Under the influence of IL-6-mediated STAT3 signaling, Socs1 serves as a complimentary regulatory mechanism when Socs3 is insufficient to limit cytokine-mediated inflammation after hepatic IR.

Hepatic ischemia-reperfusion (IR) results in progressive injury, initiated by oxidative stress during ischemia and compounded by cytokine-mediated inflammation during reperfusion. Recovery requires strict regulation of these events. Recombinant human erythropoietin (rhEPO) is thought to mitigate hepatocellular IR injury by altering the non-parenchymal liver microenvironment. This study sought to identify additional mechanisms whereby rhEPO is protective after liver IR injury. Methods Mice were treated with rhEPO (4units/gm SQ) at the onset of partial liver ischemia and assessed for transaminase and histologic injury at intervals after reperfusion. Induction of cytokines, activation of signal transducers and activators of transcription (STATs), suppressors of cytokine signaling (Socs1, Socs3, Cis), caspase-3 activation, and heme oxygenase-1 (HO-1) expression were assessed in post-ischemic liver. Effects of rhEPO stimulation were further characterized in whole liver lysates from mice undergoing rhEPO injection alone and in cultured AML-12 hepatocytes. Results rhEPO treatment at the onset of severe (90min) hepatic IR confirmed commensurate biochemical and histological protection without affecting tissue cytokine levels. Although Socs3 and STAT5 activation were induced in normal liver after in vivo rhEPO injection, this treatment did not augment expression beyond that seen with IR alone, and neither was induced in cultured hepatocytes treated with rhEPO. rhEPO inhibited caspase-3 activation in non-parenchymal cells, while hepatocellular HO-1 was rapidly induced both in vivo and in vitro with rhEPO treatment. Conclusion These data suggest HO-1 as a potent mechanism of rhEPO-mediated protection after liver IR, which involves both direct hepatocellular and non-parenchymal mechanisms.