabolismo , Granulocitos/patología , Hepatitis Alcohólica/genética , Hepatitis Alcohólica/metabolismo , Hepatitis Alcohólica/patología , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Interleucina-8/genética , Hígado/metabolismo , Hígado/patologíaRESUMEN
Previous studies on both human and mice livers showed MDB formation in both drug hepatitis and hepatocellular carcinoma. Using the drug hepatitis mouse model of MDB formation, numerous markers for progenitor cells were found in the cells forming MDBs. In current study, using the drug hepatitis mouse model, we found that the MDB forming cells expressed two additional progenitor cell markers. These markers were CD49f and TLR4.