Figure 2.

Ectonucleotidases in inflammatory liver conditions. (A) Ischemia/reperfusion injury (IRI) is triggered by the vascular damage consequent to blood reperfusion of oxygen deprived ischemic tissues, as with organ transplantation. ENTPD1 expression by donor livers and treatment with exogenous adenosine at high concentrations in preservation solutions protects grafts from ischemic damage with extended cold preservation times. Pharmacologic preconditioning through stimulation of adenosine receptors has been also associated with protection from ischemia by increasing ENTPD1/CD39 expression, via Sp1 transcription factor activation. This protective effect is abrogated in the absence of ENTPD1/CD39 but can be restored by adenosine administration. There is also evidence that exogenous and cautious ATP infusions can improve the hepatic function and post-ischemic clinical condition, (at least in part) by decreasing the plasma levels of IL-6 and TNF. (B) Numerical and functional impairment of Tregs contributes to immune imbalance in autoimmune hepatitis (AIH). Tregs and Th17-cells isolated from AIH patients display defective ENTPD1/CD39 expression and fail to control eATP mediated pro-inflammatory Th17 accumulation. Treg acquisition of pro-inflammatory properties together with low ENTPD1/CD39 expression might result from dysfunction in TGF-β signaling. (C) Liver fibrosis is driven by activation and accumulation of myofibroblasts and hepatic stellate cells (HSC), the predominant source of extracellular matrix and collagen in the organ. ENTPD1/CD39 and CD73, are upregulated in HSC, portal fibroblasts and in fibrous septa. This overexpression, mediated by SP1 and SMAD promoter elements, is a direct consequence of the myofibroblastic differentiation. Interestingly, in the setting of CCl4-derived-fibrosis, ENTPD2 expression and re-distribution from the portal areas to the fibrotic septa, has a protective role against excessive collagen accumulation. (D) In hepatic steatosis and alcoholic hepatitis, Entpd1/Cd39 deletion correlates with increased insulin resistance and aberrant hepatic glucose metabolism. Accordingly, disruption of A2AR expression in hepatocytes and macrophages also directly correlates with the severity of obesity–associated non–alcoholic-fatty-liver-disease, promoting inflammation and lipogenic events. (E) ATP scavenging by ENTPD1/CD39 expressed by CD4⁺FOXP3⁺ Tregs, endothelial cells and myeloid derived suppressor cells (MDSC) promotes hepatic tumor growth in mice. Once exposed to hypoxic microenvironment, HCC upregulates ENTPD2 expression, further supporting MDSC accumulation and immunosuppressive activity. On the other hand, recent experiments have documented occurrence of liver cancer also in Entpd1/Cd39^−/− mice. These latter findings would result from eATP-P2 receptor-mediated suppression of tumor cell autophagy and boosting of cell proliferation.