apyrase and Liver-Cirrhosis

Chronic hepatitis C (CHC) is frequently related to liver fibrosis, and several studies have suggested that the immunological activity of HCV antigens contributes to hepatic damage. In the present study, among structural and non-structural HCV antigens, elevatedIL-1β, IL-6, IL-17 levels were secreted by PBMC cultures obtained from CHC patients following stimulation with core antigen. Moreover, the percentage of core-specific IL-6

Topics: Adult; Aged; Apyrase; CD28 Antigens; CD4-Positive T-Lymphocytes; CD57 Antigens; CD8-Positive T-Lymphocytes; Female; Hepacivirus; Hepatitis C, Chronic; Humans; Interleukin-17; Interleukin-6; Leukocytes, Mononuclear; Liver; Liver Cirrhosis; Male; Middle Aged; T-Lymphocyte Subsets; Th17 Cells

Purinergic signaling is important in the activation and differentiation of macrophages, which play divergent roles in the pathophysiology of liver fibrosis. The ectonucleotidase CD39 is known to modulate the immunoregulatory phenotype of macrophages, but whether this specifically impacts cholestatic liver injury is unknown. Here, we investigated the role of macrophage-expressed CD39 on the development of biliary injury and fibrosis in a mouse model of sclerosing cholangitis. Myeloid-specific CD39-deficient mice (LysMCreCd39

Topics: Animals; Antigens, CD; Apyrase; Cholangitis, Sclerosing; Disease Models, Animal; Liver Cirrhosis; Macrophages; Mice; Mice, Inbred C57BL; Mice, Knockout; Pyridines

Ectonucleotidases modulate purinergic signaling by hydrolyzing ATP to adenosine. Here we characterized the impact of the cellular distribution of hepatic ectonucleotidases, namely nucleoside triphosphate diphosphohydrolase (NTPDase)1/CD39, NTPDase2/CD39L1, NTPDase8, and ecto-5'-nucleotidase/CD73, and of their specific biochemical properties, on the levels of P1 and P2 receptor agonists, with an emphasis on adenosine-producing CD73. Immunostaining and enzyme histochemistry showed that the distribution of CD73 (protein and AMPase activity) overlaps partially with those of NTPDase1, -2, and -8 (protein levels and ATPase and ADPase activities) in normal rat liver. CD73 is expressed in fibroblastic cells located underneath vascular endothelial cells and smooth muscle cells, which both express NTPDase1, in portal spaces in a distinct fibroblast population next to NTPDase2-positive portal fibroblasts, and in bile canaliculi, together with NTPDase8. In fibrotic rat livers, CD73 protein expression and activity are redistributed but still overlap with the NTPDases mentioned. The ability of the observed combinations of ectonucleotidases to generate adenosine over time was evaluated by reverse-phase HPLC with the recombinant rat enzymes at high "inflammatory" (500 μM) and low "physiological" (1 μM) ATP concentrations. Overall, ATP was rapidly converted to adenosine by the NTPDase1+CD73 combination, but not by the NTPDase2+CD73 combination. In the presence of NTPDase8 and CD73, ATP was sequentially dephosphorylated to the CD73 inhibitor ADP, and then to AMP, thus resulting in a delayed formation of adenosine. In conclusion, the specific cellular cocompartmentalization of CD73 with hepatic NTPDases is not redundant and may lead to the differential activation of P1 and P2 receptors, under normal and fibrotic conditions.

Topics: 5'-Nucleotidase; Adenosine; Adenosine Triphosphatases; Animals; Antigens, CD; Apyrase; Guinea Pigs; Liver; Liver Cirrhosis; Rabbits; Rats; Rats, Sprague-Dawley