5, 6 In general, various cell types, including lymphocytes, release cellular adenosine triphosphate (ATP) that accumulates in the pericellular space upon cell stimulation with polyclonal stimuli such as anti-CD37–9 or mitogenic lectins such as concanavalin A.10 Activation of P2 surface receptors regulates lymphocyte and leukocyte functions including cytokine secretion, cell migration, and

selleck products cell-cell–dependent regulatory effects of a variety of lymphocyte populations such as regulatory T cells or NKT cells.11–14 The ectonucleotidase CD39/ecto-nucleoside triphosphate diphosphohydrolase 1 [E-NTPDase1] hydrolyses extracellular nucleotides and, in concert with CD73/ecto-5′-nucleotidase, generates adenosine.15 NK and NKT cells are second only to the vascular endothelium with regard to the high levels of functional CD39 expression.16 It is clear from other models involving total renal, intestinal, or cardiac IRI with systemic vascular responses that global endothelial CD39 deletion has major deleterious effects.17 Unique among endothelia, the liver vascular

sinusoidal endothelial cell layers do not express CD39 under basal conditions.18 Other cells in the hepatic sinusoids, however, do express CD39 ectonucleotidase activity, e.g. NKT cells. Hence, deletion of ectonucleotidase activity may thus limit inflammatory responses such as that induced by concanavalin A–mediated tissue injury where NKT cells undergo rapid rates of apoptosis, precluding major progression of cell-mediated injury.14 In a comparable manner, we show here that CD39 deletion limits warm partial liver IRI by decreasing proinflammatory function of NK cells in an interferon gamma (IFNγ)-dependent manner. ADP, adenosine diphosphate; ADPβS, adenosine diphosphate beta S; ALT, alanine aminotransferase; AMP, adenosine monophosphate; aminophylline ATP, adenosine triphosphate; ATPγS, adenosine triphosphate gamma S; cAMP, cyclic adenosine monophosphate; CD39/E-NTPDase1, ecto-nucleoside triphosphate diphosphohydrolase 1; CD73, ecto-5′-ectonucleotidase; IFNγ, interferon gamma; IL, interleukin; IRI, ischemia and reperfusion injury; NK cell, natural killer

cell; NKT cell, natural killer T cell; NTPDase, nucleoside triphosphate diphosphohydrolase; PCR, polymerase chain reaction; Rag1, recombination activation gene 1; UTPγS, uridine triphosphate gamma S. Animals were housed in accordance with the guidelines from the American Association for Laboratory Animal Care. The Beth Israel Deaconess Medical Center Institutional Animal Care and Use Committees (IACUC) approved all research protocols. C57BL/6 backcrossed (for more than six generations) strains of wild-type (Taconic, Germantown, NY) and CD39-null mice were studied.15 IFNγ-null mice (B6.129S7-Ifngtm1Ts/J) and recombination activation gene 1 (Rag1)-null mice (B6.129S7-Rag1tm1Mom/J) were purchased from the Jackson Laboratory (Bar Harbor, ME).