Journal Article

Immunosuppression in acutely decompensated cirrhosis is mediated by prostaglandin E2

Garcia-Martinez, Rita, Cordoba, Joan, James, Sarah, Alazawi, William, O'Brien, Alastair J, Massey, Karen A, Winstanley, Alison, Sewell, Gavin, Auld, Grace, Fullerton, James N, Nicolaou, Anna, Gilroy, Derek W, Newson, Justine, Karra, Effie

2014

Overview

Patients with cirrhosis are susceptible to infection, but the mechanisms underlying this immunosuppression remain unclear. Derek W. Gilroy and colleagues show that plasma prostaglandin E 2 (PGE 2 ) is elevated in these patients and in mouse models of liver injury and suppresses TNF-α release from macrophages. Albumin, which binds to PGE 2 and reduces its bioavailability, is reduced in the plasma of a subset of cirrhosis patients. Administration of albumin partially reverses the immunosuppression observed in vitro and restores bacterial killing in mouse models, suggesting that future studies are warranted on the use of albumin to prevent infection in a subset of patients with cirrhosis. Liver disease is one of the leading causes of death worldwide 1 . Patients with cirrhosis display an increased predisposition to and mortality from infection due to multimodal defects in the innate immune system 2 , 3 , 4 ; however, the causative mechanism has remained elusive. We present evidence that the cyclooxygenase (COX)-derived eicosanoid prostaglandin E 2 (PGE 2 ) drives cirrhosis-associated immunosuppression. We observed elevated circulating concentrations (more than seven times as high as in healthy volunteers) of PGE 2 in patients with acute decompensation of cirrhosis. Plasma from these and patients with end-stage liver disease (ESLD) suppressed macrophage proinflammatory cytokine secretion and bacterial killing in vitro in a PGE 2 -dependent manner via the prostanoid type E receptor-2 (EP2), effects not seen with plasma from patients with stable cirrhosis (Child-Pugh score grade A). Albumin, which reduces PGE 2 bioavailability, was decreased in the serum of patients with acute decompensation or ESLD (<30 mg/dl) and appears to have a role in modulating PGE 2 -mediated immune dysfunction. In vivo administration of human albumin solution to these patients significantly improved the plasma-induced impairment of macrophage proinflammatory cytokine production in vitro . Two mouse models of liver injury (bile duct ligation and carbon tetrachloride) also exhibited elevated PGE 2 , reduced circulating albumin concentrations and EP2-mediated immunosuppression. Treatment with COX inhibitors or albumin restored immune competence and survival following infection with group B Streptococcus . Taken together, human albumin solution infusions may be used to reduce circulating PGE 2 levels, attenuating immune suppression and reducing the risk of infection in patients with acutely decompensated cirrhosis or ESLD.

• Publisher: Nature Publishing Group US,Nature Publishing Group
• Subject: 631/250/262 / 692/308/2778 / Albumins - administration & dosage / Animals / Bioavailability / Biomedicine / Cancer Research / Carbon Tetrachloride - administration & dosage / Cyclooxygenase 2 - blood / Cytokines / Cytokines - metabolism / Dinoprostone - biosynthesis / Dinoprostone - blood / Dinoprostone - genetics / Enzymes / Fatty acids / Fibrosis - blood / Fibrosis - immunology / Fibrosis - pathology / Gene Expression Regulation / Health risks / Humans / Immune system / Immune Tolerance - drug effects / Immunity, Innate / Immunology / Immunosuppression Therapy / Infectious Diseases / letter / Liver / Liver cirrhosis / Macrophages - enzymology / Metabolic Diseases / Mice / Molecular Medicine / Mortality / Neurosciences / Receptors, Prostaglandin E, EP2 Subtype - genetics / Receptors, Prostaglandin E, EP2 Subtype - metabolism